GlaxoSmithKline Aktie

Welcome, everyone, and thanks for joining GSK's Q3 2026 Results. Today's call will last approximately 1 hour with the presentation taking around 30 minutes and the remaining time for your questions. Before we begin, this slide is our usual safe harbor statement. We will comment on our performance using constant exchange rates, or CER, unless otherwise stated. I will now hand over to Luke Miels, CEO.

Thanks, Jeff. I'm joined today by Tony Wood, who will give an update on the pipeline, Nina Mojas, who will cover growth drivers; Julie Brown, who will cover financial performance and David Redfern will join for Q&A. First, let's review the company performance.

Next slide, please. Q3 was strong, and we have continued operational momentum with sales up 5% to GBP 8.9 billion. As expected, specialty is driving our momentum, including launches in respiratory and oncology. Core operating profit grew 5% and core earnings per share were up 1%. Our cash generation remains very positive at GBP 7.4 billion year-to-date. Our Q3 dividend of 17p and we're on track with our responsible business rating. Given our operating momentum and launch progress, we're pleased to reconfirm 2026 guidance today.

Next slide, please. This slide is a reminder of our key priorities to drive value for the business and our shareholders. To start, we're focused on maximizing launches. This quarter, we've made good progress on blend rep where repeat prescribers are growing as physicians and patients get comfortable using the medicine and Accenture, where we're seeing momentum building with prescribers, patients and access, all increasing in the quarter. We've now also had our first launch in non-small cell lung cancer with GidetRO for TKI pretreated ROS1-positive patients, which has already delivered GBP 3 million. And our oncology portfolio continues to grow with a further indication for Jen Purley in locally advanced rectal cancer.

We also received approval for Hipsaga in the U.S. and Japan, the first finite treatment to offer a functional cure for patients with chronic hepatitis B. Each of these products will meaningfully contribute to near-term growth as we continue to build momentum in our Specialty business. At quarter 2, we outlined clear plans to accelerate R&D, and we're now delivering on those plans. We are recruiting in 18 of the 22 Phase III trial starts for 2026, including 2 new Phase III studies for flu and the rest on track to start recruiting before the end of the year. We also presented data for several of these assets, including Gidetro, Rises, Mores and Jen Perley, demonstrating significant progress in our oncology pipeline and proof points for our approach to BD.

Finally, on simplification, we made progress on the Accelerated Growth Program, helping to reallocate resources to invest in R&D and accelerate our late-stage development pipeline. Fundamentally, this will align our cost base with our evolving portfolio and help us accelerate growth and deliver value for patients and shareholders. With that, I'll now hand over to Tony to cover our pipeline momentum in more detail.

Thanks, Luke. It's been a busy period for R&D with a number of recent approvals and pivotal data readouts. Jideytro and Hibsago approvals were received ahead of their FDA PDUFA dates and Jen Purley received accelerated approval for Atal cancer. These, together with the strength of the data presented at recent medical congresses demonstrate the value of assets in our late-stage pipeline, where the majority have potential to be best-in-class and where we've added 12 new Phase III study starts this quarter, bringing us to 18 for the year.

Next slide, please. Moving to new products and indications. Jideytro for ROS1 positive and neladakib for ALK-positive mutations in non-small cell lung cancer has the potential to meaningfully improve on Stanley care. These mutations represent 3% to 5% of all non-small cell lung cancer. Here, patients are often younger in their 40s and 50s and remain on therapy for years while experiencing high rates of central nervous system side effects and often developing brain metastases. Importantly, Jideytro is the first and only ROS1 TKI to address both selective targeting of ROS1 resistance mutations and CNS activity those aim to improve treatment for patients with brain metastases while minimizing truck-related CNS adverse events.

Similarly, neladakib is a once-a-day medicine designed to avoid off-target adverse events, which can be treatment limited for patients. We anticipate FDA approval in November supported by the ALCO study, which showed a median progression-free survival of 14.5 months in a previously TKI-treated population. Also in oncology, approval for Jemperli in locally advanced rectal cancer is based on the ASE data, which shows 68% of participants with no detectable signs of cancer, 1 year or more after treatment. Current standard of care achieved complete clinical response in around 20% to 25% cases and can have lasting consequences, including bowel and urinary dysfunction and secondary cancers.

And finally, for Hibsago. Nina will cover our launch plans for this important medicine in a moment. But I want to reiterate how transformational Hibsago will be for those living with chronic hepatitis B. These patients are at an increased risk of death from cirrhosis and liver cancer and current treatment options involve lifelong therapy. Hibsago is the first finite treatment for chronic hepatitis B, which provides the potential for a functional cure. We plan to share additional data from the development program at AASLD in November.

Now moving to our development plans for Jideytro and nelodalkib in TKI-naive patients. Jideytro data were presented at the recent World Lung Congress. The AROs response rates are amongst the highest ever reported in this patient population with a 94% overall response rate and a 15% complete response rate. The median duration of response has not yet been reached, but 86% of patients have a duration of response of greater than 12 months. Data on brain metastases in this TKI naive population showed no CNS progression events observed in patients without metastases at baseline and a 100% response rate in those with brain metastases at study entry. The emerging clinical profile for Jideytro suggests it has the potential to deliver meaningful outcomes as a best-in-class therapy to TKI-naive patients.

Neladakib is also in development for a TKI naive population. And here, the Phase I/II ALCO study shows an 86% overall response rate. Median duration of response has not yet been reached. However, 91% of patients have a duration greater than 12 months, as you can see on this slide. The corresponding Phase III TKI naive study, ARCAzAR, is more than 50% recruited. And based on available data today, we believe neladakib could have the potential to drive years of progression-free survival.

Next slide, please. Next for Ris-Rez, where emerging data demonstrate robust and consistent outcomes across a range of solid tumor types. In small cell lung cancer, the Chinese Phase III ARTMS-08 data presented at World Lung by Hans showed a 54% reduction in risk of death and a median overall survival of 18.5 months. The global pan tumor Phase I/II MBOLD-101 study has now enrolled with more than 550 patients, Data from the small cell lung cancer cohort of this study were presented last weekend at ESMO, and showed a 61% response rate, consistent with the 58% overall response rate observed in Artemis. The global Phase III trial in bold SCLC 301 is also recruiting well, and we anticipate preliminary data by the end of 2027.

Next slide, please. Also for Ris-Rez, data from the ANS Phase III ARTEMIS 11 study looked at rise versus standard of care in Chinese patients with relapsed refractory osteosarcoma was selected for the presidential symposium ESMO this week. Osteosarcoma is a rare tumor, and relapsed patients have few treatment options. The current standard of care delivers around 2% response rate and 1.5 months of progression-free survival. In this trial, Ris-Rez demonstrated a 67% reduction in risk of disease progression or death in patients with relapsed disease. A global GSK Phase II trial in bold sarcoma 202 started earlier this year and is recruiting well. The Global and bold program has now over 1,000 patients who've received Ris-Rez with more than half of those enrolled in the past 8 months. Over the next 12 months, we anticipate data readouts across multiple indications, and we look forward to sharing these as they mature.

Next slide, please. For Mo-Rez, new data presented at ESMO from the global Phase I BHOLD-1 trial confirms the potential for best-in-class activity in ovarian cancer with median progression-free survival of around 11 months in a non biomarker-selected population. These data compare favorably with current standard of care, which delivers around 6 to 8 months of PFS. As promised at the Accelerate growth event in July, we've now started recruitment for 5 Phase III trials in ovarian and endometrial cancer. Over the next 12 months, alongside Hansa, we will continue to generate longer-term data to demonstrate the durability response and safety profile of this novel ADC.

Next slide, please. Also at ESMO, we presented interim pivotal results from Azure 1, which looked at Jemperli in the treatment of patients with DMM locally advanced rectal cancer. The current standard of care for these patients achieved a complete clinical response in around 20% to 25% of cases, but involves chemotherapy, radiotherapy and surgery and is associated with significant morbidity. In ANZIO 1, over 2/3 of patients achieved a complete clinical response. And after a 2-year follow-up period, no disease recurrences were reported amongst patients who responded. The study continues to generate data and offers an important potentially curative option for patients with locally advanced rectal cancer.

Next slide, please. Turning now to vaccines. Last season, over 700,000 people, mostly older adults were hospitalized with flu in the U.S. Currently, flu vaccines, which generally focus on hemagglutinin protect only evenly are mRNA flu vaccine candidate, which has achieved fast track designation from the FDA targets both hemagglutins and neuraminidase. Neuraminidase changes more slowly. So protection may be more durable when strains mismatch. Targeting both has the potential to offer broader immunity and better, more consistent protection. In Phase II, our candidate produced stronger immune responses against both targets than a high-dose comparator supporting our decision to start a large Phase III study in more than 50,000 adults, age 65 in Opera. The study started in September. And more than 2/3 of this season's enrollment target has already been recruited. This study will run over 2 seasons, and we anticipate preliminary data next year, pending a sufficient number of cases.

Next slide, please. Across R&D, we continue to make fantastic progress in accelerating our late-stage pipeline. At Q2, we described our plans to start 20-plus Phase III studies in 2026. We've now started 18 Phase III studies with a further 4 on track to start before the end of the year. These studies have been accelerated based on our confidence in the differentiation and benefit to patients of our late-stage assets. I'm pleased with the continued hard work of our teams to deliver this previously unmatched pace of acceleration across a broad and growing portfolio.

Next slide, please. Before I close, I momentarily want to share this slide, which we presented in July. It demonstrates the expansion of the late-stage portfolio, and from 2028 onwards, we expect to build further as we progress Phase I and II studies and continue to pursue external opportunities. I'll now hand over to Nina to cover commercial performance.

Thanks, Tony. Commercial momentum continued in the third quarter, driven mainly by Specialty Medicines, up 15%. Our top-performing product was Cabenuva, which grew 35% in the quarter. More than 75% of switches continue to come from competitors in the U.S. and Cabenuva remains the only long-acting injectable regimen for HIV treatment, establishing a strong foundation with patients who prefer to take medicines less frequently. This is setting us up for success as we move closer to 2027 when we will have data for our 3 times a year formulation for HIV treatment. In prevention, Apretude is performing strongly with 21% growth in the quarter and holding market share. Nucala was also a very strong contributor, up 18%, driven by the successful launch into COPD, while extensure continues to expand the biologic opportunity in severe asthma. In oncology, we've also now launched our first medicine in non-small cell lung cancer, data. Blendrup is continuing to build as expected, while Jemperli again delivered strong double-digit growth for the quarter. Booking performance was down 2% with the drag from Shingrix, China destocking, partly offset by growth in the U.S.

We had significant growth in our meningitis portfolio, up 12%. This was driven by strong growth from our meningitis B containing portfolio in the U.S. including new contributions from the first full back-to-school season for Penni. And we now have over 90% share of the MenB market globally. General Medicines was flat in the quarter with Trelegy performance offsetting the decline of the established portfolio. In the U.S., Trelegy returned to growth up 8% as patients reached their Medicare deductibles and adjusted to coinsurance. In the triple inhaler class, we maintained market leadership in COPD and asthma However, the overall U.S. inhaler market and sit class continues to face price pressure. Globally, the sclass remains the fastest-growing inhaler class and strategy continues to grow double digit internationally, up 11% in the quarter.

Next slide, please. Starting with Blenrep now approved in 52 markets, we continue to launch globally. As we are launching more broadly, we continue to see that the hands-on experience is the clearest predictor of future use frequently changing the pre-existing beliefs. In the U.K., Blenrep is now the market leader in second line for NICE approved regimens. And in the U.S., HCPs are getting more comfortable with Blenrep and repeat prescribers account for about 1/3 of sales so far and are building. Recently updated NCCN guidelines recognize the full breadth of Blenrep data and include both DREAM 7 and REMA data in the second line plus patient population significantly beyond the U.S. label. Prescribers are getting more familiar with dosing. This is leading to an improved experience with Blenrep while also extending the period between prescriptions. This extended dosing is similar to what we have in DREAM10 first-line study expected to have MRD data in 2028.

Next slide, please. Moving to respiratory. We have 2 key launches that have enabled GSK to gain IL-5 market leadership in a class that's up 12% versus last year. The importance of reducing exacerbations that lead to hospitalizations is the highest unmet need among physicians. And the success we are having with Nucala and COPD continues to have a halo effect across all 5 of its indications. New-to-brand patients in the U.S. is up 19%, with COPD driving the majority of the growth and significant room to continue growing as only 6% of COPD patients are on a biologic.

International growth continues, up 21% in the quarter. We've now achieved market leadership in China. The success we've had with Nucala and the relationships we've established with these providers has been key as we launch Exdensur. Exdensur sales were GBP 27 million in the quarter, with the majority of sales coming from bionaive patients. Third quarter was a pivot point following the availability of the J-code in July and then roll out of the average selling price as of October. As a result, new prescribers in the U.S. were up 68% in Q3, and new patient starts were up 74% when we include those who received the free first dose through our Faster program. Access continues to build with more than 2/3 of insured patients now being covered. And significant growth opportunity remains as around 17% of patients who could be on a biologic for severe asthma still are not. Next slide, please.

Finally, I wanted to share further details on our launch plans for Hibsago. In Japan, chronic hepatitis B is a government priority and there are already established processes in place and guidelines that support functional cure. Since approval, we have received a very positive reimbursement decision and physicians have already identified patients to receive therapy. In the U.S., chronic hepatitis B is very concentrated with the majority of patients in 5 states. We have launched with a focus on patients with surface antigen level lower than 1,000 and where the opportunity to have a positive experience leading to functional cure is the highest. The U.S., Japan and China represent around 80% of the potential value for Hibsago.

Following the approvals in Japan and the U.S., we look forward to hearing from regulators in China where managing chronic hepatitis B is a national priority and where we have established a strategic collaboration with Sino Biopharmaceuticals, a recognized leader in hepatology in China. I'll now hand over to Julie.

Thank you, Nina. I will now cover financial performance with growth rates at CER, unless otherwise stated. Next slide, please. Starting with the income statement for the quarter, sales grew 5%, gross profit was up 7%, supported by product mix and efficiencies. SG&A increased 1%, including new valent costs, demonstrating smart resource allocation and improved ROI. And R&D grew 22%, in line with our accelerated growth agenda outlined at Q2, with a further 12 Phase III trials initiated this quarter. Growth was driven primarily by accelerated oncology spend on Ris-Rez, Mo-Rez more and valsatinib as well as further investment in Fulcobart and FMS Ferman Operating profit grew 5% with the margin broadly stable as increased R&D investment was broadly offset by cost of goods and SG&A productivity as we further match our cost base to the evolving portfolio. EPS was up 1% with the differential due to increased interest costs following the new Valent acquisition and a higher tax rate in the quarter.

Turning to total results. The quarter was impacted by GBP 0.3 billion accelerated growth charge with the program to simplify and reallocate spend towards R&D now well underway. We're moving at pace and ahead of schedule. And since July, we have initiated a series of changes across the organization to streamline support services, simplify our supply chain and reallocate resources. And we now expect charges of up to GBP 1 billion in 2026.

Next slide, please. Moving to cash generation. Year-to-date performance has been strong. CGFO was GBP 1.1 billion ahead of last year, underpinned by business performance with increased operating profit and favorable working capital movements. And as a reminder, the year-on-year comparison was impacted by GBP 0.7 billion as Zantac cash outflow in 2025 and a net headwind of GBP 0.2 billion from the CureVac settlements.

Turning to free cash flow. It was up GBP 1.8 billion year-to-date, including $650 million from the out-license of Lennar expat and the special dividend received due to the V shareholding change. Looking forward to the full year, we remain on track to deliver our target of around GBP 10 billion CGFO at constant rates.

Next slide, please. Over the past years, we have significantly improved cash generation, conversion of profit to cash and the strength of the balance sheet. This has enabled targeted business development to strengthen our late-stage pipeline. And most recently, with the acquisition of New Valent whilst retaining capacity within a strong balance sheet with net debt to core EBITDA at 1.8x.

Next slide, please. Looking ahead, we remain on track to deliver our full year 2026 guidance. Sales are expected in the upper half of the range, driven by specialty performance. Core operating profit is also expected in the upper half of the range and margin remains on track to be more than 31% at constant rates. This is enabled by SG&A, which is projected to be broadly stable. Cost of goods benefits from product mix and efficiencies and royalties, which are now upgraded to around GBP 900 million for the year. Whilst R&D is expected to grow significantly ahead of sales for the year, as we more than double the number of Phase III starts from the 10 expected at the start of the year to now 22 EPS growth is expected to be in the lower half of the range, with full year interest expected to be GBP 700 million to GBP 750 million including around GBP 160 million relating to the acquisition of New Valent.

With respect to currency, we now expect foreign exchange headwinds of minus 1% on sales and minus 3% on operating profit. And finally, looking ahead, we remain committed to our long-term outlook. And in the appendix, you will find modeling considerations to the end of this year and into next. Thank you. And with that, I'm pleased to hand back to Luke.

Thanks, Julie. To close, we remain focused on executing our strategy, which is built on driving top line growth building and accelerating the late-stage portfolio and actively reallocating resources to where they can create the largest value for patients and shareholders. We'll now open for Q&A.

[Operator Instructions] We will go with James Gordon from Barclays for the first question.

James Gordon from Barclays. First question was on HIV and next-generation injectables and also more broadly, what's going in HIV or -- so I read there's an update about cabo for monthly prep and that you've got the data in-house and PK analysis is still underway. But how should we read that? Does that mean you've got to do a bit more work on the PK equivalents? Are there questions there and could that delay the launch? I think there was a comment about the data next year, but do you still think you could launch in the same time lines? And is there any read-through because I believe it's the same tech for 4 monthly in Cabenuva. So could there be a delay or any extra work you've got to do there? And the broader question in HIV, there's been quite a few management changes. So Viv's CEO and CFO and fairly recent De change, -- so is this at all connected? Is there a trend there any implications? Is there any sort of reboot going on in HIV since Luke became CEO.

And then the second question was just on new launches. So Exdensur, Blenrep, and I've heard comments about you now got the J code, I think it was from the beginning of July. Was that the key thing that was holding up the launches? And do you now think we're going to see a big acceleration of inflection into next year? Or might we need to wait a little bit longer because there's some other things you also need to really see those products accelerate.

Great. Thanks, James. I think you've done your colleagues a favor because I suspect we'll be able to capture a number of themes there. So why don't we do the Bestone? I'll just say something quickly, then we'll go to David and then Nina if you can cover Exdensur and Blenrep. Look, I think, firstly, no connection to management changes. I mean the fact is that they ever got a promotion to be the CEO or CSO, these things don't come along every day. And I think that's great news for Deborah. And actually, I just want to personally thank her for her years as GSK as a peer and a team member. And as an Australian, and I hope she does very well at Celfjust not too well on the vaccine side.

Lynn ran just as a background and back to who stepped in. So it was a very quick process pretty much as soon as a Banker called the Glenn ran the USD business, and she launched the long-acting products and she has been on the V Board during this time. So she's very much up to date with an easy decision, and I've known Lynn for a long time it's by Roche days. Tim retire, remember, and Charlotte stepped in, and she remains the head of the R&D. And Charlotte worked with Tony at Pfizer and as I think you all saw at Q2, she knows what she's doing. So feel very comfortable there. I think more broadly, operationally, I want be to be closer. And so there will be more intensive interaction and supervision there, but that's not a bad thing.

Secondly, before I hand to you, David, I just wanted to make a broader point about how we want to communicate with the owners of the company and you as analysts and I guess the market more broadly. Look, we're going to call things as we see them. And we're not going to crap on Page 41 of a press release and hope now you noticed it. So we'll tell you as much as we can. We will have a plan to address it. But please just adjust your parameters on that because that's how we want to operate. All right. So with that, David, over to you.

Yes, thanks, Luke. I mean the first thing I want to do actually is just echo what Luke said around Deborah, I mean she led Be incredibly strongly through almost 10 years, obviously drove a huge amount of growth through that time. Not least this year, where betas up 10% in the quarter and for the year. And as Luke said, I mean, Limbach may not be particularly well known to the investment community, but she's very well known inside GSK, very distinguished leader with experience on both sides of the Atlantic led the North America for 6 years, so very connected in the HIV community in America. And obviously, during that time, introduced the long-acting medicines to the U.S. market. And as Luke said, Lynn, plus Charlotte Allerton, Las Shangai the Chief Medical Officer, a very well known in the HIV community, I'm very confident in the strength right through to the management team. .

James, I mean, in terms of the pipeline, I mean not much more to say at this point on extend. We have the data in-house. The analysis is ongoing. We look forward to sharing with the regulators. And obviously, we will update the market once that analysis is complete. What I would say is we're very pleased with the progress we're making with the treatment pipeline in parallel. So the first thing I'd call out actually for CABANUVA is the Phase IIIb CROWN study where we've shown the headline that showed superiority of Cabenuva in an unsuppressed baremic population compared to daily oral standard of care. And that's important because in the U.S., there's probably about 40% of the market is unsuppressed. So over 400,000 people -- so that's all people living with HIV. So that's a significant growth opportunity. We will show that data at future congress and we will also update the regulators and apply for a label expansion on that.

And just to remind you, that's actually the second superiority study of Cabenuva. We had latitude earlier in patients, people living with HIV with adherence challenges. So great progress with Cabenuva. And then with the 4 monthly formulations of cabotegravir and Recovery, I'm pleased to say the QUATTRO study recruited very fast over the summer ahead of our expectations. It's been fully recruited now for a number of weeks. The readout is at month 11. Just to remind you, it's an efficacy study comparing 4 months we 2 monthly Cabenuva, but that's obviously now very much on track to read out next year. and we continue to make progress with the 6-month lease 184 and 499 that are progressing as planned through Phase II, and we still intend to start a pivotal study with that combination with 6 monthly, which we're very excited about in 2028.

Great. Thanks, David. I'm sure we'll get some more questions on anything you want to.

Just a couple of very quick points But first of all, Charlotte is a very experienced pharma coconesist and R&D media. You saw that 2Q. And I just want to underscore, we see no read-through to the treatment portfolio.

Thanks, Tony.

So Exdensur and Blenrep, very specific question, J code has there been a milestone or a change. So for Accenture, I'm actually pretty confident that yes. Just for background, we've got the Jayco first of July. -- maybe a little bit more technical, usually with a code, the team gets something that we call the ASP document, which is average selling price document that can be shared with the physicians. So they are aware of what the price what is the price that will be reimbursed to them. That document became available on the first of October. All of that said, the numbers that we shared in Q3, we have seen significant increase in the new prescribers. So 68% new prescribers and then 74% to new patient starts that includes the totality of both sold volume and in the free goods volume that is part of our fast start.

Another piece to remember Q3 because of the summer tends to be the quarter that has the lowest number of patient visits. And as that ASP document became available as of first of October, obviously, you don't see the sales after that. I can just maybe mention every week since then has been the highest week of sales. for Exdensur 1 after another with a being the high sales. So yes, definitely for extension, this has been amongst kind of moment, and we do expect to see a change in trend. -- from now on. All of that said, it still remains -- it's the first long-acting and there has to be adjustment to that but definitely very, very positive, very positive moments. Maybe just to add, this is the time when we start seeing patients coming back. So it's 6 monthly. So we would start seeing patients after 6 months receiving again another shot, which is our whole benefit of Exdensur that patients remain on therapy for a long time. It's a very small number of patients that is reaching that point, but the numbers that we see are actually very encouraging. So let's see if that holds as more and more patients get to 6 monthly mark.

Blenrep, the way I would describe Blenrep, you have seen now that about half of the sales are coming from ex U.S. And that reflects, again, that more experienced existing ex U.S, both in the clinical setting and in the commercial setting. The previous experience is the most relevant factor when it comes to prescribing Blenrep and that's reflected in ex U.S., a lot of learnings ex U.S. that can be moved to the U.S. So we are intensifying peer-to-peer exchange in the U.S., those who have experienced to potentially impact the perceptions. I would probably say that the pre-existing perception of blender is the biggest challenge rather than rather than anything else. And we are -- we have a number of activities that are hopefully going to change that.

Next question is from Simon Baker at Redburn.

Thank you, Jeff. Two, if I may, please. Firstly, on Shingrix. I wonder if you could just dig down a little bit into the pushes and pulls within the various regions. We do see quite a divergent performance across the world. And related to that, perhaps you could give us an update also on the potential accelerants for Shingrix growth going forward. Firstly, the MACE opportunity and then beyond that, the dementia potential indication?

And then second question on Hisao. Given this is the first treatment for a very long time in that indication, perhaps maybe you could give us an idea of how we should think about the trajectory. And also the initial scriber reaction to the profile of the product and the label. We've had a few people questioning the monitoring. I'm wondering in the real world, how much of that really -- is that really a barrier to adoption.

Yes. Thanks, Simon. So -- what we'll do -- thank you. I'll cover the Shingrix component. And then Tony, you can cover the acceleration -- sorry, the acceleration and basically dementia. And then in after that, we'll come back to Hibsaga. So Simon, how would I go region by region and call out if I confuse you? So for the U.S., the IC rate is 46%, which is up 3 percentage points, which is in the middle of the 2% to 4% range that we set that we would get in a year. TRxs are okay, and we've got slightly strong at NBRx. The key thing is we're seeing stronger penetration now in the health care system. So this is the comorbid population. So we're getting some traction there. But we do need to balance that with the fact that the adult market overall vaccines market overall, is still challenging.

Now Shingrix is doing a little bit better in relative terms. So the adult market is down about 18% versus this time last year, but Shingrix is down about Inventory is usually a question we get. Wholesale is steady at 0.4%, same as last year. But the pharmacists have been buying. And so the stock level is higher right now at pharmacy, it's around 2.3 million versus 1.7 million doses this time last year. And that's likely driven by the fact that we've got a later flu season. So we'll get a clearer picture in Q4. So that's the U.S. China is, I think it's steady improvement to how I describe it. So the key is in arm demand. So we're doing about 300,000 shops a month, and that's up 60% versus last year. So I would say that's steady growth over time. And it seemed to be pretty resilient despite the structural CDC ordering stock management challenges. And remember, we called this early when it was slowing down -- and -- and look, we're basically doing what we said we would do, which is to work off the volume in the pipe. And the inventory has dropped. So there was -- summer last year was around 4.3 million doses. -- and now we're down to 1.4 million doses as of August.

So that's about 1.5 months of demand. So that's about as low as you would want it. So I would expect ideally next year, we do a reorder. But again, we're not doing mass shipments. We want to sort of match the demand. knowing it's quite -- we've got quite a long time frame between shipping and actually being distributed in China that we also need to manage -- so the rest of the world is, again, it's about -- nearly -- it's about 60% of sales. So again, solid. For the EU, it's really expansion in new countries, broader coverage. Private demand also is starting to increase, which is encouraging. We did have a bit of a softer time in Germany and France in summer. We think that's partly due to the heat, but also there's some parallel trade impact. And then on the rest of International, it's very much expansion and really driving access in markets like Brazil, Turkey, other markets like that and Saudi. Tony, did you want to -- sorry, Simon, a long answer, but a broad question. Did you want to cover the measure in Mace and.

You bet. Thanks for the question, Simon. So look, we've got a broad range of work going on looking at both the MACE and dementia aspects for Shingrix, including mechanistic studies and pragmatic RCTs. There are 2 of those going on, Simon, in Finland and Denmark, looking to enroll about 200,000 adults we're expecting initial results from those 2 studies in 2029. We'll have the first read out on the CBD data at the end these are Finland where we're evaluating the effect of Shingrix dementia in greater than 76-year-old, that's with the registry-based diagnosis in Denmark where we're evaluating effect on risk of MACE and in dementia in that case, in 65-plus population for next stand-alone, we're at the moment, expecting to be able to start the study by the end of the year, we're on our ongoing discussions with regulators at this point in time, but we will -- this will be a very broad study in 28 countries, and we've selected already 750 sites. So well underway.

So Hibsago was approved in Japan and the U.S. regulatory discussions are ongoing very intensely in China. So that's the next 1 to come. So Japan, we got the reimbursement. I think 1 of the testaments to Isago uniqueness is reimbursement in Japan was justified by the regulators with 50% usefulness premium, which is a number that you hardly see in Japan and then additional 10% premium for San designation. So very, very happy with that conversation. In the U.S. and again, in Japan, we have actually patients over the already on therapy physicians have actively asked for it as we were going through the pricing discussions. In the U.S. we got the approval, prices available. Product is going to be on the market, I think, available actually within the next, I think, 10 days or something like that. So there is on.

Questions on monitoring. Did we expect it? Yes, because that monitoring exactly as described was part of the study protocol, so we couldn't expect anything different. Monitoring is there for 2 reasons. One is ALT elevation. So liver enzyme elevation and the other 1 is thrombocytopenia. Now both of those happen relatively quickly thrombocytopenia specifically, I think it's even called today the USPI. There were 2 cases of severe thrombocytopenia that happens quite quickly after the initiation of therapy and ALT elevation is also as described in the label, linked actually to the reduction of the surface antigen. So patients who see the reduction are definitely more likely to see ALT elevation. Now how that monitoring is going to evolve, as I mentioned, it's quite important in the initial period, and we do expect that physicians will monitor early seeing if their patients are Viagen is 1 of those who have early elevation of ALT or severe reduction of severe thrombocytopenia. And then following that, we expect that these issues in patients will find some kind of balance of when and how frequently they do monitoring.

Thanks, Nina. I think also the feedback that we're getting from experts is that sort of mentally gating the first 12 weeks and then reassessing it. So essentially the language of the patients look okay, there are frequent blood draws, and we said that to you guys in past meetings. But look, if we can get to 12 weeks, we'll reassess where you are. and then continue on from that point.

Maybe it's important just for you to think how it's going to work. The first dose is administered in the physician's office. -- and then patient gets a pack of doses that they will self-administer at all, and they will need to obviously arrange the monitoring within that period.

David anything you want to add to.

Worth just underscoring a few things. In terms of thrombocyte as Nina mentioned, only 2 patients with severe cases. lower platelet count, that's easily managed through dose holding. And then on the ALT flares, more than half of the functional cure patients had a fleet a really important sign of potential response. You're going to hear more from us on Hibsago at ASLD. So I might I'll just give you a quick summary of that now, which is the long-term sustained data to 48 weeks. -- the surface antigen measurements of 12 weeks is a predictor of functional cure retreatment modeling for future approaches. And then lastly, continued description of surface antigen loss versus health outcome worth emphasizing that this is a disease with significant morbid and mortality outcomes.

Yes. And I mean, I think memory Tannis over 60% of patients who are below 1,000 at baseline could get to below 100 of surface antigen for at least a year post treatment. Okay. Good. .

Next question is from Michael Leuchten from Jefferies.

Two, please. One for Julie. It sounds like there was inventory in the top line around Shingrix. Were there any other items in the third quarter we should take into consideration? And then as you think about guidance for the full year, you beat very nicely on SG&A, in particular, in the third quarter, but the guidance doesn't go up. So just to put us on pause on why not given you do have some slight help from the royalty income and also lower net financials into the end of the year?

And then a question on, I guess, for Luke or maybe Tony and/or David, I understand this limited amount you can say about Q4 treatment as in cap treatment and the read across from the prep dose, but it's the same tech it's the same product. You clearly had an outcome with the PREP data, the PK/PD study that didn't tell you what you were hoping for? And you're saying there is no read across into treatment. Like how can you make that statement? Like how can you give us confidence that there isn't any read across?

Tony, I just want to -- well, Julie go with inventory and then David and Tony -- David, you go on the prep answer and the take identity technically, if you want .

Yes. Okay. So specifically on Shingrix, I think we've covered some of Betbut in terms of sort of quantifying the U.S. inventory build in the third quarter, -- in the quarter, it amounts to about 2 percentage points of global growth and you get these swings, as you know, very confident though in the overall picture for Shingrix. And I think China, Luke has touched on this. It's all about injections in arms and we anticipate shipping again in 2027. So I think that covers Shingrix. In terms of the third quarter and the bid, versus consensus. First of all, we appreciate it was difficult to forecast the third quarter of many moving parts, including the acquisition of New Valent. And there are a few things to flag about the third quarter. Sales were higher than our original expectations, and this included some phasing between Q3 and Q4 -- as we mentioned, we have the U.S. Shingrix inventory build, meningitis ordering patterns, and we also had Ventolin impacting the quarter.

The operating profit in Q3 was impacted by SG&A phasing better royalties, as you mentioned, partially offset by the phasing of R&D, which was very high, it was a peak growth in R&D in the third quarter of 22%. So if we move now, obviously, we're comfortable with the overall guidance for the full year. We do expect sales growth to moderate slightly, partly HIV pricing. Partly, we've talked about Shingrix because last year, we had a shipment going out in the fourth quarter to China. And then we're also lapping some of the French and Japanese launches outside the U.S. And then I think finally, when you think about SG&A, we're going to have the launches to support for Hibsago and New Valent -- but at the same time, there was a charge last year in SG&A of about GBP 0.2 billion, that will not repeat in the fourth quarter of this year. Okay?

Thanks, Julie. And David, the second question? .

Yes. I mean I think what I can say, Michael, is PET, which is the PrEP study and Quattro which is the treatment study, are very different study. So Xtend is a PK bridging study where we're looking at drug substance levels at steady state no earlier than month 13 as well as safety and tolerability. The QUATTRO study is an efficacy study comparing the 4 monthly formulation of cabotegravir with 2 monthly Cabenuva. So they're very different studies. We're very confident in the formulation that we've got. I'll probably leave it at that.

Yes. I think the key thing here, Michael, we don't want to front-run discussions with regulator that tends to backfire. So again, as I said earlier, we're telling you as much as we can at this point. But in the interest of long-term value creation, I'll limit it to that at this point. And I appreciate your understanding. And the second, we can update you, we will question.

Next question is from Kerry Holford of Berenberg.

I'm sorry, just a very quick follow-up. -- on aptitude Q4. Just interested to know whether you do have a day scheduled to review that data with the FDA, whether you can share that with us. Ultimately, when can we expect more clarity on the issues here in the next steps. And then if we think into next year, and I appreciate you won't be wanting to give guidance at this point. But just given the commentary you made July on the OpEx in Q4. In the context of those Phase I starts this year and at least I think you highlighted 6 additional Phase III starting next year. How confident are you that the necessary incremental R&D spend moving into next year? -- can be offset by SG&A savings and COGS savings in 2027.

So David, do you want to go to Julie.

I think what I can tell you, Kerry, is, I mean, we reached steady state for the last patient only a few weeks ago, not very long ago. So the analysis, as we've said, is ongoing I think we are confident we will be sharing the data with the regulator before the end of the year. And obviously, post regulatory discussions, we will updates appropriately. So that's sort of timing, but I can't be more specific than that.

Thanks, David. Julie?

Yes. Thanks, Kerry, for the question. So as you know, we've got a really good track record of delivering margin accretion, and at the same time, investing more and more in R&D. And this is part of the program around accelerated growth. So we've also got, as the business pivots more towards specialty, you do get a natural margin lift because of the SG&A costs associated with the specialty cell is considerably lower than it would be if primary care. So both of these are major factors -- so we do expect R&D to continue to grow ahead of sales. We were pleased to know not to the extent of Q3, which was obviously very high. But as demonstrated, we can deliver profitable growth through the efficiency in both the cost of goods and we've talked about the specialty pivot together with the SG&A. And the accelerated growth program is all about removing cost from what you Banco support services. and some of the manufacturing network and it's moving it towards the front line of R&D. .

Next, we're going to go to Sachin Jain from Bank of America.

A couple on some drivers into next year, if I could. So firstly, I wonder if you could just comment on the TRELEGY IRA impact you call out on the '27 driver slide, Julie. I'm assuming this is really heavily rebated to any color on additional IRA pressure. And the second one, you can just touch on Dovato. You talked about DTT tender impact in the quarter. Should we expect that to grow into next year? And then just 1 follow-up for Nina on Hibsago China. -- very clear on the approval time lines. Can you just run us through online to reimbursement, I assume this requires NLDL listing, et cetera. So just any color there. .

Sure. So David, do you want to do the VAT first, and then we'll come back to Nina to do Trelegy and Hibsago.

Sure. I mean I could be quick. I think, Sachin, I mean, at -- there are some international markets, notably Brazil, where the patents on Doter this year. And that's had some marginal impact, although, obviously, overall, we're very pleased with the commercial performance would be growing double digits and dolutegravir overall, but there was some impact in Brazil. Actually, as you know, the composition of matter that I'll talk about in the U.S. is 28%. Next year, we don't really have any other significant markets where we lose patterns. So we expect most of the trends to continue.

Great. Nina, do you want to start with ag and then we come to the Trellidor fun.

Yes. So Hibsago China, as I said, discussions are ongoing. I'm not sure I want to commit to a specific time line because -- what we have seen is a huge desire from the Chinese authorities to make the drug available. I expect it's going to be sooner than what we planned, but let's leave it with that. We are going to launch immediately. We will launch in the private market in China as it becomes available. And then with the next round of NRDL discussions, it's -- it will be, will be included. I hope by the end of next year, we should be there. .

Yes. I think on TRELEGY, we just have to rebase it. I mean, as you know, it was added to the list for CMS and I think November '25. So the negotiated price for 30 days is now 175, which is a 73% discount the '24 list price. So there will be a one-off impact in the U.S. we'll rebase that and then positioned beyond that. Again, we've been thoughtful in terms of how we resource this product in the U.S. Julie, anything you want to add on that? .

Thanks,. Obviously, just to say that the WAC price reduction, clearly, this is a product it's more mature phase. So there are rebates or returns associated with it. So net-net, not quite as significant as Luc indicated, totally included in our guidance, we judged it fairly well a number of years ago and it was built into the long-term forecast. In terms of -- we've also got Bio alongside TRELEGY impacting in 2027, together with the Biktarvy royalty stream that comes off in October in '27, which is a headwind of around GBP 70 million a quarter. And those are the main things. We've actually included a slide to help we know you'll be focused more and more on 2027. We've included a slide on modeling considerations in the appendix for those who haven't seen it just yet. .

Right. Thanks, Julie. Should we keep going, Jeff sure with questions -- if you guys are happy to keep running, we can run for another 10 or 15.

Yes. That's great. We have a number of questions. Let's go with Zain Ebrahim from JPMorgan.

Just a follow-up on the previous question in terms of -- if we think about the totality of the IRA headwind for both Rio and Trelegy is the consensus outlook for general medicines in the right sort of place for next year? I know you said it's broadly in line with your forecast, but just if you could clarify that, that would be helpful. And then on Hips ago, note you mentioned that you've got some clarity on the pricing. So how does that compare versus your initial expectations for Pepsi pricing in the U.S. that is and just remind us on how what proportion of the population here is Part D and when we can expect part D inclusion.

Yes, sure. So I'll just -- I mean, on pricing, it's about GBP 50,000 in Japan, just over GBP 100,000 in the U.S. And just -- so I'll give you some epi because I think it would be helpful -- so U.S. is about 1.7 million at 400,000 diagnosed, 120,000 treated. Japan is -- sorry, 0.9 million. Of those 600,000 are diagnosed and 120,000 are treated. So sort of similar and China, about 6 million treated. So it's in a category of sinuobviously, access and pricing is different there. Julie, did you want to cover anything beyond what we can say as it is forward-looking.

I think at this stage, we'll concentrate on giving you comprehensive guidance at the end of the year certainly by product area or product category, we'll come back to this. Yes. Anything you want to add on Hipsago, Part D split. I mean, On commercial, Nina?

Most of these patients have -- do have commercial coverage and there is no competition. which is relevant for this to which extent the pricing that the discounts go. There is just no alternative, which definitely helps.

Yes. And the cost of these patients, obviously, is a disease progresses. I mean looking at the market research, and it makes sense. I think physicians are going to concentrate on the younger patients initially and build that experience there with them. And as Nina said, I mean I think 2031 is the earliest entrant, excluding China that we would expect there. And of course, there's a history of combinations and failure in this area. So Look, let see how these combinations evolve with time.

The next question will be from Matthew Weston at UBS. Matthew.

Two questions, please. I hear your confidence in EXTENZA, but Nucala was also weak in 3Q as well. Can I understand if you've offered a debate on you in the additional access, you're talking about on Tensa or whether or not it's pressure overall in the IL-5 category as physicians prefer T slip? And then secondly, Julie, it's a Jo Walton Promamoria question. on 2027 net financial charge, you've highlighted the strong cash flow, but obviously, the cash out for New Valent and for the restructuring program. do you think that consensus has next year's net financial charge modeled correctly or we need to sharpen our pencils. .

No worries. Thanks, Matthew. So just quickly on Nucala. I mean if you look at the numbers in the U.S. volume, I think, was up nearly 40%, 39%, price is down 15%. So there is some pressure there. I would be cautious about reading that across to Exdensur. So 1 of the things we've been quite deliberate on, which is holding the line on Exdensur pricing. We want to take a long-term view here. We've got a long-acting Tesla. We've got a long-acting -- we long-acting IL-33. So if you look at coverage, I mean, in terms of commercial parity to say Nucala or benralizumab, we've gone from 18% in Q2 to 43%. And in Q3. And overall, we've got 71% of lives covered with the difference being some statutory. So that's been deliberate there. I think there is clearly competitive pressure from TLP overall on the class, but that is also being offset to a degree with COPD and COPD is helping us within the IL-5 class capture business. Nina, anything that you want to add on that.

Again, just remember, Q3 for patient visits is the weakest quarter in the year. .

Yes. Julie?

Yes. So yes, just in terms of the interest charges that are coming through. And you're right, the -- obviously, we've got some considerable cash out closed, particularly in the second half of the year with the new Vermont acquisition and accelerate growth -- the good news is it's moving at pace. So we're anticipating charges this year. We originally guided GBP 7 million -- we're expecting now charges in the order of $1 billion. This is P&L. And obviously, that's going to affect the cash flow going into next year. So in terms of the financial charge, -- we've guided for the second half of this year that New valent will be $160 million. So it gives you an idea about how much it will cost us next year in terms of interest. It's going to be over GBP 300 million. And then in terms of the overall interest charge I mean I'll guide this at the end of the year, but it's going to be in the order of GBP 900 million to maybe GBP 1 billion rates to get adverse at the moment as well, which is -- the team did a great job of financing new mail and where we did, but the rates are getting harder. And I guess with the topic of New Don, can I make a request me at that people have got questions on oncology. We just had, I think, a remarkable ESMA. So I don't know, Jeff, hopefully, someone's got a question on oncology next.

Next up, we'll go with Graham Parry.

I asked 1 oncology question yesterday, I'm afraid. So just going to go back to the Xtend 4M and just if you can help us understand what it is it needs fully characterizing about the new formulation? And can you just remind us, I think this was -- the study for monthly dosing was actually determined from PK simulations from the Phase Cabela study that you presented at CROI in 2024. So is really this just that the isn't matching what your simulations were showing? Or is this an issue of tolerability because I think you just had sort of single administration tolerability data on that. And then can you also clarify that it is the same formulation in Quattro. I think there's a bit of confusion about that based on your comments that this doesn't read through to Quattro.

So although they are different studies and one's an efficacy study, if there's a PK or tolerability issue with the extent form, why wouldn't that then translate to Quattro? And then my final question is just thoughts on AnaptysBio litigation update. You've now had the post-trial hearing. Are we heading towards a negotiated settlement here? Or are you waiting for a ruling .

Thanks, Graham. Well, I think on the second question, I would direct you to their share price on the day, and I can't say much more than that at this point. David, again, I'm not sure you can add too much more. We would love to tell you more, but again, we don't want to prejudice discussions with regulators.

Yes. I mean I think that's right. I think we need to do the analysis and then we need to talk to the regulators. So I'm not going to go into much detail. I mean, what I can say, Graham, is you're right on the PK levels were set based on the pivotal study that we did for 2 monthly. And you're right that it's the same formulation in both extend and Quattro, we are very confident in that formulation. And I think we've said it several times, there's no read across.

Okay. Thank you. Did we cover every 1 of Graham's questions we did. I think we guide up, Graham.

Let's go with Trung from RBC.

Unfortunately, no oncology question here either. But a couple of a number of -- you answered them all yesterday.

So on food allergy, you've got the XTEN Phase II data next year. How are you thinking about the opportunity here. The competitive landscape does seem like it's evolving somewhat there's perhaps more Zoageneric entry Remy is moving into Phase III. So just what's your view on how that market develops and where Xtensa can differentiate their -- then the second 1 is just on the agreement with Henry. So 1 of those assets is a PDE 34 in COPD. Just can you provide a bit more detail on some of the other targets that you're evaluating in this collaboration -- when can we expect the next programs to be optioned? How can we think about milestones economics as these progress?

Yes, sure. So thanks, Tom. I'll let Tony cover the collaboration in a second. I'll just give you -- I assume you mean Asia Roper IG not Accenture for food allergy. So yes, basically, in 2017, we'll get a Ib readout for food allergy. -- and the aim is to start the Phase III in the second half of next year. Look, this is a huge opportunity. There's about 17 million people in the U.S. that have some form of food allergy. -- and about 1.6 million of them have what returned as clinically relevant disease. So -- and you're all very familiar with the growth that Rosen. When we did this deal, we actually modeled that there would be up to 4 biosimilars entering in our calculations. Again, there are some structural limits. I mean it's about 1/4 of patients on OLED where essentially the solar, the maximum approved OLED dose, just can't find enough I to be effective in these heavier larger individuals.

So we've got a product that's essentially twice the pop of all there and yes, could be a 3 monthly shock with either 3 doses or an upside scenario, 1 dose. Look, I think we've covered the BTK is 2 tablets a day. You've got the tox heritage BTK XL 111, it's Phase 1 was due at the end of the year. So I think you need to risk adjust that and it's really a long way behind. So yes, I think we've done a very, very nice asset here. We've got a very deliberate development plan. It's properties that behaves the same way it binds the same way as all there. So factor that in and that again is part of our strategy. So Yes, I think we're encouraged with the profile that we see. Anything you want to add on that, Tony, before we go to.

No, I think you've covered the Ellen that was all about the nomogram simplification and getting to the higher weight patients as well as Luke said, -- and then in Hungary, the PD 3/4 is in early clinical development. This is very much looking for immediate dose inhaler opportunity for that particular approach. And you'll be aware of the early clinical data in the area from competitors that suggest that it is an effective mechanism we were very careful to look for a molecule that has a similar profile. We've got 11 other targets in the collaboration. They haven't been disclosed, but it's fair to say that we're on where we're engaged very actively with Hongo on selecting the next range of those for disclosure. I'm very pleased with the options that we have in front of us.

Great. Thanks, Tony. I think we should conclude. We're 11 minutes over. And thank you, everyone, again, for very thoughtful questions. I appreciate you dialing in.

Good afternoon, and good morning. Thank you for joining our analyst briefing to cover data presented at the European Society for Medical Oncology in recent days. Today's discussion will be focused only on recently presented clinical data. We will not be providing any commentary on performance as we report our Q3 results tomorrow. We are joined today by Nina Mojas, our President of Global Product Strategy; Hesham Abdullah, Senior Vice President and Global Head of Oncology R&D; and Ahmed Rabie, Senior Vice President of Global Product Strategy for Oncology. We're also joined by Eric Richards, Richard Davidson and Klaas Bakker from the oncology R&D team for the Q&A portion of this session. For the agenda, Hesham will take you through the data, and then Nina will provide some closing remarks before opening up for your questions. I will now hand over to Hesham.

Jeff, thank you very much, and it's a pleasure to be with everyone. Good afternoon to those in Europe. Good morning to those in the U.S., and thank you very much for joining us. Of course, we're just back from Madrid, very exciting ESMO. More than 21 abstracts and a number of different oral presentations as well, too, from the GSK oncology pipeline. And I'm happy to take maybe the next 25 to 30 minutes to walk you through some of the key data from our oncology portfolio that was recently presented at ESMO in Madrid.

With that, I think we could probably start off first with Ris-Rez, which is our B7-H3 ADC, of course. And I think, first and foremost, it's important to highlight that we actually presented some data from across our Phase I/II development program. This is the GSK development program, global development program more specifically as well, too. We actually had data from our Phase I/II study and specifically in small cell lung cancer. And I think what's probably important to highlight is this data certainly showed consistency between the global data set that we've generated in terms of objective response rate in second-line plus small cell lung cancer with a 61% response rate in the 8 mg per kg dose cohort. This is actually the dose that will be used and is being used currently in the second-line Phase III small cell lung cancer study across our own global development program. And then, of course, data that's been generated recently at World Lung from our partners, Hansoh, and the ARTEMIS-008 study, where we saw an objective response rate of 58%. So I think probably the first key headline to take is certainly the data from our emerging global development program is very reassuring and confirms certainly the clinical activity that's being observed in the China Hansoh development program.

Next slide, please. This is, of course, the data that was recently presented by Hansoh from the ARTEMIS-008 trial, looking at Ris-Rez versus topotecan in second-line small cell lung cancer. I think probably what's important to highlight and remind everyone of, of course, is the study was positive, demonstrating a statistically significant and clinically meaningful overall survival benefit for Ris-Rez relative to topotecan with a median overall survival of 18.5 months versus 10.3 months on the topotecan arm. As you can probably see from the Kaplan-Meier curves, the curves separate early. That separation is maintained over time. And at a landmark of about 12 months, which is certainly the median duration of follow-up on the study, there were about maybe 64.5% of patients still alive on the Ris-Rez arm versus 43.3% on the topotecan arm.

Next slide, please. This is a slide showing certainly consistency of the overall survival effect across key subgroups from the ARTEMIS-008 trial. What I'd probably call your attention to is the fact that about maybe 17% of these patients that were recruited into the study did have brain metastases at study entry. And what we did observe was that there was certainly a consistent treatment effect across this subgroup as well, too, with a hazard ratio of 0.36 for overall survival. But generally, certainly consistent survival benefit observed across all predefined subgroups, whether it be based on age, smoking history, prior PD-L1 therapy and, of course, performance status as well.

Next slide, please. Key secondary endpoints, of course, PFS by independent and investigator review, quite consistent with a hazard ratio of 0.33 for the BICR-assessed PFS, 0.35 for investigator-assessed PFS with about maybe a 4-month delta on median PFS, certainly, whether it be based on BICR or investigator assessment as well, too. Next slide, please. And then, of course, objective response rate, disease control and duration of response. What I'll probably call your attention to on the slide, of course, is the objective response rate that's been observed and I've noted previously, 58.3% for Ris-Rez versus 12.8% for the control arm with single-agent topotecan. I would say maybe close to a fivefold difference in the magnitude of effect on response, supported, of course, by the median duration of response, close to about maybe 7 months and the disease control rate as well, too. Now one point to highlight here, which I think is really important in terms of how we think about the extrapolation of data from China. And what you see in the study specifically is there's a really strong internal consistency of results. If you look at the primary endpoint and the magnitude of effect that's observed on overall survival with a hazard ratio of 0.46, key secondary endpoints like PFS with a hazard ratio of 0.33 and then the five-fold difference in response rate as well, too. And that strong internal validity and consistency within the Phase III study itself gives us certainly strong confidence in its external validity as well, too, and broader application across other countries and regions.

Next slide, please. So maybe just a quick summary then. And again, of course, just a caveat, as always, of looking at cross-study comparisons and the differences that may exist between baseline characteristics across each of these studies, just taking that into account. But at least when we look at a high level, the median overall survival from the ARTEMIS-008 compared to some of the emerging data across the B7-H3 class, but also some of the existing data as well, too, in second-line small cell lung cancer with immune cell engagers. No doubt the median overall survival with Ris-Rez is 18.5 months, certainly quite well positioned in that regard. We have two Phase III studies in small cell lung cancer, an ongoing Phase III in second-line small cell lung cancer, which is the EMBOLD-301 trial, which is currently recruiting. And then a second study in first-line small cell lung cancer that will be initiated very shortly before the end of the year in the first-line setting as well, too.

Next slide. So one of the additional data sets that were actually presented as well, too at ESMO was an analysis that we conducted from our own global development program, looking at the incidence of ILD given that this is certainly an event of interest across the topo-1-based class of ADCs as well, too. When we've looked at this across our certainly data set, whether it be across all solid tumors or specifically in non-small cell and small cell lung cancer, we do see a relatively low incidence of grade 3 or greater ILD events at 0.9%, so less than 1%. And then, of course, in the overall at least aggregate population from our own development program across all solid tumors, a 4% incidence of all grade events. And again, the majority of these events were, of course, mild or moderate Grade 1, 2 in nature.

I think when you look at also the data that's been published from the Hansoh experience in China, whether it be with the ARTEMIS-3 or ARTEMIS-2 studies, these are Phase I/II trials. We do see a relatively low incidence of Grade 3 or greater ILD events as well, too. Of course, ARTEMIS-008 being the exception to that with an incidence of 4% of Grade 3 or greater ILD.

Next slide. This was, of course, all presented on a poster at ESMO that included, of course, the ILD data for [indiscernible].

Next slide, please. And then, of course, data that was presented just yesterday, in an afternoon Presidential symposia at ESMO, I would say quite a landmark result just given certainly how challenging this disease is, osteosarcoma. Quite poorly prognostic. We have not seen any advances in standard of care over the past 50 years as one leading sarcoma expert had told us. And I think that's really important to highlight and emphasize as well, too.

Next slide, please. So this basically was a study looking at osteosarcoma patients in an advanced metastatic second-line disease setting. So patients had received certainly greater than 1 to 2 prior lines, specifically at least 2 prior lines. Patients were randomized 2:1, either receive Ris-Rez or certainly standard-of-care gem-docetaxel chemotherapy.

And then the primary endpoint of the study was PFS blinded independent review. The secondary endpoints included overall survival and PFS and objective response rate. Of course, given the sample size of the study, which is 122 patients, the study is not powered for overall survival.

Next slide, please. Key baseline demographics. When we look at the median age of these patients, it's ranging between 21 to 22 months. And I think that's really important to highlight just given the patients that are typically impacted by osteosarcoma. We have about maybe 1/4 of patients that were actually adolescents, between 12 to 18 years of age. So certainly, at least the incidence tends to also occur in younger patients, as evidenced by the data.

I think one thing to probably also highlight is this is a patient population that no doubt had a relatively high disease burden as evidenced by the fact that the majority of these patients had pulmonary metastases, and, of course, is also heavily pretreated. The majority of these patients have received prior chemotherapy and targeted therapy as well, too.

Next slide, please. The primary endpoint, BICR-assessed PFS, was met, demonstrating a statistically significant and clinically meaningful improvement in PFS, with close to a fourfold improvement, 5.5 months versus 1.4 months, in terms of the medians. Again, you see the curves separate relatively early and certainly stay separated until that 6-month landmark. I think it's important to highlight, of course, the median duration to follow-up at this point in time is about maybe 7.1 months.

Next slide, please. Tumor response assessment by BICR as well, too. The objective response rate is 15% on the Ris-Rez arm and 2% on the gem-docetaxel arm. Now one thing to bear in mind and especially with this type of tumor, just given the location of the tumor itself in the bone, oftentimes one of the challenges is really getting enough exposure to be able to penetrate these lesions, especially given the thickness of the extracellular matrix that exists around the tumor and the capsule within the bone itself as well, too.

So I would say probably objective response rate is not necessarily the most meaningful way to assess the activity of the drug, but rather, of course, a disease control rate may be a better proxy along with PFS. And here, as you can probably see disease control rate is at 76% on the Ris-Rez arm versus 33% on the control arm.

I think one other point to highlight, the dose that was used of Ris-Rez in the study was 12 mg per kg. I mentioned and alluded to the fact that higher exposure may be needed here given the need to better be able to -- better penetrate, of course, the tumor, especially given its location and site as well, too.

Next slide, please. Overall survival data, currently immature. It's about, I would say, 16% to 17% mature at this point in time, with about 10 events having occurred in each arm. The study did allow for crossover. So we did note that 17 patients in the control arm have already crossed over to Ris-Rez treatment following progression on gem-docetaxel. And despite that, we're still seeing certainly a very encouraging trend at this point in time on overall survival with a hazard ratio of 0.51. And again, awaiting further follow-up just given the relative immaturity of the overall survival at this point in time.

Next slide, please. Safety profile, I would say, certainly as expected, given the dose that was used here, but also the typical topo-1-based payload assessed toxicities or related toxicities, all predominantly relating to myelosuppression, including, of course, neutropenia and, of course, thrombocytopenia being the key ones. I think the one point to highlight here that's really important as well, too, despite certainly the higher Grade 3 event rates across the myelosuppression, discontinuation rates were quite low at 4%.

Next slide, please. Moving on to our B7-H4 ADC, Mo-Rez. We did provide an update on the data that was actually presented at SGO in April. So specifically, the platinum-resistant ovarian cancer cohort with longer follow-up now, about maybe a little over 13 months of follow-up from that cohort. Just maybe a quick, I would say, brief on the design of the study, of course. So this is our Phase Ia/Ib study. There was an abbreviated dose escalation and then a movement into dose optimization and expansion across 3 different dose levels, 2.8, 4.8 and 5.8 Q3W. And that -- it will be the focus at least of the data that will be presented on the following slides and specifically the platinum-resistant ovarian cancer cohort.

Baseline characteristics, maybe just to call out the fact that -- a few key elements to this. One, the majority of these patients had received certainly prior bevacizumab and more than half had received a prior PARP inhibitor as well, too. The other, of course, just to note here is that the majority of patients, close to about maybe 80%, had received two or more prior lines of therapy, including 36% of patients that have actually received three or more prior lines of therapy as well, too. And then a large portion of patients had tumor tissue available for B7-H4 expression evaluation.

Next slide, please. And what you'll see on here, of course, is a waterfall plot for objective response rate. I think the one point to call out more specifically here is that these are confirmed objective response rates across all those levels. What do we see? Well, what we see is certainly an objective response rate of 36% across the 2.8 milligram dose, 57% across the 4.8 milligram dose, and 62% across the 5.8 milligram per kilogram dose, which is the registrational dose that we're taking forward in this indication.

There's also a trend towards shorter times to response relative to dose, with the shortest time to response on the 5.8 mg per kg dose level. And then also a trend towards the depth of response as well, too relative to dose in that respect as well, too.

What's probably also important to highlight is the fact that responses, as you'll see on the following slides, were irrespective of B7-H4 expression levels as well. We did have actually 4 patients that had received prior mirvetuximab treatment. 2 out of the 4 patients developed a partial response.

Next slide, please. This is certainly just data specifically on duration of response. And again, what we do see is a dose response, certainly, a trend here as well, too, with the median duration of response, of course, being the longest and strongest certainly on the 5.8 mg per kg dose level at 12.2 months, along with, of course, the probability of duration of response at the 6-month landmark as well, too, with certainly that separation being evident from the Kaplan-Meier plot on the right-hand side of the slide.

Next slide, please. The same holds true for PFS. We saw the longest PFS on the 5.8 mg per kg dose level, with a median PFS a little over 11 months, and the probability of PFS for being progression-free at 6 months of 80%. I think all of these data in the aggregate reinforce our certainly confidence in selecting the 5.8 mg per kg dose level for the platinum-resistant ovarian cancer indication as well, too, along with a few of the other studies that were -- Phase III studies that we're initiating, including the second-line endometrial cancer study and the platinum-sensitive ovarian cancer study as well, too.

Next slide, please. This is data that was also presented at a separate oral presentation that was more focused on translational biomarkers from this Phase Ia/Ib study as well, too. And again, as you can probably see, we had a range of different, I would say, on the left-hand side of the slide, B7-H4 expression levels represented in the sample size of patients that were treated. And then on the right-hand side of the slide, and again, based on the color coding, as you can probably tell, responses were observed across a range of expression levels, including depth of response as well, too.

Next slide. The safety profile, as expected, and based on the topoisomerase warhead, dominated by GI and also myelosuppression events. I think just a few key points to call out in this respect. First, across all dose levels, the 2.8, the 4.8 and the 5.8 milligram dose levels, the incidence of all-grade ILD was 7%. And specifically at the 5.8 mg per kg dose level, it was 2%. And the majority of these events, 8 out of the 9 events that have actually taken place, were Grade 1/2 in nature. Only 1 event was Grade 3 or greater.

One thing to also call out as well, too is really just in terms of the Phase I study design itself, it did not mandate the prophylactic use of growth factors to mitigate neutropenia, as evidenced by the data that we have in hand. And that is only G-CSF use was only used in 8% of patients at the 5.8 mg per kg dose level. And I think for the Phase III studies, we are being much more prescriptive and strongly recommending the use of G-CSF to mitigate the neutropenia from the start of treatment as well, too. And this is being implemented across all five Phase III studies.

Next slide, please. And so just a quick recap. I've mentioned, of course, that we've initiated five Phase III trials across platinum-resistant ovarian cancer, platinum-sensitive ovarian cancer first-line, HR-proficient maintenance ovarian cancer, and then also second-line endometrial cancer and first-line MMR-proficient maintenance endometrial cancer as well, too.

Next slide, please. Moving forward to dostarlimab, and of course, this is data from the AZUR-1 study, I think everyone is well aware, of course, that we had announced last week the regulatory approval in the U.S. and then the data followed over the weekend with an oral presentation as well, too, from the AZUR-1 trial in the locally advanced dMMR/MSI-H rectal cancer patient population.

Next slide, please. And maybe just to provide a little bit of context, I think this is a, certainly a patient population that is typically treated with what is multimodal therapy, a combination of chemoradiotherapy and surgery. Unfortunately, of course, the tolerability challenges and comorbidities that has on patients is quite difficult, resulting in certain gastrointestinal dysfunction, certainly bowel and also urinary dysfunction, and certainly in certain cases, also impacting fertility as well, too.

Historical, I would say, clinical complete response rates for this patient population range between 20% to 25%. And I think that's important when we think about how to contextualize the results from the AZUR-1 study as well, too.

Next slide, please. Baseline characteristics for this patient population. I think probably first and foremost, the median age was about maybe 61.5 years. But I think what's probably important is actually to look at also the confidence intervals around that. The range is about maybe 23 to 92, indicating, of course, that we're seeing these cases even in younger patients as well. And I would say that it also highlights, of course, this emerging trend of younger onset disease across multiple types of cancers, including colorectal cancer as well.

The majority of patients had bulky Stage III disease coming into the study at the time of entry. And one thing to point out as well, too in terms of the types of tumors, about 15% of patients had a mucinous type of tumor, which tends to probably be a bit more challenging or obscure in terms of how it shows up in the MRI scans as well, making it a bit more difficult for physicians to be able to assess clinical complete response.

Next slide, please. The primary endpoint of the study was clinical complete response at 12 months. Patients actually received 9 doses of dostarlimab or about maybe 6 months of treatment. The cCR12 rate by investigator assessment at this time was 68%, as evidenced by the light-blue bars, these are the patients that actually were able to achieve cCR12 and had enough follow-up for them to be assessable for that endpoint.

I think the one point to highlight on the left-hand side in the black bars as well, too is that there's a number of different patients that have achieved a clinical complete response but don't yet actually have enough follow-up to be assessed for cCR12 at this time. So we'll continue to be following patients moving forward as well, too.

Next slide, please. These are the swim lane plots certainly demonstrating the durability of responses that have been observed across the AZUR-1 patient population. I think what's probably important to highlight here is, of course, is that 98% of the cCRs were durable. And to date, no recurrences have actually occurred so far.

Next slide, please. I think probably, just to provide a little bit more color around the type of benefit that patients were driving, so cCR12 is an endpoint that's typically assessed through two different methodologies. One, I mentioned the MRI. The other, of course, is through an endoscopic assessment. In certain instances, when there may be a bit of ambiguity around being able to declare a cCR12 or there's maybe uncertainty from the physicians around it, oftentimes what they'll do is they'll actually biopsy the patients as well, too and get access to tissue. And so there is a segment of patients in the dark-blue bars that actually have what is called a pathologic complete response at the time of the biopsy and surgery as well, too.

Limited number of patients that had actually undergone that, just about 12. But when you look at the combined cCR12 plus pCR rate, 76%, which is certainly, again, if you're comparing it to the 20% to 25% clinical complete response rate that's historically observed, quite significant and quite clinically meaningful, especially when you think about the fact that the majority of these patients were able to not only avoid chemoradiotherapy, but also avoid surgery as well, too.

Next slide, please. And then finally, I think probably just important to be able to see what this looks like. I mentioned, of course, the 2 different approaches to assessing certainly clinically -- the clinical complete response. One is through the MRI, the other is through the endoscopic exam. This is exactly what you're looking at.

So basically, this is an endoscopic assessment of the tumor in the rectum. Starting first maybe on the left-hand side, what you're seeing is this is actually one of these mucinous tumors, which are typically difficult to assess on an MRI scan. And as you can see, certainly, both from the anterior and also posterior walls, significantly encroaching and causing an obstruction within the rectal canal as well, too.

And then basically, the baseline evaluation after getting treatment, the patient getting treatment with dostarlimab for 6 months, 9 doses. And what you can see is there is a start of maybe normalization of the rectal mucosa and epithelium. Specifically, you see that manifested through the flattening, the smoothening as well, too, with probably some very residual scarring and I would probably say even slight residual evidence of the tumor. And then finally, of course, after the second follow-up assessment, complete normalization and no evidence of the tumor exists as well, too. And certainly, that gives you a sense of what this looks like in terms of the assessment of cCR as well, too.

The safety profile, certainly very consistent with what's known about dostarlimab and the immune-mediated adverse events. Important to highlight low incidence of Grade 3 events with these 9 doses of dostarlimab as well, too. And so a low tolerability burden for patients.

Next slide, please. So just to conclude, certainly we've seen an evolution in what will be the standard of care for locally advanced dMMR/MSI-H rectal cancer patients from where it was previously, as I mentioned, in the context of the prior treatment paradigm with chemoradiotherapy and surgery, to where we now see more than 2/3 of patients achieving a cCR12, 76% of patients achieving a cCR12 plus pCR, and certainly quite strong durability of these clinical complete response rates, with a low adverse event burden for our patients as well, too.

Next slide, please. I think maybe just one reminder from another data set that was presented at the World Lung Conference as well, too. Very exciting data from our Nuvalent acquisition, as everyone will probably recall, zidesamtinib or Jideytro was actually approved in late July in the U.S., 2 months ahead of the PDUFA date, which I think is important to highlight as well, too.

And here is actually data being presented from the TKI-naive cohorts in advanced metastatic ROS1-positive non-small cell lung cancer. Very quickly, I think probably the baseline characteristics, as expected, with about maybe a little over half of patients being females and certainly the same for patients being non-smokers as well, too, certainly, a good portion of these patients being fit in terms of status with an ECOG performance status of 0 or 1 and about 17% of patients having a baseline CNS metastases as well and the majority of patients having advanced disease and 1/4 having previously received chemotherapy or chemoimmunotherapy.

Next slide, please. And just to highlight, of course, the waterfall plot from 94 patients that are TKI-naive, and an objective response rate of 94% based on independent review with a CR rate of 15%, which is actually close to doubling the CR rates that we've observed with third-generation TKIs as well, too, which I think is important to highlight. Next slide, please. Duration of response, also extremely encouraging at this point in time, and specifically looking at the landmark duration of response at 12 months being 86% with the median duration of response not yet reached at this point in time.

Next slide, please. And then the same holds true for progression-free survival, looking at the landmark PFS at 12 months of 90%, and the median PFS not reached.

Now one thing that probably for us to think about and consider as well, too is how this drug was actually designed. It was -- in terms of the medicinal design of the drug, it was really designed to have this brain-penetrant activity while also being TRK-sparing as well, too, to minimize any CNS effects or side effects that is, while also making sure that it addresses intracranial or brain metastases as well.

And that was certainly evident in the ARROS-1 study in this TKI-naive cohort. In the subset of patients that did have brain metastases at baseline, intracranial objective response rate was 100%. And certainly, the intracranial CR rate, complete response rate was 70%, which is quite profound. And then, of course, the median duration of response in these intracranial metastases is not -- at least duration response in the brain metastases has not been reached.

Tolerability wise, I would say certainly a very good tolerability profile. Low incidence of Grade 3 events. I think probably I'll call your attention to the right-hand side of the slide, where we did see a really low discontinuation rate, only at 4%. And specifically that related to treatment-related adverse events at 1%. Dose reductions also infrequent at 11% and 12% as well, too.

With that, I think what I'd probably do is hand it over to Nina for closing remarks.

Thank you, Hesham. And I'm reflecting on the data and amazing data that were presented, but also on Hesham's ability to present all of this in such a short period of time. So thank you, I think it's quite impressive.

Okay. Before we go into Q&A, this slide is trying to capture the importance and the impact of the data. So to focus first on the first two boxes, so Ris-Rez in second-line small cell lung cancer. Why are these two data points important?

The first one, you have seen that in the Western cohort, so Western population of second-line small cell lung cancer, we are seeing 61% response rate. And that correlates very well with 58% response rate that has been observed in the Chinese Phase III study, ARTEMIS-008. And that study has shown unprecedented, the longest median overall survival that has been seen in the second-line small cell lung cancer. And I think this data give us confidence in the activity and the promise of Ris-Rez in second-line small cell as we are going to witness from the Phase III study, which is ongoing at the moment. So very high confidence in second-line small cell for Ris-Rez.

Another set of data, Ris-Rez in relapsed refractory osteosarcoma. For anyone of you who were there yesterday at the session and listening to the discussion, I think you get the full picture of what that disease is and how devastating it is and the lack of progress over the last decades. For Ris-Rez specific, it's an illustration of this asset being a pipeline in an asset with yet another indication, very difficult to treat indication, successfully tackled.

Jemperli, over the last few years, we have heard repeatedly the magic of Jemperli in the dMMR locally advanced rectal cancer. Now pivotal data in a study that on its own is quite unique have confirmed the efficacy, and we are actually just in the process of launching following the approval in the U.S.

Jideytro, ROS1 inhibitor in TKI-naive, was presented at WCLC a couple of weeks ago, again demonstrating best-in-class efficacy. And based on this data, FDA is going to review the first-line label, resulting, hopefully, very quickly in the approval for indication in TKI -- for TKI-naive patients.

Then last but not least, Mo-Rez, actually Mo-Rez had very good ESMO, with data presented in PROC or platinum-resistant ovarian cancer. Looking at the data, response rates plus duration of response and PFS that has been observed indicate that this asset is at the top end, if not the best, in efficacy in this setting. Or more specifically, in ovarian cancer, obviously, PROC indication is the beginning, ADCs are very intense -- have intense development programs in ovarian cancer. And the question is going to be where is -- which asset position either in platinum-sensitive ovarian cancer or eventually in newly diagnosed, so first-line ovarian cancer.

So with this, again, I'm just going to thank Hesham for an amazing presentation and the read-through. I think we are going to open the questions, and Jeff is going to manage that.

Yes. Thank you for those of you who have not raised your hand and have a question. Please feel free to raise your hand, and we'll try to get through as many of you as we possibly can. I see James Gordon is up first, from Barclays.

One on Ris-Rez and one on Mo-Rez, please. So in Ris-Rez, so the efficacy looks good, but I think there's a 42% Grade 3 AE rate in the Phase III. So that does look challenging. And it doesn't look like it's lots of ILD, that looks all right. But it looks like these 42% of patients had to have dose interruptions or delays. So might it be a bit too high dose? And is that something you think you can improve in terms of tolerability in Phase III? Would you want to try and improve it before taking something that challenging into Phase III? That's the first question, please.

And the second question was on Mo-Rez, so the B7-H4 where the data looks strong in ovarian and endo. But then on Friday, Genmab had also a very strong Phase III efficacy data for Rina-S, so its folate ADC, and there's a few other ones of those in development from other people as well. So how do you think about folate ADCs versus B7-H4 for gynecological cancer? Because it looks like at best, Mo-Rez is probably about the same, but they'll already be on the market and quite well established. Is it going to come down to some sort of subgroups or something like that? Or might it be you do a folate, then a B7-H4?

James, thank you very much for the question. I'll start off first maybe just addressing the question around Ris-Rez. And I think probably 42% that you might be referring to is coming from the osteosarcoma study. And I think maybe as I've just highlighted as well, too, the dose that was used in that trial was actually the 12 mg per kg Q3W dose. That is not the dose that's currently being used across a number of key tumor types that we're exploring.

Specifically, we're actually using the 8 mg per kg dose level Q3W across both small cell and prostate cancer as well, too. And I think from our perspective, again, most of the, I would say, safety and tolerability at least profile is very much being driven by the myelosuppression and the neutropenia. And from our perspective, certainly, the use of growth factors in the Phase III studies should certainly help mitigate that. But then at the same point in time, we're not using the high dose, the 12-milligram per kilogram dose, that Hansoh used in their osteosarcoma Phase III trial. We're actually using the 8 mg per kg dose level.

In terms of the second question that you actually had as well, too and specifically regarding Mo-Rez. I think, first and foremost, of course, I think we're all well aware that we saw that the announcement from Genmab around the Rina-S study as well, too, and announcing positive results. From my perspective, first and foremost, I think it's important for patients, important for patients to be able to have treatment options, especially with this emerging class of antibody drug conjugates. With that in mind, I think we have to look at the data that we have at hand. There's things that we know and things that we don't know. The things that we know are the hazard ratios from that trial for PFS and overall survival. The things that we don't know are the medians.

However, I think, again, acknowledging the caveats that exist with cross-study comparisons, what we do have is actually Phase I data from across both programs. And when we look at the Phase I data, specifically with Mo-Rez, which we just presented over the weekend in PROC we saw a confirmed objective response rate of 62% from the Phase I Rina-S study, it was 46%. So that's one.

And then second, when we looked at also PFS as well, too, I think as you probably saw, at the 5.8 mg per kg dose level, the median PFS was 11.1 months for Mo-Rez. And then for Rina-S, it's about maybe 9.5 months.

So I think we just have to keep in mind that, at this stage, we have to wait and see what the data looks like from their Phase III trial. But certainly, I think what's probably become evident is that there is some level of relationship between clinical activity in the context of response rates and depth of response. But also, certainly at least with these ADCs, the duration of response and the PFS as well, too.

And at this stage, we certainly feel pretty comfortable with the level of clinical activity that we're observing and then how that's manifesting in duration of response at a little over 12 months and then PFS a little over 11 months as well, too.

Now in the context of subgroups, again, I think for us, when we looked at expression levels, as you probably saw from the data itself, we see no correlation between clinical activity and expression levels. Broad activity across whether it be B7-H4 expression low or high, I think that's data to be weighted from their Phase III trial as well, too, to see what, if any, relationships may or may not exist with FR-alpha expression levels as well, too.

And I would just add for PROC, PROC is the first step for all of these ADCs in ovarian cancer. Eventually, hopefully, the efficacy is going to confirm for many of these to be moved into earlier line of therapy. And this is probably where the more important competition is going to happen. And as you know, studies are only starting in these settings as we speak.

Excellent. Let's move to next question from Shyam Kotadia from Goldman Sachs.

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Yes.

Perfect. So there's a lot of focus on novel-novel combinations in oncology with ADCs and new IO backbones. How do you think about this potential in gyno? We've seen activity with VEGF in ovarian cancer. So could B7-H4 be a potential partner for VEGF PD-1 bispecifics?

Yes. Shyam, thank you very much for the question. I think we'll start off first by saying no doubt that the standard of care has evolved in endometrial cancer, and we've seen that first with the advent of checkpoints. As you may probably be aware, our first-line endometrial study in the MMRp segment of patients, it's a maintenance trial, but it's also looking at to combine Mo-Rez or B7-H3 with the existing standard of care PD-1 agents. And so that's probably one component of it.

The second probably is getting directly to your question, which relates to, could combining with bispecifics in this space be an opportunity? I mean certainly, we've seen some preliminary data from other competitors, including Pfizer as well, too. There seems to, at least again, given the single-arm nature uncontrolled nature of the study, but there seems to be a signal of additive effects between PD-1 VEGF and chemotherapy. So it's something that we certainly take into account.

Maybe the one thing that I would just highlight, of course, is that we do have an existing collaboration with Summit Therapeutics. And specifically, that is at this time directed more towards the Ris-Rez program and exploring combinations of Ris-Rez with ivonescimab in lung cancer across both small cell and non-small cell lung cancer as well, too.

So I think it's something that we would take into account, take into consideration and maybe think about.

Excellent. We'll go next up for a question from Peter Verdult from BNP Paribas.

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Yes.

Sorry, guys. I'm actually at ESMO and struggling on the mute function. Peter Verdult, BNP. Sorry. Just a couple for Hesham, please. Lots of doc excitement around the B7-H3 ADCs, but docs saying it's too early to differentiate and perhaps pointing to some of your competitors having stronger data in patients with brain and liver mets. So would love to hear where you agree and disagree with the idea of there being a lack of differentiation right now amongst the B7-H3 players.

And then secondly, on development plans for Mo-Rez, just to follow on from James' question earlier on, not on folate itself, but look, anyone who was at Madrid, and I'm sure you guys were there, it was a tidal wave of ADC data. Lots of different targets, but a lot of them are topo-1 payload. So the idea of, are you really going to do sequential therapy if you failed on topo-1 payload and the idea of acquired resistance? So I would love to get a little bit of thoughts there in terms of how that shapes your development plans.

Yes. Peter, thank you very much. Let me start off first with the question around Ris-Rez and B7-H3 and the class of agents and differentiation as well, too. I think first and foremost, we probably need to rebaseline in kind of where we are today. And where we are today is we've dosed more than 1,100 patients across our development program, the GSK global development program. And then Hansoh has 2 positive Phase III studies out of 2 Phase III trials that have read out data across second-line small cell lung cancer and across osteosarcoma. So those are facts that we could start with. I think, certainly, the data that we've seen at least from our own small cell lung cancer experience, seems to also give us confidence in the translatability of those results moving forward as well, too.

With regards to differentiation, I think probably maybe just it's helpful, because I called it out during the data presentation as well, too, I think it's helpful that maybe if we can go back to the slide specifically with the subgroups. Because I know you touched on, for example, patients with either brain mets or liver mets. I think it's a good one to maybe just look at in the context of the data itself from across the ARTEMIS-008 trial.

And specifically, in one of the defined subgroups, about maybe 17% of patients that were actually recruited into the study had brain metastases at baseline. And the hazard ratio for overall survival in that segment of patients was 0.36. So I think from that standpoint, certainly, we feel pretty comfortable in terms of the drug's effects, not only systemically, but also in patients with brain mets at baseline. So I think that's probably important to touch on.

With regards to differentiation relative to other agents in the class, I think really when you think about -- and we'll touch on this with Mo-Rez as well, too, when you think about physicians, physicians always think about 2 things. They think about efficacy and the type of benefit patients are experiencing, but also tolerability and safety as well, too. We've touched on ILD, which I think certainly across the class has been variable, including with other types of platforms. So I think maybe that's something that we have to take into account is, maybe not all linker payloads, topo-1 payload platforms, are created equal. I think it's one thing that we need to consider.

And when you look at, for example, the incidence of ILD across our own global development program that was presented at ESMO, 4% all grades, 0.9% Grade 3 or greater. So that's the safety side of it.

In terms of efficacy, I think we've also touched on at least the data from the second-line small cell ARTEMIS-008 study. Median OS, 18.5 months, when it's benchmarked either to other competitor trials or existing standard of care in that setting with immune cell engagers as well, too.

So I think probably certainly the data, the clinical data will be a key driver of decision-making for physicians. And I think that at least as you look at the class as well, too, safety will become another key differentiator. And I think over time, no doubt, as we continue to evaluate and assess biomarkers, translational endpoints in other tumor types, this is something that will no doubt become a key part of how physicians make choices, along with combinations, combination partners.

A good example of that, for example, is as we're moving into front-line small cell lung cancer, we're considering 3 different opportunities. One, which is the now, combinations with PD-L1; two, looking at combinations with bispecifics; and then three, of course, looking at combinations with immune cell engagers. And I think that will be equally important for physicians as they make choices moving forward.

In regards to Mo-Rez, I think you touched on, I think, effect, which is there's been an explosion of antibody drug conjugates in gynecologic malignancies. I think we have to all acknowledge that and be grounded in it. And again, like I said, I actually think that that's a good thing for patients from that standpoint.

I think at the end of the day, I think physicians are going to use the same criteria. They're going to use safety and efficacy. I think when we look at across a number of different classes of agents, whether it be TROP2, whether it be looking at other B7-H4s, whether it be the CDH6 class or others, certainly, safety is going to be a question. It's going to be a question whether or not there is, for example, some that come with ocular toxicity, some that come with ILD, some that come with stomatitis. Those are all key variables that we'll take into account, and that's what they tell me when I speak to them.

The second really will be the efficacy. And I think we've seen a variation in the efficacy as well, too in the performance. Now we don't know if that's related to internalization of the target or the antigen itself. We don't know if there are maybe some slight differences in the topo 1-based payloads or not. But I think one of the things that we saw over the weekend was, no doubt, these ADCs are certainly evolving the environment within the tumor. You probably saw the data that was presented from the Mo-Rez Phase I study. What you saw in that certainly it was inducing some immunological changes within the tumor microenvironment as well, too.

We'll continue to learn about that. But I guess, probably what I'm saying is typically across the entire ADC class, we've seen response rates range between 40% to 60% or 65%. Mo-Rez is delivering a 62% objective response rate. It is in the upper tier of that class. And I think that's something that's important to anchor to as well, too, at least in platinum-resistant ovarian cancer. And I think for us, again, continued work on biomarkers, translational endpoints over time to continue to better assess whether or not there's any additional ways to optimize benefit-risk, is something that we're going to continue to evaluate and look at.

Excellent. Let's go to the next question. Thanks, Peter, from Seamus Fernandez at Guggenheim.

Can you guys hear me okay?

Yes.

Great. So my question is actually on the evolution of treatment in ovarian cancer. We have sort of the PARP1/2s in the maintenance setting. But these ADC data are obviously establishing a unique new bar potentially for treatment. But just interested to know how you're thinking about the sort of utility of PARP I/II like Zejula in the context of these evolving data, but also there are more PARP1 -- highly selective PARP1s that were revealed at ESMO. How are you thinking about the potential for selective PARPs emerging as potential paradigm changing or shifting assets? Or is your focus really going to be exclusively on advancing your ADC programs in combination with other therapies like immunotherapy ahead of pursuing potential PARP combinations.

Yes. Seamus, thank you very much for the question. I'll start off first by saying no doubt the advent of PARP inhibitors has had a really meaningful impact in advanced ovarian cancer patients. And I would say probably much more, of course, in the BRCA mutant and HRD-positive segment of patients. And it will continue to be, certainly, a key part of the decision-making in treatment for that segment as well, too.

Now one thing I maybe just want to reiterate and highlight as well, too, when we think about Zejula, Zejula is actually a PARP inhibitor that is more selective for PARP1 than it is for PARP2. So I just want to make sure that I point that out first and foremost.

In terms of how we're thinking about the landscape, I think for us, really, no doubt, Zejula has continued to do well in those segments where it's approved currently, whether it be in the U.S. or Europe. But at the same point in time, our focus is definitely on Mo-Rez moving forward. And that includes not only thinking about later lines of therapy, but also moving into earlier lines as well, too.

And I think maybe one thing that's maybe a bit underappreciated is the fact that we actually have access not only to data that we're generating across our own development program, but also the Hansoh development program as well, too. So I can tell you, like I see this data with the team, including, of course, some of my colleagues in R&D that are with me today, Richard Davidson, Eric Richards and Klaas Bakker, we see this data in real time.

And I can tell you there's like really interesting data that we see, of course, in platinum-sensitive ovarian cancer. The data hasn't been published yet. But it gives us additional confidence in thinking about ways that we can continue to evolve the treatment paradigm. For example, displacing platinum-based chemotherapy in this disease segment of patients, and thinking about different combinations as well, too moving forward across both ovarian and endometrial cancer as well, too. And that's really where our focus is moving forward.

Excellent. Thanks, Seamus, for the question. We only have a few minutes left. Let's try to go through 3 final questions here, first with Graham Parry from Citi.

So just what your thoughts are on the IMDELLTRA-Imfinzi combination in maintenance in small cell lung cancer, whether that changes the recruitment of patients that you think you need for your first-line small cell lung cancer or even third-line -- sorry, second-line studies for Ris-Rez.

And then secondly, just your thoughts on what drove the lower grade 3 ILD rates in your trials versus the ARTEMIS-008 China study. Just differences in how patients are managed with ILD.

Graham, thank you very much for the question. I'll start off first with the data from Amgen IMDELLTRA in the first-line maintenance setting. Again, great to see such an improvement in median overall survival and PFS as well, too. I think if you ask me, is this of course going to change how physicians practice and especially in this maintenance setting? Absolutely, it will. In the short term, no doubt about it.

But I think probably at the same point in time, as we're thinking about first-line development, there is an element that's missing here that may not necessarily have been accounted for, which is actually the start of treatment, the initiation of treatment and the challenges that currently exist with chemotherapy, which can typically consists of a platinum-based doublet of cis-etoposide as well, too. Not only is it the tolerability burden and the challenges that it actually provides for patients but also the fact that oftentimes in this disease setting, as you're well aware, patients respond quite a bit to it, but the responses are, of course, very short-lived. So there's a lot of limitations that exist in that regard.

What are we trying to do? Well, at least for us with Ris-Rez, one of the things that certainly we're going to be aiming to do is trying to help evolve the treatment paradigm at induction. Induction and then maintenance, not just maintenance. And I think probably for us, I mentioned earlier that we're going to be looking at combinations, whether it be with existing standard of care, PD-L1, bispecifics given the emerging data and access to those through Summit, or certainly based on the IMDELLTRA data thinking also about immune cell combinations as well, too.

With regard to the recruitment into the studies, I think this is something that we've certainly already taken into account, including on the -- on our second-line Phase III study, which is currently recruiting. So we are certainly recruiting -- or looking to recruit a proportion of patients that would be tarlatamab-exposed. It's something that we've already addressed, had engagements with health authorities with and factored into the program.

With regards to ILD, I think there's a number of different variables that we have to take into account. Parts of it, of course, as you look at specifically the ARTEMIS-008 study. You might wonder, why was the incidence higher than expected relative to the experience that we had on our global development program? Well, bear in mind that about maybe 37% of patients recruited into the ARTEMIS-008 study on the Ris-Rez arm had actually received prior radiotherapy, which is quite -- and I would say, prognostic in terms of the incidence of ILD.

The second, I would say, is also the fact that about maybe 13% of patients on the Ris-Rez arm actually were patients that had limited-stage disease and then progressed. Typically, these patients are treated with definitive or chemoradiotherapy that's administered with a curative intent. So again, the radiotherapy theme there is important to highlight.

And then, of course, the other element in this, of course, is the follow-up, so there are about maybe 12 months of follow-up on the study. So certainly relative to other agents that have published Phase III results that had sort of follow-up on the trial as well, too, that's certainly another variable to take into account.

And then finally, of course, it also really depends on data collection and which types of preferred terms for the incidence of ILD were used. Are you using broader, as we call it, search criteria in the database to look for events and the fact that these events actually that Hansoh reported were never adjudicated. And I think that's something that's important to highlight as well, too.

So for us, in terms of our Phase III development program, we've certainly done a lot of education with the investigators, awareness about ILD monitoring patients as well, too. And I think you probably see that borne out in the analysis that we presented at ESMO as well, too. And even in the small cohort of patients that were treated either with a 6 mg per kg or 8 mg per kg dose in second-line small cell lung cancer, the incidence of all-grade ILD was actually 2%. Again, this is a smaller subset of patients, about 50 patients, but it gives you a bit more of the direct small cell lung cancer read-through as well, too.

We're just there on time, but let's try to squeeze in, if we can, two real quick questions. First, we'll go with Steve Scala from TD Cowen.

I actually have 2 bigger picture oncology questions, which are hopefully appropriate for this call and maybe best directed for Nina or Ahmed. But there's a general investor perception that China-only data is not a good predictor of global results, but GSKs and other companies' data at ESMO seem to be pushing back on that perception. So I'm just wondering how does GSK view this? Should China only data be viewed as always reliable or only in certain circumstances? And if so, what circumstances?

And secondly, given GSK's extensive experience in vaccines, does the company have any preclinical efforts directed at therapeutic Neoadjuvant antigen therapies?

Yes. Steve, on China data, I think everybody will go through the journey on a data-specific level. And the reason why we actually did the global cohort is exactly to understand which level we can be confident that the China data do represent this specific China data to represent something that we can count on. And I think Hesham is probably in a better place to respond to this, but everything that we see in second-line small cell lung cancer, that specific class, gives us high confidence that genuinely Phase III study from China are actually solid data that are reproducible.

Regulatory question is something completely different. And I think I'll probably take it, I mean I'm sure Hesham can make a comment. But in terms of trust or confidence in the data, I think this is exactly why we did the Western cohort, to confirm that. But Hesham, I don't know if you want to add.

Yes. No, thank you, Nina. Just to build on, Nina, what you were highlighting is there's typically just a few variables that we take into account when we're trying to think about or consider extrapolation of data. I think, first, you have to, of course, look at the baseline characteristics of the patient population and how it compares typically what you observe in a Western patient population. So I think that's one. I think at least when we looked at the ARTEMIS-008 data, relatively at a high level, quite consistent with what you'd observe in a global population.

The second, I think you have to also look at, for example, the standard of care, the control arm that's being used on the trial as well, too, and how it behaves as well, too. And I think probably the data point here with ARTEMIS-008, the control arm is the topotecan control arm, the most recent data set that's actually been published from a global Phase III study is from a study called the LAGOON trial with lurbinectedin. The study actually was a negative study in second-line sponsor lung cancer, but the control arm was actually a physician's choice of topotecan or irinotecan. And it actually delivered a median overall survival of about maybe 10.7 months relative to the topotecan control arm in ARTEMIS-008, which delivered a median of 10.3 months. So you see that consistency again.

And then the reference I made during the presentation really around what are we seeing in the internal validity of the results from the trial is consistency in treatment effect, the magnitude of effect as well, too. So it's on the primary endpoint, it's on the key secondary endpoints, and it carries through, and the magnitude of effect is strong. And I think all of those are good indicators and variables that help you think about the strength of translatability.

On the question of like how regulators view the data from China, well, I think probably the one thing that we've seen is there is this regulatory, I would say, dissonance that exists in the context of how different regions or countries may view them differently. I think we've seen certainly data from China serve registrational purposes, for example, in regions like Europe, in regions like Japan as well, too. Not necessarily, of course, in the U.S. But I think it's certainly important to have that perspective.

Question about...

There was a question, yes, the second part of the question, yes. Vaccines, yes. I think it's an important point to highlight, of course, just given the heritage that we have in this space, and specifically also the mRNA platform that currently exists. I'd probably call your attention to the fact that we actually have an existing, I would say, academic partnership with Oxford. Specifically, it's a translationally oriented immuno-prevention program evaluating and assessing neoantigens that are most likely to elicit an immune response relative to cancer vaccines as well, too.

So that is currently ongoing. It's a multiyear collaboration as well, too. And it's an area we continue to evaluate and assess on an ongoing basis relative to what's happening externally in the competitive landscape.

Also over the weekend, we saw the data being presented from Moderna. I just want to make sure that I acknowledge that as well as too. And more recently, we've also seen data that's been also not positive in other tumor types, including in colorectal cancer as well, too.

So I think there's still a question that remains around how much can be extrapolated from a highly immunogenic and immune-sensitive tumor like melanoma relative to other tumor types that may either be less immune-sensitive, colder or having lower tumor mutational burden as well, too. But we are assessing and evaluating different considerations in that regard.

Great. Just one quick final question then, if Kerry Holford can come off mute, from Berenberg. Kerry, we'll give you the last question here as we try to wrap up.

Thank you for squeezing me in. Clearly, a lot of focus more broadly on ADC this year at ESMO, not least within your pipeline. So maybe to end on a sort of big picture question, if we ask you to take a 10-year view, how much of traditional chemo do you think ultimately be replaced by ADCs? And GSK within that, what sort of share do you ultimately target within that ADC world?

Kerry, everybody is looking at me here in the room to try to come up with an answer. Look, I don't think we are approaching this from the angle of what is the total amount of chemotherapy is going to be, that is going to be replaced. Yes. ADCs will replace a significant portion, but ADCs will not fully replace chemotherapy. It's going to be very indication-specific, sometimes even line of therapy specific, definitely very tumor specific.

I think with the 10 years view that you quoted, we are probably looking at beyond topo-1, and then what are other drug conjugates that are going to end up on the ADCs with even multi-mode of actions in the same target. But what we do see is obviously a great benefit, but we also need to be aware, ADCs are not -- they're not completely benign therapies. There are toxicities that are coming with ADCs. I think we need to look at what is going to be the duration of therapy, how much can be tolerated.

So I'm not sure I would look at it fully from how much of chemotherapy can it replace. It's very likely it will go into earlier lines of therapies because that's where the drug, where the shot on goal for potential cure is. I would say, at the moment, out of the totality of oncology, it's still a minority, unfortunately.

It's just going to be another platform that could complement or could add with different therapies or different tumor types, but -- and we're still starting with this.

Excellent. Well, thank you. Thank you for sticking with us for extra 10 minutes. And we'll conclude the call at this point.

Hi, everyone. Thank you so much for being with us here today. My name is Courtney Breen. I am the U.S. biopharma analyst here at Bernstein. I am thrilled to be sharing the stage today with Kaivan Khavandi. He is the SVP and Global Head of Translational and Development Sciences at GSK. I know you have a focus and is responsible -- and are responsible for respiratory, for hepatology, for immunology, inflammation.

Can you give us a little bit of context about the scope of your role and the things that you focus on in the company because it sounds quite vast?

Yes. Great. Well, first of all, Courtney, thanks for having me. So the role, I guess, has 2 aspects. One is the end-to-end accountability for R&D for respiratory, immunology and inflammation. So that's a fully integrated unit from discovery, target choice through to translation, clinical development, asset leadership through to product approval. So the full life cycle of assets, as you described, it currently represents a lot of activity through to the late stage in respiratory medicine and hepatology, but also, I think, some very promising programs in what we're increasingly thinking of just as comorbid disease that's the consequence of chronic inflammatory pathology.

The other hat is the Translational Development Sciences, which is a relatively recent organization, which integrated 3 key components of the organization across categories, so oncology, specialty and Vaccines & ID, and that was Asia R&D for reasons that probably are obvious and the opportunity that we see represented by China, in particular, perhaps the unrealized opportunity to partner with China for translational medicine. The second is genetics, genomics and single-cell technologies, which we see as one of the most high confidence areas to be able to build an understanding of target trait pairings. And the third being real-world evidence or development sciences, which integrates epidemiology and causal inference from large-scale routine health care data.

Fantastic. It's a broad scope. And I think the seat that you have covers it means that you must have to think about some of the topics that we've been discussing throughout the day today in terms of the role of China and kind of innovation that's happening there as well as AI and drug discovery and drug development, and these are critically important themes that I think keep popping up in so many of our conversations. So I might squeeze in a couple of questions on those as well. But perhaps to start with your kind of therapeutic area orientation. Respiratory has been a long-standing strength for GSK and you have had leadership in the COPD space and among others. How do you see the franchise evolving from here? And where do you see the biggest opportunities for growth over the coming years?

Yes. So you're right to point out that GSK has got what I would really say is a unique heritage in respiratory medicine. But I think to pioneer is to be forward-looking and to continue to think about what's coming next rather than reflecting backwards. And so whilst that heritage in inhaled therapeutics and, I guess, the first wave of targeted biologics with the IL-5 franchise continues to be really important to the portfolio, Trelegy, Nucala are incredibly important products. I think what we're seeing is the maturity of how we think about asthma is not necessarily true of a disease like COPD. And so in asthma, we know that there are very effective therapeutics. And part of the reason is that we understand that the majority of that disease process is driven by Th2-driven inflammation. And so a number of now monoclonal antibodies have been developed. that are effective, one of the key challenges is bio penetration and persistence.

So there's an unusual level of poor persistence to biologics in asthma. And in fact, the majority of patients come off short-acting biologics within a year despite the fact that they are safe, well tolerated and the efficacy is unequivocal. And so that's led us, of course, to think about what could enable penetration and persistence. The 2 things that we've identified is, one, a deliberate approach to the comorbid profile and the indication mix for any mechanism, and we're seeing that different biologics have a slightly different flavor of where they're effective across different disease processes, a number of which overlap in patients with asthma.

And then the second is how do you reduce the burden of the management and administration. And obviously, that's led us to have confidence that an ultra-long-acting biologic, which almost completely relieves the patients of any burden of engaging their management with just 2 injections a year is going to be one of the key enablers. In contrast, in COPD, it's more a case of understanding the underlying drivers of risk. And so it's a much more scientific mechanistic proposition that we see. The scale of the problem is vast in COPD. So it's 300 million patients affected globally, a life-threatening disease. And as of today, only 2 approved advanced therapies with Dupixent and Nucala. And both of those are reserved for one segment of the disease.

And so we really have invested time to understand what's driving different segments of COPD and then what's the rational approach to trying to interrupt those disease processes with the right mechanism. And so that led us to diversify alongside IL-5, which remains a very important mechanism in obstructive lung disease to acquiring an ultra-long-acting TSLP and also progressing our program for a long-acting IL-33 as well as a number of other approaches, including a PDE3/4 inhaled approach and also what could end up being the first oligonucleotide in respiratory medicine, we have a program that's currently in Phase Ib, which is an siRNA.

Fantastic. How do you think about positioning some of these assets relative to one another? There's obviously a lot of potential innovation. There's also a lot of competitive pressure in some of these places. And so can you just help contextualize the relative positioning that you're contemplating at least at this point in the development process?

So the simple framework that's been extrapolated from the asthma field is one that stratifies based on eosinophils as a surrogate of Th2-driven disease. So you've got these thresholds of patients with eosinophils over 300, an intermediate level of Th2-driven risk, which is eosinophils over 150, where we acknowledge there's going to be other pools of risk and then eosinophils under 150, which is kind of considered to be T2 low. And what we understand, of course, is that IL-4, 13 as an example, is restricted to those with eosinophils over 300. Nucala was able to generate an evidence base that showed clinically meaningful effects over 150, enhanced effects over 300. And again, the TSLP mechanism appears to be, although obviously being tested in pivotal studies now, effective in those with eosinophils over 150.

But now we're starting to gain a more sophisticated view. There are certain mechanisms that are effective in improving FEV1, lung functional spirometry. There are certain mechanisms that make the patient feel better. And those may be discordant with approaches that improve exacerbations or even improve survival. And we know this from other settings. The analogy I always draw is to heart failure, where diuretics make you feel great. They don't make you live longer. Beta blockers make you live longer and don't improve how you feel and ACE...

Make it worse sometimes.

Exactly. And ACE inhibitors are the most prognostic. And I think in COPD, we're going to start seeing this more sophisticated understanding of what mechanisms deliver what. And that, again, will likely lead to combination approaches as well. And of course, IL-33 now, and we predicted this and we initiated programs, for example, testing IL-33 in non-CF bronchiectasis, which is a disease process that's largely not Th2 driven. It's neutrophilic inflammation that drives that disease process. And obviously, at the ERS Congress that we've just come from last month, we've now seen that the IL-33 mechanism is effective in patients without elevated eosinophils or Th2 drivers of risk.

Fantastic. And continuing on the IL-33 mechanism, we've seen some mixed results for some of your competitors in this space. And I'm thinking here of kind of Sanofi and Regeneron. And I'd love to get your thoughts on what did you learn from some of those studies? And what gives you confidence in the GSK995 asset relative to what we've seen play out elsewhere?

Yes. Yes, it's been a kind of storied history for IL-33. I think there's probably a clear molecular differentiation between ST2 receptor monoclonal antibodies, which might limit the mechanism to one potential pathway and then everything else. So people might be aware of the hypothesis that there's a redox-dependent set of activity that IL-33 signals through. It starts off in its reduced form that can signal through the ST2 receptor, but there's also an oxidized form, which again is oxidized from the reduced form that can signal independently of ST2 potentially through the RAGE pathway. So if you're an ST2 receptor blocker only, you may miss a potentially relevant signaling pathway through RAGE.

If you're a potent neutralizer of the ligand, which is what our program is, then you're going to neutralize the entirety of that reduced form. It doesn't have a chance to become oxidized. The sort of black and white differentiation of our program is that it's long-acting, so every 3 months. But what we really invested time in, as you say, was to, first of all, understand from competitor pharmacology and clinical data reading out where we're seeing evidence of a differential effect based on patient characteristics. And we've also got a universe of data internally in respiratory medicine, genetics, genomics, clinical data as well as a Phase II study with IL-33 to also integrate into those data sets and understand what's the correct population that's going to be responsive to IL-33.

Based on what I've just described, the astegolimab data from Roche at 15% annualized exacerbation reduction is understandable if the ST2 receptor was limited in terms of what it could do. The confusing data was itepekimab, the AERIFY studies from Sanofi. But we do also recognize that those studies were challenging in one of the studies, there was effectively almost -- there was very little exacerbation. So I think you have to separate the operating characteristics of a study to be able to demonstrate a treatment group difference from biological enrichment. Tozarakimab then took forward a Phase III population where they mandated that patients answered yes to a CAT score domain where they said, do you have a particular problem with cough from your COPD and do you have a particular problem with productive mucus from that cough.

And that was because in the Phase II study, they saw an enhanced effect in patients that had imaging evidence of a mucus plug. That's a surrogate for neutrophilic inflammation. And so we take those insights, astegolimab just published in the Lancet pooled data from across their pivotal program. You can see, for example, in patients with more severe lung function decline, the mechanism appears less able to provide a benefit. That might not be surprising when you consider this isn't a circulating cytokine. It's expressed on the lung epithelium. And in patients with advanced lung dysfunction emphysema, they've lost that cell type in the lung. And then internally, the data set that really is proprietary to us was based on the observation that IL-33 is largely expressed in the lung epithelium, but the vascular endothelium.

And IL-33 has clear evidence of causing endothelial dysfunction. And so we signaled a couple of months ago that our intent is to take forward a more conventional pivotal program to demonstrate the benefits on exacerbation reduction. But for patients with COPD, they have an incredibly high comorbid burden. And what you really want is to keep them alive and out of hospital. And so you don't really want to be separating whether the reason they've decompensated and arrived in hospital because of a degree of heart failure or their COPD or their metabolic profile. And so we've been waiting for the right mechanism to be able to evaluate a study that says, actually, we're going to evaluate the benefit on CV hospitalizations, respiratory hospitalizations and mortality. And so that's the cardiopulmonary outcome study that we have shared, we plan to start next year as the third pivotal program there.

Fantastic. And I know you've got the TSLP, the long-acting TSLP also in development. This is already a pretty clinically validated mechanism. What do you believe your asset needs to show to demonstrate differentiation going forward, particularly recognizing pipelines are kind of long-actings are kind of coming in a few different places.

Yes. So increasingly, we want to bag the benefits of the modality being ultra-long acting, and that is not trivial, as I described, because most patients come off short-acting biologics. So I think that the long-acting components, if it replicated a TEZSPIRE-like data set would be a highly successful product. We know that TEZSPIRE is effective in asthma, irrespective of eosinophil levels. It was demonstrated what I consider to probably be best in disease activity in chronic rhinosinusitis with nasal polyps with the WAYPOINT. COPD, not confirmed efficacy yet, but being studied, but the COURSE data suggested that it's efficacious in patients with eosinophils over 150 and 300. So if you were able to replicate that and provide a product that patients could persist on, then I think that's going to be highly successful.

However, the modality plus component comes in with what do we understand from the mechanism, how can we bring our innovation to trial design to the benefit of the product profile. And so for example, for that program, the PERSIST asthma study is recognizing that if you want to have long-term benefits of treatment and achieve clinical remission type benefits, you really need to try and intervene earlier in the disease process. Now that makes sense. But from a trial point of view, if you don't have enough substrate of events to demonstrate a treatment group difference, that's very difficult. And so we have one pivotal study that's kind of more classical for asthma with TSLP, which is those patients have exacerbated twice in the prior year. But we have another study where the patients are only required to exacerbate once. And we've got some other criteria to make sure that we are able to simulate an event rate that's going to give us confidence that we can show a treatment group difference.

So that's a great example where we've kind of borrowed from competitor data. We've got an understanding ourselves of how the mechanism links to the disease process. And then we've got this wealth of understanding around clinical trial design to be able to ultimately achieve a product profile that's going to allow for eligibility of patients at a less advanced stage of their disease. And we're doing exactly the same thing with Exdensur for COPD.

Absolutely. And you're kind of across those studies that you referenced, I think it's 6 in total that you're advancing [indiscernible] in Phase III. The conviction required to initiate those are all kind of in parallel in some respects rather than sequentially, does that come purely from this kind of very well-understood biology and some of these other pieces you're speaking to? Or kind of have you seen something internally that kind of makes you say, all right, this is the right time to go big on this asset?

Yes. So all of the above, and we did have a Phase II study in asthma, the NAZARE study. We're going to share those data next year, but they were very, very clear that we achieved the pharmacology necessary for twice yearly dosing. That was obviously something that we weren't going to take a risk on, and we wanted to make sure we had empirical data in our hands. We did, of course, benefit again from our partners in China and Hengrui, who also evaluated the same molecule in patients with nasal polyps. So actually, we've got a wealth of data. We've got a GSK Phase II confirming the pharmacology necessary. The data was very strong indeed, actually. We've got competitor data. We've got our China partner data in nasal polyps. And so I would describe that as an extremely high confidence set of pivotal study starts.

Great. Yes. That makes a huge amount of sense to move forward with initiating all these studies. I want to kind of continue in this space, but go beyond to pulmonary hypertension. You've got HS235, I believe, which is an activin trap in development. Can you talk a little bit about what gives you conviction in this mechanism? And kind of why do you believe that this has the right balance of safety and efficacy to advance at this time point?

Yes. So acknowledging that this program is relatively earlier than everything else we've spoken about, I think that, that mechanism is extremely exciting. Again, it builds on the evidence base that's been generated by WINREVAIR sotatercept, which I think everyone in the field acknowledges as being transformative to pulmonary arterial hypertension, Group 1 pulmonary hypertension, the first mechanism of many, but the first mechanism that's demonstrated remodeling of the pulmonary vasculature that provides evidence of disease modification. And that product has been very successful post launch, but has some very real liabilities. And so even actually as recently as yesterday, their label was updated to reflect the HYPERION study from an efficacy perspective, but marketing data that's led now to new language around GI bleeding.

So pericardial fusions, telangiectasia, potentially GI bleeds. And because of the unmet need and because of the efficacy, the product is still successful and penetrating well in PAH. But if you can overcome that, then you have a product which the benefit risk profile becomes pretty remarkable really. And so the proposition was if you can be more selective and not inhibit the ligands that are signaling through to the bleeding and the adverse events, but preserve the efficacy, then that will be a very clear proposition. And so 35Pharma came with a real heritage in understanding medicine design that modulates the TGF-beta superfamily of signaling. And in that instance, recognize that activin A and B are key to inhibit to modulate the efficacy, but BMP9 inhibition is probably leading to the bleeding risk. And one of the reasons that we recognize that is that if you have a genetic loss of function of BMP9, you literally develop the phenotype of the adverse events.

You develop a hereditary hemorrhagic telangiectasia. And so this medicine was designed to spare BMP9, inhibit activin A and B. But the really exciting bit on top of all of that is that GDF8 myostatin is a protein that we know leads to skeletal muscle dysfunction, insulin resistance and inflammation. And so if you're not dose limited like sotatercept is, you're able to unlock additional metabolic pharmacology and benefits and anti-inflammatory benefits, which then if you think about Group II pulmonary hypertension, which, again, sotatercept has a signal of efficacy from pulmonary vascular resistance in the CADENCE study. But those patients have an average BMI of over 30. A lot of them have metabolic perturbations, diabetes, comorbid risk. So imagine if you're able to treat the pulmonary vascular remodeling and offload the pressures and treat the patient more holistically in terms of their metabolic risk, then that's quite tantalizing and of course, we have clinical data at the point of the deal, we had multiple ascending dose data up to 20 weeks that did empirically observe actually 0 of the adverse events of concern.

Wow, that's really exciting because it is a patient population with so much unmet need and with kind of adverse events that they do have to navigate today. We began pivoting towards kind of the metabolic angle, and I think you've got a product in development. Can you hear -- can you share, sorry, some thoughts on the potential differentiation of your asset versus kind of some of the experimental other FGF2s in development and REZDIFFRA? And how do you think about the MASH subgroups relative to the opportunity for your asset?

Yes. So I'll start off with what attracted us to acquire Boston Pharma and access that program was the observations of what was achieved across the class with FGF-21 analogs. And that was unequivocally transformative observations in cirrhotic F4 MASH, where something that was thought to be impossible just a few years ago was demonstrated that you could actually reverse the patients and shift them from cirrhotic disease to non-cirrhotic disease. And that's enabled based on the clear benefits on fibrosis and reversing fibrosis. And that's in a setting where none of the other mechanisms you mentioned have had any degree of efficacy. So for example, semaglutide has been tested in F4 cirrhotic MASH. And what was observed was an effect that favored the placebo arm over GLP-1.

So I think FGF21 has a very clear, compelling and important proposition in cirrhotic MASH, and we know that those patients have an incredibly poor outcome. In F2/F3 MASH, again, fibrosis improvement is the single most important factor that predicts improvements in liver-related outcomes. But actually, the mechanism is also a pretty potent metabolic modulator. So it actually was initially developed for severe hypertriglyceridemia. So it does improve atherogenic lipids alongside best-in-class fibrosis improvement. And collectively, what that means is you've got highly competitive data for MASH resolution and then you've got best-in-disease data for fibrosis improvement. And importantly, a mechanism that's probably entirely additive to GLP-1 agonist or as you say, resmetirom. And actually, there was a clinical data set that was really important for us when we did the deal, which was a study undertaken by Steve Harrison in Oxford, I think, in collaboration with Phil Newsome, where they had patients that were on stable GLP-1s and then they were given an FGF21 analog.

And what you saw there was that the benefits of the FGF21 were completely additive on top of the GLP-1. And then our products, we were the first major pharma to transact on a deal for an FGF21 agonist. There was a number of factors that related to that, the most simple being that it's a monthly dosing proposition in a portfolio that as you have highlighted in this chat has significant conviction around the benefits of long-acting injectables. There was other attributes. We saw the ability to scale manufacturing better with mammalian glycosylation, very low antidrug antibodies observed. But really, it's the class that we found incredibly exciting. And then finally, I described this completely unique proposition in cirrhotic MASH. That pathology is quite adjacent to alcohol-related liver disease, which is actually the main driver of liver transplant in developed countries.

And so if it's effective in F4 cirrhosis, we think that derisks a completely open area for a number of reasons, stigma and otherwise, a prevalent life-threatening disease in alcohol-related liver disease. So the proposition then is if you're a clinician, do you really want to be trying to weigh up the impossible task of is this patient's disease driven mostly because of metabolic risk, mostly because of alcohol intake, which, of course, fluctuates as well? Or do you want a product that's effective in steatotic liver disease irrespective of etiology or stage. And so I think that proposition is why we think it could be an incredibly important product.

Fantastic. Super, super helpful in understanding that scope and ability to apply that asset across the range of liver issues there. As we've been discussing kind of some of these assets, many of them have come in through external acquisitions, external innovation, I think, 35Pharma [indiscernible], Nuvalent even recently. How do you think about the role of M&A or licensing in building the pipeline from here? And perhaps if you can make some comments given the breadth of your role and the contemplation of early research in China and how you're assessing that external versus internal trade-offs?

Yes. So I think that there's now an appreciation that the conventional model of you do some target finding, you operate in a discovery setting, 5 years later, you look to test whether that's relevant in humans. You then have a sort of transition to development product mindset. You might have not generated evidence that actually would be really important for trial design. You might have generated evidence and delayed the product for things that aren't -- don't -- aren't material to how you're going to develop the product. That world has changed now. And so for us, it's really a case of how do you build the translational confidence that circumvents that.

So can you build an understanding of a mechanism in a way that allows you to apply it directly to the patient population study. And in doing so, therefore, short circuits the long runway of "discovery." I mean a good example of that is what we've just discussed. IL-33 has been around for a while. The first-in-class players weren't the ones that were successful. It was trying to deconvolute the target to trait pairing and sometimes just tweaking the population and eligibility criteria in a trial is enough to overcome the heterogeneity of that disease. And so then when you think about that in the context of BD, we don't want to be testing for the relevance of the mechanism in biology with a potential 0 value proposition. And our CEO, Luke Miels has been very clear on that, that he wants to take forward derisked biology and immediately test for differentiation and the product proposition rather than whether this matters at all in the disease process.

That doesn't necessarily mean the biology has been derisked for everyone. It means can GSK bring the best of our translational understanding and apply it to data sets ideally to have a proprietary interpretation of that and interpret it as derisked and take it forward into late-stage development. HS235, which is the pulmonary hypertension program is a good example of that. It's an early-stage program, relatively small data set in Phase I, but enough to understand the relevance of the biology and the mechanism of the disease process, the potential differentiation proposition and then a relatively tractable small study to be able to confirm that and advance into product development.

China is the same enabler, right? So you're able -- you don't have to undertake 10 years of discovery and biology activity. You can circumvent that. We take our translational data sets and understanding around human causal confidence. And then we're able to test that at a pace that is unmatched today and probably will remain so. And so we've established something that we've labeled the China -- the global China translational hub, where in partnership with companies like Hungary, we're able to, again, tell our biology teams, you've got the privilege of taking that understanding of human disease and applying it in a way where you can truncate that the distance from insight into trial design into product application.

Yes, absolutely. And kind of one of the other things that came to mind as you were speaking through those elements is where AI might be helping you and your teams in the most material ways. I mean we've had some various players on the stage here today, some that focus on applying AI in the discovery space, some that focus on applying AI in the development space and kind of perhaps with a more operational orientation, but can be equally as important in some respects in terms of outcomes. You've got obviously a pretty long purview in the company from that discovery all the way through in some of these indications. And so can you just speak to what you're seeing at the moment in terms of the potential for application, the potential for real impact today versus the hopes for the future?

Yes. So what's established and now business as usual is the application of AI to efficiencies, and those efficiencies range from real-time intel on trial enrollment across the global footprint, integrating that with competitive intel and insights, automated development of regulatory documents, so some pretty high stakes activity. So we've been able to reduce cycle times from completing a study to developing first draft of modules for a submission to regulators based on automated development of those documents. Medicine design, again, I think every company has to be using AI for both small and large molecule design. But the grail that I think everyone is focused on is can you use AI to reason over novel -- I'm not going to call it discovery, and I'm not going to call it target discovery, but target trait pairing.

That's really our job is how do you understand whether your target is interrupting a disease process in a precise patient phenotype. And that's where we do have examples that I'm hoping will be substantiated shortly where if you're able to integrate multimodal data sets, and you hear that phrase, but just to kind of highlight what does that really mean? A multimodal data set could be, for example, how do you relate an observation from a cell phenotype to an imaging trait to a clinical functional outcome in a manner in which it informs how you match that target, as I say, to a patient population.

That's quite difficult to test through conventional a priori statistical methods. And we're seeing this more and more that, for example, you can learn something about, for example, what's happening in your lung alveolar macrophages based on what's happening in your bone marrow or you can understand a fibrotic pathology through a nonfibrotic cell type. And so I label that as these latent spaces of information that have been untapped based on conventional methods. If you're able to host the data in the correct environment, and that brings lots of really important but boring things around the ontology of the data set, and you can layer on top of that the appropriate tools. The tools are largely commoditized now and then query it with the right clinical and biological insights so that you're not unbiased because the universe of biology is too vast, but you're able to skew those queries and frankly, curate the right data so that it has a higher yield and likelihood of surfacing something meaningful, then I think that gets us to that grail. And we've got an example of that. I shared with someone earlier today that 2 years ago, we had a Meet the Management event and one such environment where we're able to integrate genetics, genomics, imaging data, clinical trial data was in COPD.

And whilst I think some of our competitors were empirically testing bispecifics through trial and error, we systematically looked at every single combination in that multimodal data environment AI-enabled and simulated which of the combinations is likely to be redundant, additive or synergistic. And we disclosed at the time, and we were the first to describe this combination that TSLP33 was the combination that would give you additivity and potentially synergy. And at the time, that wasn't very well understood external to us why that could be the case because the jury was out on IL-33. And now after last month's data readout at the ERS, it becomes very clear that and logical, and I think now we're going to see a wave of activity around that combination approach. And we applied that, of course, to a pipeline that's developing approach with that combination. We actually just started a Phase II study where we're co-administering our 2 monospecific antibodies. And actually, we're using our presence in China to expedite that through to demonstration of additive efficacy.

Fantastic. And one other kind of practical question about this. How much is this changing the way that your teams work or the way that you're thinking about your organization kind of over the coming years? And are you needing to kind of build things internally? Or are you able to kind of get solutions off the shelf from vendors that are able -- enabling you to kind of make some of these advances? I'm thinking all the way through development.

Well, I think the magic happens, as I described, in the integration of those different enablers and domains. So the good thing is GSK wasn't early -- recognized very early the influence that AI was going to have. And so we do have 150 AI engineers internally in a dedicated group in R&D who have built proprietary tools. And so we're not dependent necessarily on external frontier models. Again, we invested time to make sure that we were accessing data sets that are likely to have yields when applied to these technologies and hosting them in the correct environments. And we, again, were a company that made an early recognition that those had to be human data sets rather than animal models that don't translate.

And now having the correct end-to-end mindset and increasingly, physician scientists are leading discovery and translation through this kind of reverse translational approach where you take a clinical observation that might come from a large routine health care data, you qualify the causal association you might have observed with high confidence human causal instruments like genetics. You design the right pharmacological perturbation and clinical experiment to be able to test that and then it seamlessly transitions to product development. So what does that mean for an organization design? It means this kind of siloed chronology of sequential, as I said earlier, discovery biology, going through the motions of IND enabling, start to think about trial design, start to think about a medicine profile. It's collapsed into basically a single effort that happens frankly, at a single time point. And what that requires from a people point of view is the right experts that can think across that life cycle of an asset, the right data sets to be able to access and query and the right tools to be able to enable those queries to inform actionable insights that inform product development.

Fantastic. It sounds like there's a lot of opportunity ahead, both with the pipeline you already have in hand and the work that you're doing to continue to build that over time. And it sounds like there is some exciting innovation, not just on the kind of biology or pipeline, but innovation in the way that you're doing things as well. So thank you so much for your time today. It's been an absolute pleasure to have this conversation with you.

Great. Thank you, Courtney.

We'll kick off the next session. Thank you very much, everyone. It's Sachin Jain here from the European Pharma team. It's my pleasure to introduce Glaxo. From the company, we've got Julie Brown, CFO, which is very timely just after the recent CMD, also IR folks at the front.

So we'll just do Q&A. I think, Julie, if that's all right.

So we'll just kick off big picture. We're just on the back of the CMD, where the management team outlined sort of new strategy, new midterm targets, et cetera. So perhaps you could just see that as an intro to this session.

Yes, sure. Good morning, everybody. I'm delighted to be here, and thanks to Sachin for the invitation. So yes, we recently did a presentation at the end of July. And the work that led to that was really 2 major work streams. The first one was all about how could we accelerate growth, how could we accelerate the assets within the company. That was led by Luke, our new CEO, and it was all -- it was called the Strategic Portfolio Review.

And then on the other side, we were looking at how would we fund the acceleration. So we were determined that it would be a sort of self-funded situation. And we looked at how we could simplify the organization to drive that funding, which resulted in a funding saving of GBP 1.9 billion that we could then put on the right-hand side in terms of strategic portfolio review. And through that work, we came to the conclusion we wanted to accelerate 7 major assets across about 18 indications. And interestingly, there was a big emphasis there on the oncology portfolio and the opportunity that, that gave us.

So net-net, as I mentioned, it resulted in GBP 1.9 billion of savings. And we decided to say the majority of that would be funding the pipeline. But what we also said was there'll be an element that would drop through to the margin in the years that people were concerned about, which are the years where we lose the dolutegravir patent in HIV, which is 2028 to 2030.

So it gave us the ability to say through that period, our margin will be stable to improving. So the organization I think we were really proud of the communication. We were pleased with the reaction to the market. I can tell you now when I was in the U.S. last week, working with the team in the U.S., we've got a lot of change going on in the organization. It's caused a level of energy around those projects, together with an energy around how we can simplify further and drive further productivity in the business.

And I think very importantly, we've built a track record now of being able to do this well. Over the last 5 years, if you think about the '21 to '26 period, we've actually delivered strong top line growth, more than 7% sales growth as expected, more than 11% profit growth as expected during that period. This is all based on guidance for this year. And together with an improvement in our margin of over 500 basis points, at the same time, is taking our R&D spend up significantly. So we've proven, I think, we can invest significantly in R&D, but still deliver productivity through the P&L.

Okay. Very good. So I'm going to kick off with some of the common questions I get asked on the big picture. So obviously, the target is greater than GBP 40 billion. Consensus, I think, is in the mid-high 30s. What do you think the biggest deltas are as you now look at it versus consensus?

Yes. So consensus is now at GBP 36.4 billion, not that I count. But it's at GBP 36.4 billion.

So the biggest deltas -- and to my mind, it's quite usual to have a gap sometimes between the company and the sell side because typically, I've done extensive work on this when I was in one of my former companies was with AstraZeneca for a long time. Typically, the sell side pick the asset up when it reaches a certain degree of maturity and it's got certain data behind it. And so this is quite a pattern.

But the largest area -- I mean, there are puts and takes across -- I've charts in my mind, there are puts and takes across the board. But the largest area of difference is oncology. And there, you've got a difference coming through with the ADC portfolio, Mo-Rez and Ris-Rez. We just had fantastic data on Ris-Rez just recently at World Lung. But that's one of the areas of difference. BLENREP is another area of difference together with small differences in products like Jemperli. And again, Jemperli, we've got endometrial cancer on the market. We've got rectal cancer just read out.

And we've also got colorectal coming, and we've got head and neck coming in '28. So because of this, you get the recognition of the indication isn't fully accepted until it comes through. I emphasize, all our forecasts have got PTRS adjustments against them to probability of technical and regulatory success.

Do you put almost the entire delta to oncology? And are there any -- you sort of have puts and takes. Are there any assets where you think consensus is too optimistic that then drives the oncology delta even bigger, if that makes sense?

It does. I mean I wouldn't want to go into the specifics because the other difference is you get puts and takes of, say, GBP 0.5 billion across the board. And there are elements where the market is a little bit stronger and there are elements -- and it tends to be the newer products that's a bit slower to recognize. So consensus is a bit slower, for example, with some of the HIV innovation. It's also a bit slower with Excentia. And we can talk about Excentia...

I get both of those. I guess my question, I sort of left it open, but you think HIV cliff is roughly correctly modeled in consensus?

I don't want to be drawn in to guiding by therapeutic area. I think we've come a long way with HIV. I think the market was concerned that the patent expiry effectively started earlier than it did in material terms. I think we've established now and the market consensus is much closer that the material impact on HIV is 2029 and '30 because we lose the Dovato patent in December '29 and Juluca in July 2030. And this is in the U.S. because the U.S. is the material point. And we've got a whole strategy around protecting that business.

And from the top line, we'll do big picture margin, and I'll come back to specific products. So shape, you sort of alluded to the bulk of the savings drop through in the '28, '29 period. But just perhaps you could just give us a sense of the shape of the margin. What I'm getting to there is the Nuvalent sort of comes in next year, bit of Trelegy pressure and then the savings, I think you've referenced is coming through more '28, '29. So do I think of that as more flattish or whatever wording is for next year and then an inflection in '28 or whatever color you can give?

Yes. I think we've sort of decided not to guide the margin year-by-year. I think -- I mean, as you know, there are so many moving parts in the business. What we're confident of is that the savings -- I mean, just come from internal -- doing internal work on this. We're absolutely confident these savings will come through. We are confident because of the amount of work that's gone on into the margin -- the integrity of the margin going through it and also the drivers of that in terms of, number one, the business is more and more moving to specialty, which means it's a very selected specialist sell, which means you get margin accretion coming through from specialty.

And the specialty part of our business, I mean, it used to be when I joined in the beginning of '23, we were 1/3, 1/3, 1/3. We were 1/3 vaccines, 1/3 specialty and 1/3 Gen Med. We're now just over 40% specialty. By 2031, we're going to be over 50% specialty. So it gives you a natural lift to those margins. Secondly, we've got the Accelerate Growth program, as you say, when the savings have come through, GBP 1.9 billion coming through by 2029. And then also on top of that, we've got this drive for productivity that we started a number of years ago. And you've seen the evidence through the margin accretion and through our SG&A to sales ratio coming down. And that's where you'll see the bulk of the impact of the change in our business as we're driving the SG&A down through productivity, and we're driving R&D up.

And I then move on to launches, especially the ones that are ongoing, BLENREP and Excentia, there was sort of a narrative of you've obviously been clear on both, we're going to slow and take time and potentially inflection post J-code. Now the data we see that's not particularly obvious. And so the simple question I get is 2Q sales were, if combined, around 60 consensus. Next year is just shy of 800. That requires a lot of lifting from here. So just how do you think about how the curve inflects and level of comfort to the extent you want to comment to that consensus number next year?

Yes. So let me take the 2 products, Excentia and BLENREP, I'll take them separately. And I was -- I spent last week in the U.S. with the brand teams actually just talking about the overall position. So with Excentia, I'll come back to your point about the J-code. Excentia is a 6-month treatment for severe asthma. It's groundbreaking because it's a biologic, and it means basically that somebody is protected with just 2 injections a year and it's got very good data underpinning it because it's a 72% reduction in exacerbations that cause hospitalization. So fantastic data.

That's the good news. The bad news is because it's 6 months, it means that there's a big outlay for the physician if they are wanting to prescribe it to a person. And therefore, there's a system in the U.S. called the Buy and Bill. The problem, therefore, before you've got the J-code, and it's interesting, there was a lot of emphasis on the J-code, but it's not just the J-code, it's the administrative part of the J-code taking effect in the insurance system. And that's happened just a couple of weeks ago.

So therefore, the J-code was the 1st of July. I think people thought it would be like this. It's not like that. But what's happened now is we would expect having removed one of the largest barriers. And when we do physician-to-pysician research, you find that the actual outlay, the initial economic outlay for Excentia was seen to be significant because it was 6 months rather than 1. That's a big change. And therefore, now it goes into the administration, it goes into health insurance plans. That barrier to actually prescribing it, knowing that the prescription can be fulfilled is going to be very different as we go into the fourth quarter.

Okay. So as J-code happened, but it still needs to work through the administrative system, which has just happened and we should see an inflection fourth quarter.

So the administrative system piece was a couple of weeks ago, and then it's got to go from there into the plans, whether it's Aetna or United or whoever it may be going through into the plans. That's only then is the physician assured of getting reimbursement.

I touch on 2 other topics. So payer coverage the last time, I think you commented was running like 50%. And I think I asked a question at one of the breakfast that, that sort of typically needs to be north of 70% to see physicians comfortable enough to prescribe. Where are you with payer coverage?

I think this is a topic that we definitely will cover at Q3. I mean it's moving as we speak. And like I said, I was in the U.S. last week. And so I think let's pick it up as part of the Q3 because literally, the contracting piece is critical. Now you've got the administration and you've got the J-code.

That unlocks payers, if I...

Unlocks payers. It unlocks payers.

And then the third bit was the bridge program.

You -- did you want to talk about...

Yes, I'll just do the bridge program on Excentia, then we'll go to BLENREP.

Okay. Yes. So we had a sort of an access program running. In this period, in particular, it was more -- it was required because of this -- the reimbursement piece. That's gone well. I mean it would go well because it's an access program. The key thing is once you've got the insurance coverage in place and the reimbursement in place, it's actually then moving those patients from the access program into commercial.

Because you're dealing with a 6 months, this is one of the -- 6 months is fantastic, but it's also got some disadvantages. You've got to wait until the next dose is ready before you're doing it. So yes.

Okay. Very clear. So some updated 3Q payer coverage bridge program...

The team are very comfortable with how it's moving. We've got a fantastic guy in the U.S. who's in charge of this area. And yes, I left feeling optimistic, but understanding much better about the dynamic in the U.S. market.

Let's see BLENREP then.

Yes, BLENREP. BLENREP is different. BLENREP is different because with BLENREP, we always said we would go slow to go big. So BLENREP has got a history, as we all know. And the benefit of BLENREP is it's got fantastic data for those who are not so familiar with it. It halves the risk of death from multiple myeloma and it triples progression-free survival. So the data is fantastic. It is going into an area of the market that currently is quite unmet because 70% of the patients in the U.S. are community. They're treated in the community. And most of the other therapies that have got that level of efficacy that I spoke about at the beginning, you need to be hospitalized to be able to have the treatment CAR-Ts and bispecifics.

So BLENREP is a 30-minute infusion that can be dealt within the community, a very, very different situation. So there's an unmet medical need. The problem with BLENREP is it's got eye side effects. And the reason, therefore, it has to be very carefully monitored. And in the U.S. before each dose, the eyes have got to be checked. And we found through the trials, DREAMM-7 and 8, that there is a resolution of the eye effect as long as you elongate the dose, but the physician and the patient have to understand that the efficacy is not lost if you elongate the dose. So it's got to be managed very carefully.

And we really wanted to ensure that it was almost a white glove treatment with physicians and with patients also understanding this and basically managing this situation because you've got to connect the physician say yourself with the eye professional, say, Constant on the front row and the 2 of you have got to work together before you can carry on with the dosing. So net-net, we wanted to deliberately do this. And also, we feel that physician to physician conveying the experience is an important part of the uptake. We never thought this would be big, like big soon. We thought it would be big over time. The other important factor with the U.S. is we've got registrations now in over 50 countries.

The U.S. is the only country where it's a third-line label. Everywhere else, it's a second-line label, which means it follows on from Darza from J&J. So the advantage in most of the countries is you're going in much earlier, you probably saw the nice data that BLENREP got a leading share in second line in the U.K., which was the first country we launched in. The U.S. isn't going to be in that position because it's going in third line. That means the patients are usually older, frailer, more difficult to get a positive experience than it is in second line. So net-net, we'll go slow to go big.

Okay. So is it fair -- I'm not putting words in your mouth, but Excentia good level of comfort that we get there 27 payers administrative. BLENREP, sounds like you -- it's tracking as you thought, and consensus may have got the shape wrong short term.

No, I'm not saying that actually. I'm not saying that. As you say in aggregate across the 2. No, I'm not saying that consensus has got it wrong. Don't take that message.

Just, I guess, recognize the dynamic underpinning it, about why you don't go up in a way that some products do. It's a different characterization of the product.

Very clear. I'll move on to some other launches, if I may. So hep B around the corner. We had a physician survey, tough to model, where is the level of excitement targeting. I think Nina has talked to sort of 5 or 6 states, which there's particularly amenable. So just any updated thoughts on how you're thinking about that launch, pricing, cadence?

Yes. Well, there's been -- it's interesting this one because when I first joined and people were asking Tony what he was most excited about in our pipeline, which is almost 4 years ago. His answer was bepirovirsen, which tells you something, but he was excited about it all those years ago. And the reason, as we know, is that it's basically giving 19% like 1 in 5 people a functional cure and it's reducing surface antigen far further. So net-net, you've got like 49% of people benefiting from this. And together, it's taking the surface antigen level down to a level that should not cause liver cancer. So it's got very, very good data.

I think as Nina mentioned, the commercial opportunity is in 3 countries: China, the U.S. and Japan. We've now got approval in Japan and the pricing negotiations are ongoing. So net-net, we feel we're in a strong position in Japan. China, the population affected by hep B is huge. It's like 75 million. And in China, there's a lot of stigma associated with the disease. In the U.S., the other countries have comprehensive testing for hep B. In the U.S., it's not across the board.

And so therefore, we find there are certain states in America, usually the California, the West Coast, together with Florida, together with some on the -- in the South actually, in the Southern states. So those are the major states where it's most prevalent and where we believe there's an opportunity.

We're excited about it just because key opinion leaders, and you may have seen some of the calls, I'm sure you joined, they said this was transformational. And it is transformational because previously, these people were on NUCs and the functional cure rate was a single-digit low percentage. And they felt like they got flu all the time, but they were on them. With bepirovirsen, they take it for 6 months. And then basically, for 1 in 5 people, it leads to a functional cure.

And halfway through the treatment, they get a good readout about whether they will be the 1 in 5 or not. So net-net, we're hugely excited. Again, I was with the U.S. team that are leading the charge on this. The excitement is phenomenal, really, really. And we've got, again, a very, very relatively new appointment on this team.

I'll take China first. So China approval from memory is mid next year?

I'm expecting it to be.

How long -- you talk to the payer dynamics in China to get this going because obviously, you referenced it as a huge opportunity. So we think about China as a '27 or more into '28 sort of dynamic?

Yes. As you say, and you've done a model also on this, probably bepirovirsen is one of the harder products to actually model for us as well as probably for you guys. And I think it depends on -- obviously, you've got reimbursement and you've got access points. But you've also got how the testing works, how the follow-through works and just whether people have often asked us, are you dealing with a bolus or are you dealing with an even growth with this one? You could be dealing with a bolus because those patients who are already on some form of the diagnosed, they're being tested, they're on some form of treatment, there's likely to be a high rate of switch of those people. But in terms of guiding on each year and guiding on by country, I can't really get drawn into that. And it's a really hard call.

When you meet with the U.S. team, do they give you a sense within your 5, 6, 7 states how they sense the size of that bolus. I mean I've got KOL feedback. Just interested what your team say on that.

They're giving -- at the moment, we're doing -- we call it the plan, we do the plan internally at the moment. There are -- there's not a single case. There is not a single case on this one. I think it's hard. So for new launches, you normally deal with a wind sock around it depending on a whole series of factors. We did the same with Excentia actually. And this one is difficult.

Even broader.

It's even broader. It's even broader. And it's those -- it's for the dynamics because of the dynamics we've talked about.

Last one. I think at the CMD, Nina alluded to hep C type pricing, not exactly, but what's your payer reception to that if you've had the conversations? Because again, our KOL feedback is the functional cure rates are a lot lower than hep C and therefore, a bit of surprise on that pricing. But obviously, you must have had those convos. So any color you can give there?

Yes. I mean we're relatively comfortable with the comment around pricing. I think it's because the data is so phenomenally different from how people are currently being treated. And previously, the treatment with NUCs was just so -- the side effects were so serious and the benefit was so low.

This is probably why key opinion leaders say this could be transformational. Against, I think something like 75% of liver cancers are caused by hep B. So again, transformational for people, transformational for health care systems.

Move on to the next set of launches. So Nuvalent assets.

So just I think one's come, one's pending. I think your commentary has roughly been consensus and roughly the right place. But again, excitement, launch prep, et cetera, as we think about into next year.

Yes. No, again, the oncology team in the U.S. at the moment are on fire because of the Nuvalent. We met some of the members of the Nuvalent team as well. We're delighted, obviously, with zidesamtinib because it was -- its approval was ahead of its PDUFA date.

And we're very, very well prepared for the launch. It's underway. Patient recruitment is going strongly. Yes, I mean, our U.S. head and the team are, I think, really proud of that one. We've got neladalkib, which is of the 2, the larger opportunity. Neladalkib initially will go into second line. The PDUFA date is towards the end of November.

And again, all the preparation is going extremely well for the launch, including recruitment ahead and everything else. So yes, neladalkib is looking very positive. Again, the data from neladalkib is, as you know, it's a fourth-generation ALK. But the data is very compelling when you compare it with current lines of therapy. Lorlatinib, it's got a much more tolerable profile to lorlatinib. These are young patients in the 40 to 50 age group, usually females.

They want to be able to work. They want to be able to go out and do things. And unfortunately, the side effects of some of the competitor products have not enabled them to do so because it can lead to psychosis and it can lead to serious weight gain. So net-net, we feel very proud of the profile of neladalkib.

The big opportunity for neladalkib further down the track is the first-line indication, which comes a number of years later and the trials are ongoing associated with that. So yes, we're very pleased.

Since you mentioned, I was going to ask, but you said a number of years later, frontline, you haven't really given a lot of color on time lines. I asked the question on CMD, 35% study recruited is a little bit slower to me. So that feels like '28 '29 read. Is that roughly correct? We should be thinking about that inflection sort of towards the end of your forecast period?

We see it in that sort of time frame. The recruitment is going really well. I'm not sure when you got your last data set.

CMD.

Okay. So it's a couple of months. Yes. No, I mean, obviously, I was in the U.S., better not give all the information that we're going to give at Q3. But the recruitment, and it's a good sign. And I think because of the side effects of current -- you got 2 things going on, efficacy on the one hand. And neladalkib is still going strong. It's 84 months overall survival. Some of the competitor products are so much less than that.

They've got a more tolerable profile, but they're dealing with much shorter. The one that obviously lorlatinib has got a longer duration of effect. The problem though is the side effects are serious. So you've got a combination here with neladalkib of tolerability and efficacy. And that should be a winning formula. So again, we...

But we should think about some update on patient recruitment at 3Q, but the time line is towards the end of your forecast?

I wouldn't say because we go to the end of 2031. I mean we're seeing '29. And we think the uptake on that should be very strong because the market conditions and the market competition is relatively weak compared with the profile we've got. We're excited about neladalkib.

So I've gone through a lot...

To your point, the centers are up and running together with the patient recruitment is quick, which is a very good sign of a successful product when you've got a strong uptake.

Okay. So we've gone through a lot of launches and positive drivers into next year. Perhaps I could touch on or perhaps you could think list for where you think some of the headwinds we should think about. I have my list, which is Trelegy, IRA sort of vaccines, annualization and the bolus. But just if you could comment on those 2 and anything else we should think about for '27?

Yes. I think for '27, the major headwind comes from Trelegy, I think in terms of step down because we've got the pricing impact through going into the IRA. And we factored that in, and we've known it's been coming for quite some time, and we factored in very early on. So -- and actually slightly better than we anticipated originally when we were guiding a few years ago. So Trelegy, I would definitely call that out. I think in terms of, obviously, the major other point is that the product -- some of the products now that have been driving a lot of growth become harder to lap the higher base. You see that with Shingrix to some degree. Having said that, there's a big opportunity with Shingrix still because we are only 12% penetrated in the rest of the world versus 45% in the United States.

So there are still growth opportunities with some of these products, but you're just on a much higher base. I don't think there's anything else to call out because there are also growth drivers coming through Excentia, BLENREP, Nucala COPD has grown very strongly. And one of the benefits we found with launching Nucala in COPD, which again has got good data is the halo effect then on severe asthma also has a benefit.

So yes, I don't think there's anything else major -- -- we start to see some HIV erosion coming in, but it's in smaller markets, but it's not eroding HIV overall. Like it's just a downward pressure.

Any other specialty products you call out base effects?

No, I don't think so. No major...

I might have missed it, but have you guided to the Trelegy IRA impact?

We haven't given the specifics of it. And important to remember with Trelegy, it's one of our highest rebated products. So sometimes people look at the list prices and say, okay, we're dealing with a major issue. It's heavily -- it's got a very significant RAR on it. So net-net, we haven't given the specifics of it, no.

I'll ask the question the answer as you will. So Novo basically on Ozempic, which everybody is saying because IRA have been no deviation to historic pricing. The average IRA price cut is like 20%, 25%. So should we be thinking about that sort of top to tail for Trelegy next year?

I wouldn't be drawing any further on. It's all in the forecast. It's all in the guidance, all in the forecast.

Okay. So if we move on now, and I'll do the sell-side CFO question for me. So I will ask it on the third quarter, but we've sort of done the top line pushes and pulls for next year. One of the -- and you sort of referenced in your intro, one of the hallmarks of your tenure or at least recent years has been the operational financial leverage. I'm less clear and just interested as to how that plays for '27?

Nuvalent, both margin impact and net financial impact. So -- and I'll ask the question answer as you will. But should we think that pattern continues next year with operational financial leverage? Or is it a bit tougher given what we know is coming?

It definitely -- well, I suppose it gets tougher as you drive productivity through the organization. And you see we've done quite a lot of that already with -- you've seen I've been putting pressure on SG&A to drive productivity, to invest in R&D. We've been doing it for a number of years. The reason -- the major tailwind now is the program that we recently announced, which gives us the GBP 1.9 billion. It ramps up '28, '29 are the big more significant year. So it doesn't give you a massive lift, and we're not dropping any of that through in '27.

So what we deliver in '27 in terms of leverage doesn't come through the program we just announced. It's more about just productivity. I won't guide on the specific margin in a particular year. What I can say, though, is there's no reason to see us dropping that margin. We believe that when we guided a number of years ago that we would be more than a 30% margin by '26. We are on track to be -- then we guided -- re-guided to say more than 31% margin by '26. We are on track to deliver that. We've made commitments to the market. We will deliver.

I'll move on to some competitive aspects, if that's okay on the top line. So 2, just interesting. So you mentioned Nucala COPD. And if you're with the U.S. team, reimbursement takes time, but Astra has some interesting data, PDUFA first quarter. Just interested if that is coming up in conversation as to potentially impact Nucala?

It's -- yes, it certainly comes up in conversation. Our view is Astra has some good data for sure, and they've got the benefit of being able to go across the eosinophil range. Nucala got a good label, as you know, for COPD because we were able to go quite a lot lower at 150 plus. The Nucala uptake, as you probably saw from the chart that Q2 has been extremely strong in terms of -- compared with Dupixent. We continue to see that with Nucala. It's performing very, very strongly. And together with that, as I mentioned, what we're finding increasingly is you've got -- Nucala has got a very extensive label now. It's been on the market for a while, and it's got nasal polyps, severe asthma, HES and EGPA, multiple indications. And what we find with the population is they've got comorbidities.

So it's much easier for the doctor because COPD is very heterogeneous disease, it's much easier for the doctor to have something that's more comprehensive. It really is. It's one of the reasons that we decided to accelerate Excentia indications. And as you know, instead of rolling them out year-by-year, we went for 4 or 5 in 1 effectively. We've got EGPA readout coming up with Excentia. The reason for that is this comorbid argument. Now AstraZeneca have got a very good label for COPD, but it's one in multiple. And that's a big -- I think, the big difference.

Very clear. The second one, and I've spoke to Deborah a lot about this is the lenacapavir. So I know that once weekly from Gilead and Merck. So I understand her message on reasons for protection, so we won't go over that. What I'm sort of more interested as a CFO, as you have to sort of think about the puts and takes, how do you think about that into next year and potential impact to Dovato growth in particular?

Yes, we -- like I say, we watch the competitors like hawks. I think the reason we feel strong about HIV is, as you probably know from this -- you got evidence from patients, you've got evidence from physicians. The evidence from patients when we've done assessments of what they prefer and the patient voice is huge in the U.S. They prefer long-acting injectables. And when I first joined the business, I thought why? Why would you prefer a long-acting injectable over a tablet?

They prefer them because they know they're safe with them and the frequency of the injection and the stigma associated with having HIV is significant. So 90% in the SOLAR study, this is patients preferred long-acting injectables. And then physicians prefer them and the data monitoring committee stopped that trial in LATITUDE because the data was so strong with long-acting injectables because they know they've got the protection.

So we've got 2 months on the market. We've got a readout importantly for prevention this year for 4 months. We've got a readout next year for the next one in terms of treatment. And therefore, we feel in a strong position because the preference is long-acting injectables. I mean it's great that there's innovation, but we believe injectables are better than orals.

Okay. Last topic, BD. Guardrails of what you want to do. I mean every time I see Luke, it's kind of like I want to do more quicker and bigger. So I mean I'm paraphrasing, obviously.

But just how would you talk to the urgency of continuing to add assets within the organization?

I wouldn't necessarily call it urgency. I would call it in my experience for sure, the best science is never just internal. The best science, you've got to keep your mind open and you got to be reviewing both all the time. And we have this SPR group, the people who review the pipeline every 2 weeks. We have a BD meeting. We had one yesterday every month. So we're looking at the best science in the industry and the BD team and the scouting team. There's a lot going on in China, as you can imagine at the moment. We do a lot of work in terms of -- and then we're looking together with the internals.

So I wouldn't say it was sort of urgent. I would say it was wise. I would say it was the right way to run a business. And we've got a healthy balance sheet. We -- post the Nuvalent acquisition, on a pro forma basis, we're just shy of 2x net debt to EBITDA. So we've got a healthy balance sheet, and we drive productivity through the P&L to be able to absorb more and build the pipeline.

And you've seen what we've just recently done. We've gone from 10 Phase III starts that we announced at the beginning of the year to 20. In fact, it's 21 now because we just announced mRNA over the last couple of weeks. So yes, we -- I think it's a sign of a dynamic company.

So that 2x, what sort of headroom does that give you for deal size as it sits?

It gives us reasonable -- first of all, we've got -- still got even after Nuvalent, reasonable deal size for the rest of this year. But then very importantly, we've guided more than GBP 10 billion of CGFO, cash generated from operations, for this year. So the company generates -- we've been able to generate capacity to be able to do the Nuvalent deal, and we've continued to do that because one of the other things I'm focused on is the conversion of profit to cash, which has improved a lot if you look at the data over the last few years because we've got a team focused on just that conversion.

Last one, just because I'll get -- is the next, are you focused on a more Nuvalent-type larger deal? Or are you sort of done that and we're sort of back to the smaller earlier stage stuff?

It's entirely dependent. I mean I've got the list in my mind as I'm answering this question, entirely dependent on where we won't be driven by late or early. It will be driven by the quality of the asset. And yes, it will be the quality of the asset that will win through.

Perfect. Yes. We're up on time, Julie. So we've covered a lot of ground there. So thank you very much. Thank for the rest of day and great session.

Thank you.

So good afternoon, everyone. Thank you for joining this session for the GSK fireside chat. For those of you who don't know me, I'm Sarita, European Pharma Equity Analyst at Morgan Stanley. And I'm very pleased to have Hesham with us today, who heads up oncology at GSK. Thank you very much for joining us.

Before we get started, just some housekeeping, which I'm sure you've all heard. But please note that this presentation is for MS institutional clients and employees. For important disclosures, please see the Morgan Stanley research disclosure website, at www.morganstanley.com/researchdisclosures.

Okay. So with that, let's get started. Perhaps we can start with the overall oncology strategy. At the Accelerate Growth CMD, you laid out kind of a much broader opportunity across lung, prostate, GI, gynecological cancers and then significant late-stage investments. So when you think about oncology today, where do you still see the genuine gap? Are there areas of oncology that you've deliberately chosen not to go into? And where are the areas of interest moving forward?

Yes. Well, Sarita, first of all, thank you very much for the kind invite. It's great to be with everyone today. It's great to be at this conference as well, too. I know I was here last year as well, too. So fantastic. With that in mind, probably just kind of reflecting a little bit on the past 4 years of oncology at GSK. I think everyone is well aware, of course, that we had stepped away in 2014. We've come back. But I think probably if you ask me what was the secret recipe in all this, it's focus. It's focus. It's being very methodical in terms of how we've approached the rebuild that's taken so far with GSK.

It's not often that a big pharma company steps away from the field of oncology and then tries to reenter it. And then when it reenters it, it starts to have a lot of great success moving forward as well, too. But I think it was probably owing to a number of key variables. First, we really tried, to your point, focus on disease areas where we felt like the unmet need continues to exist and where we can establish key capabilities across talent, disease knowledge and of course, better characterizing the biology of the disease as well, too, to help drive discovery research efforts, but also a translational focus as well, too. Let alone the fact that not only did we rebuild these capabilities in these key disease areas, but also we reestablished our medical affairs presence and commercialization efforts as well, too.

We started first in key heme malignancies, so across multiple myeloma and myelofibrosis. I think everyone is well aware, of course, BLENREP and momelotinib or Ojjaara has kind of been the key pillars in heme malignancies for us, but also building on the success that we've had with ZEJULA and of course, dostarlimab as well, JEMPERLI across ovarian and endometrial cancer, respectively, in gynecologic malignancies. And from there, we started to continue to add additional tumor types that we felt like, again, where our capabilities could be built and the depth of experience could be developed, and then where we felt like the unmet need continues to exist.

And so now that has expanded to thoracic malignancies, lung and head and neck, GI malignancies with a focused emphasis on colorectal cancer, again, building on the success that we've had with JEMPERLI. And then finally, now starting to move into prostate cancer as well, too. Certainly, we just are starting to initiate 3 Phase III studies with our B7-H3 or Ris-Rez antibody-drug conjugate. But we're also building a portfolio of assets that are giving us a good critical mass across different therapeutic modalities in prostate cancer as well, too.

This has all been, I would probably say, a mixture of organic growth, so in-house portfolio discovery research efforts, but also inorganic growth, a lot of business development. You've seen some of the recent BD deals that we've done. I think probably Nuvalent is the most notable. But then at the same point in time, just this morning, we announced another licensing for a trispecific immune cell engager in multiple myeloma as well.

Perfect. And you touched on BD M&A. So Nuvalent was perhaps a much larger later-stage transaction than we've seen recently in oncology for GSK. Should we think about Nuvalent as a one-off opportunity? Or has that changed the size that you would look at in oncology? And perhaps because you mentioned it, you can touch on the T-cell deal from this morning, too.

Yes. I think it's a really key question. Probably over the past few years, if you ask me about what is the philosophy that we've had around our business development activities in oncology specifically. Well, I would say, first and foremost, there is a framework that we follow. And the framework goes along the lines of the following: One, is the licensing or acquisition going to address a key unmet need that we feel like is very unique at this time. That's the first point. The second really is around the medicine or the medicines that are involved and specifically with regards to are they differentiated in the context of their medicinal design, in terms of their mechanism of action, in terms of the pharmacology and the properties that they offer? And do they provide what is the potential for a best-in-class profile?

The third, is there preliminary clinical data that exists that gives us additional confidence in the probability of technical success of the assets? And then the fourth, of course, does it align to key strategic disease areas of interest for GSK and where we have these capabilities that have been developed across R&D, medical and commercial. And when I think about Nuvalent, I mean, certainly, it's not just a singular asset. I think we have to think about it. It's not a 1 asset deal. It's actually 2 key assets, and then there's also a discovery pipeline of programs as well, too.

The 2 key assets, of course, are neladalkib, which is a fourth-generation ALK inhibitor with a best-in-class potential. And then, of course, also zidesamtinib, or JIDEYTRO, which was just approved in July of this year in ROS1-mutated patients as well to ROS1-positive patients as well. Again, 2 assets. I think the deal size quite large, but we've also done deals across the board. So everything that has ranged from $1 billion to $2 billion. So for example, the Sierra Oncology acquisition for momelotinib was about maybe $2 billion. The IDRx acquisition for velzatinib was about maybe $2 billion. And we've done larger deals.

I think that the bottom line really is it depends on what type of synergy complementarity and the profile of the deal itself and how it adds to our existing portfolio. I think if you look at Nuvalent, for example, I think it probably now gives us that piece that helps us kind of form what is a franchise in lung cancer, 2 different assets, highly differentiated, best-in-class potential. And then we have our Ris-Rez B7-H3 ADC, which we actually just presented certainly through our partners' Phase III data for at World Lung. And we've got a lung franchise that's emerging as well for us in that context as well, too. So moving forward, what do I expect in terms of deals? I think probably across the range of everything that we've done from either licensing like this morning, of course, this trispecific T-cell engager in multiple myeloma to acquisitions that we've done like IDRx and certainly Sierra Oncology. And when it happens, and it depends, certainly larger deals could exist if they present themselves as well, too.

Okay. Very clear. And I do want to get into Nuvalent and B7-H3, as you mentioned. But before -- when we think about 2031 sales and the overall GSK target for over $40 billion of sales, and I appreciate you're not commercial, but maybe thinking about it in a different way, what are the 2 or 3 most important oncology assets to achieving that target? And where do you have the most conviction?

Yes. It's -- probably it's an interesting for me time to reflect on the progress that we've made, but also where the pipeline is at right now as well, too. I think if you look at it, 4 years ago, we didn't have many medicines approved. We've got 5 medicines approved now, a sixth to be approved by the end of the year, which is, of course, neladalkib has a PDUFA date in November of this year, but then also 3 additional assets, B7-H3, B7-H4 and velzatinib that are likely to hopefully make it to the market by the '28, '29 time frame as well, too.

Biggest opportunities. I think no doubt, B7-H3 is a key asset, just owing to its broad expression profile across a number of different solid tumors. So that includes, of course, thoracic malignancies, GI malignancies, GU malignancies like prostate cancer as well, too. So we oftentimes refer to it as a pipeline and an asset, right, just given how broad its applicability is. B7-H4 Mo-Rez as well, too, especially in gynecologic malignancies, velzatinib i GIST. And then probably there, like people might look at GIST at face value as a relatively more orphan patient segment.

But I think duration of therapy is really important. And I think when we look at, for example, imatinib or Gleevec now and the fact that it delivers probably somewhere between 28 to 32 months or 33 months median PFS in frontline GIST, you're looking for a meaningful improvement over that. And so duration of therapy is a critical element, similar to probably how we look at the Nuvalent assets as well, too. Nela and Zide, if we're thinking about ROS1-positive patients, about 2% of lung cancer, ALK-positive patients, about 4% of lung cancer, but duration of therapy is very critical, especially if patients are on treatment for several years. So I think these are all assets that are going to be contributing to those 2031 ambitions. And of course, along with BLENREP as we think about the future of newly diagnosed patients, DREAMM-10 and frontline multiple myeloma as well.

Okay. Lots going on. Maybe we can start with Nuvalent and JIDEYTRO over the weekend -- JIDEYTRO, and apologies for my pronunciation in first-line ROS. The data is still perhaps relatively early in a small number of patients, 94 patients. So help us understand where we are with filing for first line. What else do you need to see to kind of get comfortable with the regulatory path?

Yes. Well, the data was actually presented. I was at the plenary session yesterday morning in Seoul, and I just got in yesterday night into New York, and quite a warm reception to the data, quite robust, spectacular, I would say, certainly for ROS1-positive patients as well, too, in this first-line TKI-naive non-small cell lung cancer patient population. 94 patients, 94% objective response rate in terms of at least the durability, we're seeing a PFS landmark at 12 months of about maybe 90%, certainly a duration of response landmark at 12 months of 86%. So quite durable, quite strong treatment effect and very clinically relevant.

And then, of course, the medicine was designed to have these brain-penetrant properties and in that subset of patients that had brain metastases and typically in these ROS and ALK-positive patients, about maybe 30% to 50% of patients typically develop brain metastases. We saw 100% response rate in terms of intracranial response, which is probably, again, very important for patients. So overall, a lot of confidence, very strong support for how we feel about the drug at this stage, especially when you think about comparisons as they're made to, for example, third-generation TKIs as well, too.

And we're still planning on filing in Q4 before the end of the year. Now one point to also highlight in that regard. Of course, I think it's well established, at least from a regulatory standpoint that the -- given the orphan nature and the prevalence of the disease, of course, as well too, we've seen single-arm studies and single-arm data sets serve as pivotal and certainly registrational data sets in this first-line TKI-naive ROS1-positive patient population. So we feel very comfortable with the approach that we're taking from a regulatory standpoint as well.

Perfect. Very clear. And when we think about Nela in the first-line ALK lung cancer setting, lorlatinib has set a very high bar for efficacy and particularly for durability, brain control. ALKAZAR the frontline trial is versus Alecensa. So is it meaningful enough to show superiority to Alecensa? Or would you need to show at least on a cross trial, something lorlatinib like to change practice?

Well, I think we have to look at the -- where the uptake of these medicines is right now. And I think if you look at the most recent market data and the uptake and the usage and physician usage of these drugs, we're actually seeing about maybe 45% use of alectinib in the frontline setting with about maybe 35% of patients use of lorlatinib. So alectinib is quite still a relevant control arm in that frontline setting as well, too, and that's why the study was actually designed that way.

Now I think if we look at other third-generation TKIs and the comparisons that were made, they were actually made to first-generation TKIs to crizotinib. And so I think that's something to just kind of bear in mind and take into account as well, too, in their pivotal studies. But the data, at least certainly is at least in that second-line TKI pretreated patient population quite strong and probably also gets at the fact that Nela, similar to Zide was very much from a medicinal chemistry design, designed to address not only the single ALK mutations, but also the compound ALK resistance mutations as well, too, along with, of course, its brain penetrant activity.

So from that standpoint, I think we'll be able to see very clearly, hopefully, the treatment effect over alectinib. And at the same point in time, probably something to highlight, of course, the data that's been generated and presented for Nela in this first-line TKI-naive patient population as well, too. Looking at, of course, not only the objective response rate, which is quite high, but also the duration of response at 12 months being at 91% versus 70% with the third-generation TKIs as well, too. So we expect to see that separation hopefully happen early between certainly Nela and alectinib into that Phase III study. And by the way, the recruitment in that trial is going quite well.

Okay. And could you remind us when the trial is due to read out? And is there a potential for the trial to read out earlier at interim? And could you give some color on when that could happen?

Yes. I mean I think I'd probably say that it's difficult to tell when the data would read out because there are a number of different variables that go into that. First, of course, is the -- I would say, one, the recruitment rate is very critical. So I think that plays a key role. The second, of course, is the event rate and how quickly events actually occur. I think bear in mind, of course, that in this instance, we're going up against a second-generation TKI, not a first-generation TKI -- and then the third, of course, is when does that separation happen between the 2.

I was just referring to the duration of response and already seeing at least based on cross-study comparisons and of course, with all the caveats that they provide. But we're hoping to see that separation occur early. And of course, as is the case with any clinical trial, oftentimes, there are different levers to be able to incorporate into them, including, of course, looking at potentially interim analyses that hopefully can provide additional insight into overwhelming treatment effects as well.

Very clear. And you touched on duration of response. These patients stay on therapy for a long time. How should we think about the tolerability profile with Nela, particularly the liver piece versus some of the neurological metabolic side effects that we see with other TKIs?

Yes. I mean the experience that we've had to date, at least looking at the, I would say, the liver transaminitis that's been observed with Nela is that these are oftentimes quite asymptomatic, transient and quite reversible as well, too, oftentimes reversing within a span of about maybe 2 weeks or so. Certainly from a TKI perspective, from a thoracic oncology standpoint and especially in this driver mutation segment of patients, physicians are oftentimes quite comfortable, of course, with how they manage these types of transaminitis cases.

Liver function tests are typically conducted for patients when they come in as part of their more standard or routine, I would say, battery of labs that are conducted with the visits that they have. And so generally, from that standpoint, we don't have much of a, I would say, probably concern in terms of having confidence in their reversibility, their monitoring and the transient nature that they have as well, too, and the fact that they're asymptomatic as well. Like I said, the majority of these events have manifested in that way.

Perfect. And perhaps we can move on to Ris-Rez, the B7-H3. You presented some exciting data over the weekend in relapsed small cell lung cancer. Perhaps for the benefit of everyone in the room, it would be great to hear your thoughts on the data set.

Yes. I would say, again, quite robust data for the B7-H3 ADC Ris-Rez at World Lung from our partners, Hansoh. Phase III data in second-line small cell lung cancer, looking at Ris-Rez versus topotecan. The data quite compelling and quite internally consistent, which I think is important. So hazard ratio of 0.46 for overall survival, hazard ratio of 0.33 for PFS and probably close to 5x improvement in objective response rate, and along with the durability, of course, as well, too.

And that's quite probably notable as well, too, including the median OS that was observed on the Ris-Rez arm, which was about maybe 18.5 months, which is quite, I would say, important as we look at the benchmarks that have been previously set in that second-line space, including with immune cell engagers, where we see about maybe a 13.5-month median OS and with other B7-H3 ADCs, which ranged around between 12 to 13 months. So again, quite a robust data set and certainly an important inflection point for the Ris-Rez development program moving forward as well.

Amazing. And this is a China trial. So how confident are you that the results will hold in a more global population, particularly given some of the other things we saw at World Lung with EVOKE-03 being better in China patients. So how should we think about that across the global population?

First, I think there's always nuances to how we think about these comparisons. But I think probably for us, at least as we think about ARTEMIS-008, there's probably 2 or 3 key variables that we have to take into account. The first is, I think you have to look at the behavior of certain, I would say, elements of the study itself. For example, the control arm of the trial. In this instance, the topotecan control arm, it demonstrated a median overall survival of about maybe 10.3 months.

Now let's put that into context with regards to how the control arms of other Phase III studies globally have looked when topotecan has been used in this disease setting. And probably the closest or most recent analog is the study from lurbinectedin, which is the LAGOON Phase III trial, which actually didn't meet its primary endpoint, didn't demonstrate that lurbinectedin was better than topotecan. But the control arm on that study actually demonstrated a median overall survival of 10.6 months. So it is consistent. The control arm behaves in a very consistent way with at least the global data set from another Phase III study.

The second I would probably say is I think we are very fortunate to be able to have the ability to look at data sets from Hansoh in real time, but also our own internal global development program, the GSK conducted global development program as well, too. And of course, we have Phase I/II data as well, too, in the small cell lung cancer setting in the second-line patient population. And we've seen at least the data published from Hansoh, their Phase I/II data at World Lung a couple of years ago as well, too. And I can tell you, without disclosing the data, the data is very consistent on the GSK side as well, too. So that gives us additional confidence, at least in terms of the translatability of the experience in China relative to a global population in the GSK development program. And stay tuned. You'll see that data in several weeks' time at a key scientific congress as well, too.

And then finally, probably the third component that gives us, of course, additional confidence is the robustness of the data, as I had alluded to as well to earlier. Oftentimes, if you see 1 data point be positive, but there are outliers in the additional data points or in the subgroup analyses, it makes you wonder whether the treatment effect is truly consistent or not. I think when you looked at a number of different primary and secondary endpoints, the data is highly consistent.

And then across different subgroups is also very consistent as well, too. So all 3 points probably give us additional confidence and belief that the results are certainly more extrapolatable to a global patient population, including our own development program. We actually have an ongoing second-line Phase III study, which is actually recruiting quite well in this second-line small cell lung cancer population.

And you talked to the kind of consistency, the robustness of the data and perhaps not for the U.S., but could the China-only data be sufficient for an approval ex-U.S.?

Yes. I think it's a great question. And what I would say is I think we've seen examples in the past where PD-1 inhibitors that have Phase III studies that have been conducted in China support registration in other countries, markets and regions, including Europe. So I think for us, we just have to evaluate the data set, look at any potential options that might exist and explore different strategies as part of our regulatory thinking as well, too.

And you mentioned several B7-H3s in development. So kind of what underpins the confidence in Ris-Rez being best-in-class? And perhaps you can touch on the rates of ILD versus some of your competitors, too.

Yes. Well, first of all, I would say we've been executing at pace. That's probably the headline that I want to leave everyone with is the pace and the acceleration that's taking place on this program has been quite, I would say, fast. We've actually just recruited and treated our 1,000th patient on our global development program as GSK, which is fantastic and phenomenal. We're initiating 5 Phase III studies. So 2, of course, in small cell lung cancer, second-line small cell lung cancer, which is ongoing, first-line small cell lung cancer forthcoming. And then 3 pivotal studies across different lines of therapy in prostate cancer. So 1 in late-line metastatic castrate-resistant prostate cancer, another head-to-head against chemo in a chemo-naive metastatic castrate-resistant prostate cancer and then another in a metastatic hormone-sensitive prostate cancer population.

In terms of the ILD rates, I would say we have data from our global development program that will actually be presented at a key scientific congress in a few weeks' time, which I think we probably find very interesting in terms of the rates and the incidence of ILD that have been observed in our global development program, and maybe unique relative to other linker payload platforms that exist in the class as well, too. Probably, I would say, a data point, a reference point to highlight is, of course, our B7-H4 ADC actually uses the same linker and payload as well. And we presented data on -- preliminary data on ILD at SGO from that program, and it showed only a 3% incidence of ILD, the majority of the events all being of low grade as well, too.

Perfect. And before we get into the B7-H4, you mentioned the broad prostate cancer development. So what gives you confidence that you can kind of take a B7-H3 or ADC from the metastatic setting into the more chemo-naive sensitive setting?

Yes. I think looking at, of course, the data that's been presented already publicly by Hansoh, we've seen a 37% confirmed objective response rate in metastatic castrate-resistant prostate cancer. That response rate was not interacting in any way, whether it be with prior chemotherapy or no prior chemotherapy as well, too, very consistent, which I think is important.

The second, of course, is we're actually generating our own data set in our own global development program. So again, we have the ability to be able to view both of these data sets, look at their consistency as well, too, which gives us additional confidence and stay tuned. That data set will probably be presented at a key scientific congress in the first half of 2028 in prostate cancer as well, too. So again, we feel very, very comfortable with being able to take on an ambitious and initiate an ambitious program in prostate cancer moving forward.

Perfect. And when we think about Mo-Rez, the B7-H4 ADC, it's a similar question in a way. We've seen encouraging data in ovarian cancer, but there are a lot of B7-H4s in development. So what differentiates Mo-Rez and what's kind of underpinning the confidence in it being best-in-class?

Yes. So Sarita, I think that's an important question. And first and foremost, no doubt, there's a number of different ADCs emerging in this gynecologic oncology space. But our confidence, first and foremost, in the linker and the payload technology, which has been established and based on the Hansoh experience, our experience across both Ris-Rez and Mo-Rez is important.

The second, I think we've seen already the preliminary data that was presented at SGO, 67% confirmed objective response rate at the 5.8 mg per kg dose in platinum-resistant ovarian cancer, and a 67% objective response rate across the 4.8 mg per kg dose level in second-line endometrial cancer as well, too. That is probably, I would say, in the top tier of numerical response rates that have been observed across the class of ADCs in gynecologic malignancies, which I think is important and relevant.

The third really is execution is one component, speed is one component, but also translational strategy becomes very critical. And although we haven't necessarily seen any interactions between B7-H4 or antigen expression and clinical activity, we see broad activity across different antigen expression levels. We're also continuing to look into biomarkers. And I think what we're learning with ADCs is certainly, we're moving much more from univariate antigen expression focus to much more multivariate biomarkers, including, of course, looking at the sensitivity of the tumor to the linker and the payload within the tumor microenvironment, which I think now, again, makes us think about not only oncology but ADCs through a different lens and could potentially, of course, be important in terms of further optimizing the treatment effect and the benefit risk overall.

Very clear. And you touched on B7-H4 expression, and I believe in endometrial cancer, it was kind of widespread efficacy irrespective of expression. Some of your competitors, for example, Astra with Puxi-Sam are looking at a biomarker-specific approach. So is B7-H3 just not the right biomarker? Or is there something specific to your asset, which means it's kind of more broad?

To be honest, I think it's a question. I probably can't comment much on the molecules for other sponsors and their experience with it. But I think they see something in their data that could be indicative potentially of an interaction between B7-H4 expression and treatment effect. For us, it's not something that we've seen so far, specifically in our platinum-resistant ovarian cancer data set either as well, too. But we're looking, like I said, at probably more multivariate biomarkers as a means of, again, further enhancing the treatment effect that we've already observed as well, too.

And I think it's important because in a space where we're going to have a number of different competitors, I don't think we can purely rely on just looking at numerical values of response rate. When you talk to physicians, when you talk to experts in the gynecologic oncology space, the 2 key drivers for how they're thinking about how they'll manage patient care moving forward and especially with the presence of multiple ADCs directed towards different targets, whether it be folate receptor alpha, whether it be B7-H4, whether it be TROP2. One, of course, is how much can you optimize the efficacy?

And then two, what does the safety and tolerability look like? And we've seen that certain antigens with ADCs have unique toxicities like stomatitis, which can become quite a big challenge. Others, for example, ocular toxicity in that gynecologic oncology space. And then others as well to certainly looking at peripheral neuropathy and certain types of unique toxicities.

Perfect. And perhaps taking a step back, you have a lot of exciting mechanisms already in your portfolio, ALK, RAS, the ADCs. Is there a particular mechanism emerging, whether it be PD-L1, VEGF, pan-RAS, et cetera, that you think is particularly exciting that GSK is not currently operating in?

Yes. I mean, I don't know if there's 1 singular kind of mechanism. And to be honest, Sarita, you mentioned a few of them as well, too. Interestingly, we just did a deal, of course, a couple of weeks ago for probably what is a unique first-in-class antibody targeted therapy conjugate in this RAS space. So some are taking, of course, this pan-RAS approach. Others are taking a pan-KRAS or more KRAS selective approach. We actually basically looked at evaluating a more unique approach, which is basically pairing an EGFR targeting antibody with a pan-KRAS payload to help drive a much more targeted and specific delivery of the mechanism through the internalization of the receptor as well, too. And we think that there are ways to look for this best-in-class, sometimes first-in-class potential if you understand the biology well enough and then you also find the right technology to pair with it as well.

And for us, I think the RAS space is 1 element. I think you've seen how we've come into the ADCs as well, too. But also even these driver mutation segments, it's very important. I mean I think about like, for example, the JIDEYTRO data and say, wow, you can actually more than double the CR rate in these first-line TKI-naive patient segments, 15% CR rate and with the hope, of course, that these are durable and potentially could drive to more curative states. I think that's fantastic.

For example, with Nela, if you can design an asset that is much more selective that spares patients, the metabolic changes and effects that actually gets away from the neurocognitive effects and CNS effects that other medicines in this space have so that it increases the tolerability burden for -- sorry, helps improve the tolerability burden for patients. That's what we're really trying to do. We're really trying to target these best-in-class medicines. And I think, hopefully, that will be important for patients moving forward.

Perfect. And in the last couple of minutes, is there something you'd like to highlight in the oncology portfolio that you think we should be focused on that we're not? Or is there something about oncology at GSK you think the market is missing?

Yes. I would say maybe 2 or 3 things. I'll start off first and say, wow, what a difference do 4 years make, right? And I would say the journey that a big pharma company has taken from stepping away from oncology and then coming back into it and then having success. There's actually -- just for those that might be interested, there is a Yale -- I'm going to do a plug here. There is a Yale Oncology Conference taking place on November 9 and 10 in Connecticut. I'm actually going to be giving a keynote and the keynote actually will focus on some of the key learnings from this journey of a case study for a big pharma coming into oncology and what's been done well to get us the success that we've achieved to date. But we have now 5 approved medicines, 6 by the end of the year and then 3 more by 2029, so 9. That's quite a journey in only a few years' time.

The second, I think I'd probably say stay tuned for B7-H3, B7-H4, velzatinib, and then, of course, Nela in first-line TKI-naive patients. I mentioned that we've made a lot of great progress with the first-line study, the ALKAZAR study. Maybe this is something that I'll share now. We're actually probably at about -- we said that maybe the growth event, we were at maybe about 35% recruited. We're at 47% recruited. So this is only just in a span of about maybe 4 or 5 weeks. So we're moving at pace. The execution is quite -- I would probably say, methodical and excellent.

And then the third really is choices that we make. Choices matter strategically, what you do, but also what you don't do. Strategy is about actually both. And I think for us, we've been disciplined in what we do and what we don't do. And I think that's helping us succeed as we move forward now. And I'm looking forward certainly to what the next 12 to 24 months will bring.

Amazing. Thank you so much, Hesham. Thank you.

It gives me great pleasure to spend time -- all of us to spend time with Julie Brown, CFO of GSK today. I've got a few prepared questions we're going to go through, and then we're going to open up to the floor for questions, or if you would prefer to submit your questions via the pigeonhole, I can look at those via the iPad. So without further ado, Julie, thank you so much.

So first question I was going to just talk about the new CEO. So could you just talk a little bit about the changes Luke is making to speed up and improve the quality of investment decisions at the company?

Yes, sure. Good morning, everybody. Nice to see you. Yes. So Luke has become the CEO from the beginning of the year, and he was an internal candidate. So he knows GSK well. He's worked with GSK for a long time. What he did from the very beginning was his focus was really on 3 priorities. The first one was all about accelerating R&D. The second one was to fuel the launches. And the third one was simplification.

So what he's done in those early stages is he really wanted -- he set up a group that was called the Strategic Portfolio Review Group, and they met every 2 weeks with the people who run the programs. So effectively delayered by going directly to the people who are running the programs and looked at how we could accelerate the major assets or the prioritized assets within R&D. At the same time, we also set up another group, which was looking at how we could simplify the way we run the business, how we could use technology and AI to simplify the business.

The benefit then of the 2 coming together was we said we want to accelerate R&D, we want to fund the launches, but we don't want to change the operating profit profile of the company. So we needed to find the funding through the second group's work running in parallel with the first group around accelerating R&D in those assets. And the benefit has been, and we announced a major change program just recently at the end of July. So we were targeting almost $2 billion of savings, $1.9 billion of savings that could be -- the majority could then be reinvested in the pipeline. It means that we've got 20 Phase III starts this year from 10. We started off at 10. We've now got 20 Phase III starts across 7 assets and around 18 indications. So this is really showing that GSK is changing into a more asset-rich company.

The other point which we decided to do is we decided to allow part of those savings to drop through to the margin in the period when we lose HIV dolutegravir patent protection, which is '28 to '30. So we've now said, during that period the margin will be stable to improving. So net-net, there's been a big change program running in the first 6 months. Together with, of course, not to mention, the biggest deal we've done for quite a long time, which was the Nuvalent deal, which was a $10 billion deal -- just over $10 billion deal. Yes. So it's been a busy 6 months since we started.

And actually sort of sticking with that phrase of the company, keeping busy. Could you just share a few thoughts on the kind of long-term improvements with regards to R&D that GSK expects to be driven by moving a lot of the U.K.-based R&D to Cambridge U.K. to the Bio Campus?

Yes, so we decided to move. For those of you that don't know, we're currently in Stevenage, and we've been in Stevenage for quite a long period. And we took the decision to move to Cambridge essentially because you've got a total biotech ecosystem in Cambridge. You've got access to some of the most prominent hospitals in the U.K. like Addenbrooke's. And you've also got over 400 biotech organizations built out of that together with obviously the university.

So it creates this ecosystem that our scientists can then work in, so that we will have new labs, new state-of-the-art facilities to really motivate those scientists to do their best work. And they will be interacting all the time with either hospital, university all on the doorstep, which we believe will make a difference and really energize the organization. Similarly, we work very closely with academic centers in the U.S. And the benefit is, you can sort of shorten the period from research into translational medicine into the clinic. And that's the whole ethos of what's driven the change. Yes.

Just expanding a little bit on those relationships with East Coast institutions. So is your sense that hopefully, the ability to forge those academic relationships on the East Coast of the U.S. will get stronger with the move to Cambridge as well?

Yes, absolutely, both in the U.K. and in the U.S., but also very importantly, increasingly, we've built additional capability in terms of BD to access BD opportunities in China. So I would say these are the key focal points. U.K., Cambridge, East Coast of the U.S., together with some biotechs in California, you've seen us do deals with those, and very importantly, also China. And we've done very significant deals there with 2 major companies, Hengrui in respiratory and Hansoh in oncology. So that deal scouting capability and those relationships and proximity mean you can get quicker from research into commercial.

Yes. I'm just going to switch to HIV for a minute as well. Could we just talk a little bit about the advantages that GSK sees with shifting to the longer-acting therapies and away from the tablets, and what that might mean for share shifts in U.S. HIV mid- to long term?

Yes, of course. So with regard to HIV, we have got a very strong franchise with dolutegravir. And we've been pursuing long-acting therapies for the simple reason that patients prefer longer-acting therapies in HIV. It means that instead of having a daily oral tablet that reminds them that they've got HIV every day and they stand the risk of viral breakthrough if they forget a tablet and then they can pass HIV onto somebody else, the benefit with a long-acting injectable is that they are protected for the course of the duration of that injection.

And so at the moment, we've got 2 months on the market, which means that the person has got to have an injection 6 times a year. So we've got 2 months on the market. And we are the leader in terms of HIV treatment for long-acting injectables. It's probably important to say that an integrase inhibitor is at the core of this, and we're the only company with integrase inhibitor at the core of HIV long-acting therapies.

Now to Justin's point, we are moving increasingly from once every 2 months to once every 4 months. That's a big transformation, because it means the person goes in 3 times a year usually coincides with the testing for sexually transmitted diseases. So it fits with that. And we're anticipating having the final readout of that in '27 and the launch in '28. So that's basically 3 times a year. And then the next stage is to move to basically lasting for 6 months, long-acting injectables for 6 months, which is twice a year. So that's a big step forward.

Treatment is the most value opportunity, and it's 90% of the market in HIV. So it's a large component. And this is where we're in the leadership in terms of when we'll bring those products to launch. And to the point about the patient, when we've done a study, we did a SOLAR study, 90% of patients prefer long-acting injectables to orals. And it's because of this lack of stigma, it's no need for a reminder to take their medication and it's the assurance of protection.

And then from the physician point of view, we did a study called LATITUDE, which was again comparing daily orals with long-acting injectables. And again, the data monitoring committee stopped it early, because the data was so compelling that people were more protected with long-acting injectables. So this is the big change that's going on now and will continue to go on as we launch longer-acting therapies in HIV.

That's super great. And could we just talk a little bit about that 2031 patent expiry for that long-acting HIV molecule, and why GSK doesn't see that as a material headwind?

Yes. So the Cabenuva -- so if I step back, the treatment solution will always be a combination of 2 products. And with regard to the product we got on the market for treatment, you've got a combination of Cabenuva and rilpivirine. And that means you've got the treatment, you've got the integrase and the capsid. So putting the 2 together. In terms of the patent estate, Cabenuva is a single asset. The new chemical entity patent expires in 2031, which is what Justin is referring to.

There is the prospect, as you put combination products together, Cabenuva with rilpivirine or the next generation of assets, the patent estate will go for longer. And we've got applications with the patent office to take us to 2035, beyond that, 2040s. So we are not concerned about the patent situation, because we've got all these applications pending. And the newer assets, which is the 6 monthly treatment, would be VH184, VH499, that patent estate would be brand new. So this is why, as we convert the business and we're leaders in treatment, this is where you feel assured about the future of HIV.

So switching on to oncology, and you kind of mentioned Nuvalent a few moments ago. But could you just delve a little bit more into the rationale for that transaction and the impact, and in terms of other niches, where GSK is confident it could win in oncology and why?

Yes, of course. So we did a lot of work on the Nuvalent acquisition. As you can imagine, it was a big deal for GSK. And we had studied it for a long time. For those of you that are not so familiar with it, it's a precision oncology company. And rather than being a single asset, which a lot of our deals have been single assets, this actually brings with it 2 major assets, very late-phase assets, who were late Phase III together with the Phase I.

What Nuvalent did, being a precision oncology company, is they were looking for opportunities in non-small cell lung cancer, which is one of the largest cancer markets, to be able to make changes, so that therapies that were efficacious but had tolerability issues, they could amend the product, so that it could address that tolerability problem. And this is essentially what we did, what we were looking for. So the first one was neladalkib, which has actually got its PDUFA date already in November this year, so very, very soon.

The other product was zidesamtinib, which is ALK and ROS1 treatment for non-small cell lung cancer. And this has also been approved early by the U.S. FDA. The PDUFA date was actually in 2 months, but it was approved in July. So it's come early. So now we're in the process of launching zidesamtinib, and neladalkib comes in just a few months. Both of these assets are tackling the genes that cause tumor replication, but they are doing so in an efficacious way, but with far less side effects. So some of the competitor products have some limited use because of the side effects, the side effect profile.

And when you think about the patients in this case, in non-small cell lung cancer with ALK and ROS1, they are typically quite young. They're 40 to 50 years old, typically women, non-smokers. And so they're working age and not having a tolerable medicine to be able to take means effectively, they can't work so well. So this is a big innovation, and we're excited about the launch and then the next stage, which is a neladalkib product that's coming shortly.

Super. And are there other niches within oncology you would talk to, blood cancer, possibly where GSK also thinks it can generate outsized returns as well?

Yes, no question. I mean, there are a few products to pull out in this regard. We've got Blenrep, which is already on the market for multiple myeloma. Again, Blenrep had fantastic data behind it. It can be used in the community, which is 70% of the U.S. market. But the data is, basically it halves the risk of death and it triples progression-free survival. So there's astounding data in an oncology field.

The second to draw your attention to will be the 2 ADCs, antibody drug conjugates. So we've got B7-H4, which is for gynecological indications, endometrial as well as ovarian. And then we've also got B7-H3, which will first go into 2 major tumor types, small cell lung cancer and also prostate. But the beauty of B7-H3 is it's actually a pipeline within a product. And the opportunity to take this into multiple tumor types gives a very, very significant commercial opportunity.

And then the final one just to draw to your attention is velzatinib, and this one is basically for gastrointestinal stromal tumors. And there we see this as a second-line opportunity with first-line trials ongoing. So coming into, again, a market -- and one of this is one of our features, we will look for opportunities where the market is not satisfied either through efficacy or tolerability. And this is another example of that.

I'm going to change gears to vaccines, if that's okay. Could we talk a little bit about Shingrix's potential, both U.S. and ex U.S. life cycle management?

Sure. So Shingrix, for those of you that don't know, I'm sure in terms of the audience, but Shingrix is a great asset. It's a vaccine, obviously, for shingles. It's got an astounding amount of data behind it and exposure to a huge number of patients already -- people already, I should say, because it's a vaccine. The data for Shingrix was phenomenal in terms of almost an 80% efficacy rate, and the longevity was 6 to 11 years, majority 11 to 8 years (sic) [ 8 to 11 years ]. So once you have Shingrix, it protects you for that period of time.

The U.S. is obviously the major market. The U.S., it's all about the level of penetration that you can achieve, i.e., how many people in the U.S. population are vaccinated. And the good news is, we've been growing that penetration level, and we're now up to around 45% penetration of people in the U.S., and we're now into the category of harder to reach. So we're anticipating getting an additional 2 to 4 percentage points of penetration in the U.S. market each year is where we're tracking at the moment.

The second part of the world is obviously, you've got Europe, international, and part of that is China. And with regard to the rest of world markets, the top 12 markets in the rest of the world, the penetration level is still low. It's still 12%. If you compare that with where we are in the U.S., it's a big difference. So it just shows the opportunity to penetrate more. And our European growth of Shingrix, as you probably saw from Q1 and Q2, has been very, very strong. It's been way into the double digits. And we've had very good success in the private market and the public market in a number of Scandinavian countries in the first half of this year. So we're penetrating further and further when it comes to the opportunity for Shingrix.

And then the final major market, of course, China. Again, we had phenomenal efficacy data in the Chinese population with 100% efficacy of the Shingrix vaccine. And we're working with a partner, Zhifei. It's private pay in China. So depending on the situation of the Chinese economy, depends the rollout. So we're working with Zhifei, who is a phenomenal partner, but just responding to the macro situation that we found in China at the moment. But net-net, Shingrix, we've guided more than a $4 billion assets. I think in the first quarter, it was around already $1 billion. So it's doing incredibly well.

And I should answer the second part of your question, which was MACE and dementia. So what we found through observational studies is that -- and we believe it may be the adjuvant component of Shingrix that it potentially reduces the degree of inflammation people experience when they get shingles. And that means there's a potential benefit in terms of cardiovascular events together with dementia. So what we decided to do is to do studies in terms of dementia, but then we're running -- we've initiated a major trial for MACE.

This is one of the assets we decided to accelerate for cardiovascular events for Shingrix, where we're doing trials now that should lead, if successful, to an extension of the FDA label, which could be very compelling, because through the observational work we've seen, we've seen the potential for between 30% and 40% reduction in the risk of events such as cardiovascular events. So this is a major -- this is one of the targeted areas that we came up with as part of the work that we referred to at the beginning.

Brilliant. I'm just going back to the U.S. for a minute in terms of what seems to be like a bit still of an anti-vax environment that we have, if you would agree. And just any thoughts you might have about how that potentially becomes a tailwind mid- to long term?

Yes. Yes. This is a very topical question. I mean, unfortunately, what we find is that if vaccination levels drop because of public policy or sometimes commentary, unfortunately, the rate of illness increases, because people are more susceptible to the disease, whatever that might be. And we've seen that with MMR vaccinations, and we saw sad situations happening with measles and young children dying as a consequence. So not only is it better for people, but it's also better for the health care system, because the U.S. spend around $9 billion a year on vaccine preventable diseases and around 80% of that is adults that could have been protected from the disease that they then got that cost them and the health care system a lot of money.

So what we find is, as I mentioned, when it drops, it then comes back again, because people need it, and actually parents -- our MMR business was really, really strong at the beginning of the year because people were worried about measles incidence. So net-net, what we do believe is this will go in cycles. We believe it will come back at some point. We continue to invest in vaccines. We've just taken mRNA for flu, which is obviously going to compete with high dose, into the market, into the clinic. And so we're behind it, we will stay behind it, and we expect the commentary and the rhetoric to start to change based on scientific evidence.

Yes. Got it. I'm going to change tack to lung diseases now or respiratory. Could you talk a little bit about Exdensur that you just launched and the competitive differentiation that product has?

Yes, absolutely. So Exdensur, which we used to call depemokimab. So Exdensur is the brand name. And this is a big innovation. The reason -- it's an IL-5. It's in the IL-5 category. We've already got a product on the market for an IL-5 for respiratory disorders, which is Nucala. The big benefit of Exdensur is the dosing. And instead of having medication once a month or, in some cases, once every 2 weeks or once every 2 months, Exdensur runs for its 1 injection once every 6 months. So it's very compelling because for somebody who's suffering from asthma, they can basically have 2 injections a year and be protected from exacerbations.

Now you may say, why is that so important? The reason it's important is because each exacerbation injures the lung function. So from the patient point of view, you want to avoid the exacerbation. The other thing is, exacerbations can frequently lead to hospitalization. And again, that's cost for the patient, cost for the health care system. And Exdensur has very strong data. So there's a 72% reduction in exacerbations that result in hospitalization. That is a phenomenal piece of data and extremely competitive.

And the other opportunity with Exdensur is there are very few people on biologics in asthma, in serious asthma. There's only 1/3 -- about 30% of people are actually taking biologics, which means there's a golden opportunity to encourage those people to go. And so the bio-naive market opportunity is significant, we call bio-naive. So net-net, I think this is a golden opportunity, because people also, the 30% that do have biologics, there's quite a high dropout rate. And we think that's because they feel protected, they feel safe, and then they stop taking the monthly therapy and then they then exacerbate, which then does exactly what I said.

So the longer you can keep the therapy, the better. And this is 6 months. We launched it earlier in the year. We got the approval in December last year in the U.S. We've got approval now across a range of countries. And the key with the U.S. market, especially for a 6-month therapy, is you need the J-code because it takes away the risk for the physician of holding 6 monthly treatments without being sure of reimbursement. And the J-code gives access to reimbursement. And that came in just a couple of months ago. So this next Q3 results, Q4 results, Q1 the following year, will give a much better line of sight in terms of how this is performing.

I'm going to change tack to liver diseases, if that's okay. Could you just spend a few minutes sort of explaining why the company is confident that in what seems to be a very high unmet need market, the company will be able to lead there?

Yes. I think in terms of liver diseases, there are a number of assets to pull through. I mean bepirovirsen is probably the first one to call out. So bepirovirsen just recently had one key opinion leader call it totally transformational data to be able to support the launch. The product called bepirovirsen has now got Fast Track designation or SENKU in Japan; Fast Track designation in the majority of major countries across the world. And that's because of the power of this data. So people with hepatitis B go on, if not treated, to develop liver disease. And in China, in particular, it's a major issue because there's a lot of stigma associated with hepatitis B. They have regular testing similar to the way HIV is seen in the West. So it's a major issue.

And the data we got was basically that -- and this is revolutionary, in 19% of patients, bepirovirsen offers a functional cure for hepatitis B. So it means they take 6 months of therapy and then they're effectively cured, which is groundbreaking, because otherwise they will be taking daily tablets, which are not tolerable. And then we found an additional percentage of patients also have a benefit from reduced surface antigen, which means there's less chance of going on to develop cirrhosis or liver cancer. So this is a major innovation.

So around 50% of people have a chance to either be functionally cured, which means they don't need to take therapy thereafter, or they can have surface antigens reduced, which has a medical benefit. So this is a major -- I can't stress how important, a major, major innovation. And like I say, we've now just got approval just over the last few weeks in Japan. And in terms of commercial potential, for those of you interested in the financials, there are essentially 3 markets that will make up 3/4 of the business. And that is the U.S., China, because of the incidence level, and Japan, the major 3 markets. And then coming behind that, we've got products for steatotic liver disease earlier in development. But again, products that we are accelerating, efimosfermin, et cetera, we're accelerating them considerably as part of this program, so that we can bring them to the market earlier.

Yes. Can we just circle back to margins a little bit more? Could you possibly just expand on the moving parts we need to think about going through those HIV patent expiries '28 to '29 and '28 to '30, and the mitigating factors, and the reinvestment of the $1.9 billion? Very, very helpful.

Yes, of course. So when I first joined GSK, I went out and did investor listening sessions. And people quite often fed back that they were concerned about the dolutegravir patent expiry. There was uncertainty at that point as to when it was actually going to have an impact. And we clarified that it would be between '28 and '30, with the majority impact between '29 and '30, which is when the U.S. patents go. As you know, we are protecting the dolutegravir business ourselves by introducing long-acting HIV injectables with longer patent estate that we talked about, Justin. So that's all underway.

In addition, we are pivoting our business more and more to specialty, which brings with it margin benefits, because the SG&A associated with specialty products is so much lower than it would be if you were dealing with other parts of the range. So net-net what we see is that we will be able to hold the margin stable through the dolutegravir period, which is '28 to '30. And we made that commitment about 3 years ago, and we're holding that commitment, and we're confident of being able to do it.

Now what we decided to do with the Change Program that we announced at the end of July, which is a $1.9 billion savings program. We decided the majority will go towards investing in those assets, like 20 Phase III starts, 7 major assets, 18 indications. We will invest in that. But an element of it, we will also drop through to the margin in that period of '28 to '30. And that means our margin through that period will now be stable to improving.

People have asked me why is it stable to improving? Because depending on how the pipeline is performing, it will determine whether we put more priority towards investment, but it will be at least stable, and we have the option, our choice to have it is improving. So that's sort of given people, I think, a reassurance through that period. And I'm pleased to say that consensus expectations over that period have now risen as a consequence from where they were before.

I'm going to ask last one of my questions. And thank you very much, I've got 5 questions in the pigeonhole. So thank you for that, and we can have more. So last one for me before going to the pigeonhole would be on M&A. Could you just share some thoughts about, it's been a very busy period for the company, your ability to sustain the rate of activity, which sort of started in 2022? And then just a few thoughts on how, as an organization with M&A, you guard against sort of biting off more than you can chew?

Yes. Yes. It's a very good question. I think R&D pipelines increasingly are built through very good sourcing of internal and external. You've got to have both. You've definitely got to have both. And therefore, we've got very, very strong teams scouting for the right opportunities in different parts of the world, as we talked about U.S., Europe, certainly the U.S., and very much now China, increasingly in China.

To Justin's point about -- we've done a lot this year. We've already done -- we've done 35Pharma, we've done RAPT. These 2 deals were around $1 billion to $2 billion. And then we also did Nuvalent, which was a $10.5 billion deal, but it was $7 billion net, because they had cash in sterling. It took our leverage level to just less than 2x net debt to EBITDA. So it was a fairly significant deal. We are very committed to a strong investment-grade balance sheet, and we will maintain a strong investment-grade balance sheet because we want our investors' money to stay totally safe. And you can see that what we've done recently is we funded ourselves to do the acceleration of R&D and bring in these assets, in fact.

And we committed as part of the Nuvalent deal that we would -- it's immediately sales accretive because the assets are launching now. It's operating profit accretive next year. It's EPS accretive in 2029. So you can see that we are generating income cash ourselves to be able to offset the headwinds associated with doing this. So net-net, I'm very comfortable we won't bite off more than we can chew. We hold that balance sheet dear to our hearts as well as looking for the best assets as well as exercising capital discipline inside our organization to generate savings to fund what we're doing. So again, you can feel assured about that.

Thank you. So I'm going to go to the questions from the audience there, if that's okay. First one is very high level. It's sort of your view on what stock markets are probably getting wrong about the company. Any thoughts you might have there?

Yes. That's a great question.

As well as easy one.

Yes. I think in pharmaceuticals -- I spent most of my life in pharmaceuticals. I had 6 years in the consumer goods product, but most of my life in pharmaceuticals. It takes a while in pharma. Things don't happen overnight. Cycles in industries vary hugely. And in our industry, you have to prove that things have changed. And you prove it only with 2 ways really. You prove it with data readouts, usually Phase III data readouts, and you prove it with commercial execution once the product is on the market. And that is really delayed -- well, that takes a long time because lead time, cycle times are long.

And I think, obviously, GSK was a conglomerate. It had a consumer health care business. It only became a pure-play biopharmaceutical business in 2022, so not that long, as you mentioned. So it just means that we have got to prove to the market that we have changed and that we're different. And we're doing it, because if we take consensus, I know some of the buy-side models are different and they're higher. But the consensus models for our sales by 2031, we guided more than $40 billion, and we guided a margin stable. Consensus earlier on, the sales were $33 billion, $7 billion adrift. And the margin was down to 25%, so 5% significantly adrift.

And what we've been able to do over time, I think, through data readouts, you don't win everything in this industry. If you're doing better than 60% in Phase III probability of success, it's pretty good result. And we've had a lot more than that. If you can prove these points as time goes on, then the market starts to believe in the matter. And consensus has now moved. We haven't got all the figures in, but the consensus has now moved from what was around $33 billion up to around $37 billion, either close to or on $37 billion. And the margin consensus we were just talking about, Justin, our margin through that dolutegravir period has now moved to around 30%, 31%. So it's a big change from where we were. And we just got to prove it. We recognize that. We've got to get the data readout. We've got to get bepirovirsen on the market. We've got to get the commercial success of these assets. And that's what we'll prove the day.

I've got one on HIV now. How confident is GSK in switch rates from tablet dolutegravir-based therapy to long-acting with regards to cushioning the revenue losses? And how dependent is that vision on the launch of the twice yearly injection?

Yes, it's a very good question. We're very encouraged by what's happening already with the switch from oral to long-acting. The SOLAR data, 90% of patients are preferring it, which is phenomenal. And we've now already -- even though we're only on the market a number of years with Apretude and Cabenuva, which are the long-acting, you take it 6 times a year, it lasts for 2 months. We've now got -- over 30% of our business in the U.S. is already transferred to long-acting injectables, which shows when you're only dosing people 3 times a year and twice a year, this is going to be a major breakthrough for them because that, again, will be very, very supportive.

The point about dependence on the 6 monthly or twice a year, because we own treatment and we're taking patients from 2 months to 4 months to 6 months, we own it. We own treatment. There's a big competitor out there that has moved into prevention. They've got a 6-month prevention way forward. They haven't got treatment yet. So this gives us the advantage. This is why we're confident that we will navigate the dolutegravir patent expiry.

Another one on HIV. Are there any concerns over availability of nearby clinics to administer the HIV injections in the U.S.?

This is a great question.

Not mine.

It's a great question. Whoever came up with this one, it's a great question. This has been a constraint. It's undoubtedly a constraint. There would be more throughput of injections if clinics had more capacity in the U.S. They have been building capacity, and we've engaged in training and nurse support for the training, et cetera, to enable there to be a higher level of throughput. The benefit is, in moving from every 2 months to every 4 months, basically you can deliver twice the amount of therapy.

And obviously, 6 months, you can increase it further again. But even just focusing on going to 4 months, where we're expecting the launch for treatment to be 2028 and for prevention for 2027, you're already doubling the capacity in the United States, which again is a big factor supporting the commercial strength through that period. Yes. I wish -- but obviously, you're in the hands of health care providers, and we can't change that. We just have to try and influence the benefits of the therapy.

And a follow-on question would then be, could you talk about the margin structure for HIV long-acting injectables versus HIV tablets?

Yes. The margin structures in HIV are healthy. They're very, very healthy. It's a very profitable business. In terms of -- it's a very specialized cell as well. So the SG&A component is relatively low. The gross margin, obviously, oral gross margins are very healthy. You've then got the move, and we've already made the move to Cabenuva and Cabenuva and rilpivirine in the combination. The rilpivirine component of that comes from Janssen. And therefore, you have got a pay away that's going to Janssen. So there is some pressure on the gross margin from the Cabenuva-rilpivirine combination.

The longer-term solution, which is the 6 months, this is where the combination of the 2 assets is basically an integrase inhibitor, VH184, and it's a capsid, VH499, and they're both GSK assets. This is where the margin structure improves again. So yes, it will vary. There's nothing simple, explaining anything in HIV, but it will vary as we go through these different cycles of products. The most important message is we can assure you of profitability through a loss of exclusivity of the franchise and that we've got next-generation assets coming through the pipeline, and we lead in 90% of the market, which is treatment.

On oncology one now, if that's okay. Certainly, when I chatted to Nina at the CMD, she talked about, I think, even now that returns on R&D in oncology are one of the highest in the company, if not the highest, despite the scale of the company there. Could you talk a little bit about how sustainable that would be going forward? And with all of these pipeline products coming through in oncology, would that allow oncology to still remain, from an R&D return perspective, the leading segment within the company?

Yes, oncology returns -- I mean, obviously, we've been in an investment phase in oncology for quite a number of years now since we did the TESARO deal essentially. So we've been very much in an investment phase. And the beauty of oncology is once you get a product onto the market, and we're expecting to have a number of products onto the market now through this next 5 years, the economics -- I mean, the payback is phenomenal. They have very high gross margin. They're often orphan drug status. It's another benefit of zidesamtinib and neladalkib from Nuvalent, both orphan drug status. Means you're more immune to MFN and IRA, et cetera.

So the margins are healthy at the gross level. And because it's a very specialized cell, you are dealing with specific oncologists in a specific field, the SG&A is relatively low. Hence, you do get a very good ROI. The issue occurs in oncology is if you're not getting the products through to the market. And then you're investing heavily, but you're not getting them through. But we're now on a trend of getting these products approved and on to the market.

Yes. Another one on China with regards to the M&A and how confident is the company that it can continue to replicate the success that we've already seen so far, as you alluded to with Hengrui and Hansoh?

Yes. We're very confident. I mean, the relationship with Hansoh and Hengrui is very strong. There was a big meeting even with them last week actually. They are exceptional at identifying products, identifying unmet medical need, identifying tolerability challenges, and modifying the asset accordingly to meet that need. And therefore, we're delighted with the collaboration we've had with them. They're also, in parallel, producing their own data in Chinese patients. They retain rights to Chinese territories, and we have the rights to the rest of the world, which obviously gives us a big opportunity. And so it's a good partnership, and we can run in parallel.

B7-H4 is a great example. They've had very strong data in endometrial and ovarian cancer. We've been publishing progression-free survival data in the low 60s and the high 60% range, respectively. So the 2 companies together, both producing data in different parts of the world with different patient populations, it's a very strong collaboration. And we will continue to do that. I mean, with Hengrui, we struck a respiratory collaboration recently that gives us access to the lead asset together with another 11 assets behind it.

Yes. Going to the other end of the scale, you, of course, would have seen the speculation of Astra and Bristol-Myers Squibb. So we'd love to get your thoughts on why that is not something that GSK needs to entertain with regards to large consolidation.

Yes. It was an interesting time at the beginning of August. And I think, obviously, there was a lot of commentary in the press and obviously, a lot of commentary from shareholders at the time. And the commentary and analyst reports on it as well that the pros and cons of mega mergers. There was a period I was -- I mean, I was part of the team that put AstraZeneca together. There was a time when it made a lot of sense, and I was on the Roche board around the time we sealed the deal, the final deal with Genentech.

So there was a time when it made a lot of sense. I think there are benefits of scale, but then now the majority of big pharmas are sizable scale. I mean, when the mergers were occurring before, companies were a lot smaller. So I think the scale is there. You need a certain scale to be able to compete in pharmaceuticals. I think the majority of the top 20 or so have got that level of scale. And there is always -- whenever you do a major merger of that sort of size, you've always got some element of disruption to R&D. And you've kind of got to weigh those 2 factors up. You've also got to navigate when the patent expiries are occurring and how you get through them, because every company faces these patent expiries. So I can't comment on what AstraZeneca is going to do. I mean, for GSK, we are focused on now integrating Nuvalent, driving those assets forward, launching them successfully, accelerating that pipeline, like I said, 20 Phase IIIs. We've never had that level before. It's been 6 and 7 a year. We got 20. This is what we're driving for, focused on our business.

Going back to the Accelerate Growth Program and the $1.9 billion of SG&A that could get reinvested. Are there any particular assets or pipeline milestones you would like the audience to think about with regards to this is a really promising asset, and that's going to merit -- going to need a lot of reinvestment to maximize the NPV. Any sort of few you would call out there? Or is it a bit too early to go there?

In terms of SG&A or just general investment?

I think more a case of just the other situations with certain drugs where actually it could be a situation where that merits another 5 Phase III trials. So quite a lot of that -- a certain chunk of that $1.9 billion is going to get reinvested as opposed to dropping down, which might mean the margin pressure might be a little bit more, or is it too early to talk about it?

Yes. I think we focused the attention of the $1.9 billion on around -- there were 7 major assets and 18 additional indications. And it was interesting that of the 18 indications, 11 are oncology, which kind of brings you back to where -- and if we take B7-H3 as an example of that, we refer to it as a pipeline within a product, which is unusual. And we're going first with small cell lung cancer and platinum-resistant prostate. There are multiple other tumors that could follow this.

And you saw with Jemperli, Jemperli first went into endometrial. We just had a very positive readout for rectal cancer. Phase II was 100% efficacy. We're going into head and neck with Jemperli. Probably oncology areas would be the areas you would target doing simultaneous pursuit of solid tumors. I think that would be probably the area I would call out. You also can go into first line more quickly following second line. Again, it's an area in oncology I would call out. There were some respiratory elements as well that I would also continue to look for. And as we get readouts in the respiratory field and hepatology field, you want to invest behind the success. Yes.

I hope this one doesn't come across as a curveball. I ask this question at the end of every kind of meeting like this. So are there any particular issues that we've not discussed that would keep you awake at night?

We've been very comprehensive, I think. I think all your questions and the ones from the audience have been really, really strong. There's nothing actually that keeps me awake at night. I mean, I sleep really well. We cannot do in this job. I sleep really well because I don't get much sleep actually. But I just think we're focused on making the most of the company. We're focused on being able to get that valuation to where we believe it should be.

I think we're a very good buy at the moment, but that's for sure. And we're focused on bringing these assets to the market and to the patients who need them the most. And you just listen to one of these patient stories like neladalkib, relatively young, mostly female non-smokers hit with non-small cell lung cancer with a gene expression that causes the cancer to replicate quickly. The treatment on the market, which is probably the best at the moment, causes sometimes psychosis, weight gain. They've now got or they will have a new opportunity to take something that doesn't do that. It's major.

Brilliant. We've got 15 seconds left. So I think we'll end it there. Julie, thank you so much for your time. Really appreciate it.

Thank you.

Good afternoon, and welcome to this GSK Q2 Results and Accelerate Growth event. Today, we look forward to having a good event. And if we could have the agenda slide on the screen, please. Just a few words on logistics before I hand over to Luke. The first thing is that we have a Q&A session for you planned at 2:45 and another one then at 4:20. After the first Q&A, you will have a short break, and the event is planned to end around 5:00 p.m.

Next slide, please. Also note the legal disclaimer on our cautionary statement regarding forward-looking statements. And I would like to add that any definitions in terms of our reporting as well as assumptions on accelerated growth can be found at the end of this deck. Lastly, if we comment on performance, any of these comments will be made at constant currency or CER, unless otherwise stated. And with this, I'm delighted to hand over to Luke.

Thank you. Welcome, everyone, and thanks for investing your time here to join us in person at the London Stock Exchange and on the webcast. If anyone wants photos of the South Cambridge Railway Station, which is a lovely orange color, Mick Readey has them, so we can send them to you after.

Seriously, today is in 2 parts. The first, we'll give you an overview of our Q2 results. Then we'll move to what is the primary focus of today, which is GSK products and our plan to grow the business and how we'll create value for both patients and shareholders. So first, I'll cover the results we announced today quickly. So Q2 performance was strong. We've got continued operational momentum with sales up 5% to more than GBP 8.4 billion. Core operating profit grew 7% and core earnings per share were up 9%.

Our cash generation remains very positive at GBP 4.3 billion, and our Q2 dividend is 17p. And we're on track in terms of our responsible business rating. In July, we also closed the acquisition of Nuvalent. Nuvalent is a precision oncology company closely aligned to our approach to Vd. And I'm delighted to say that this acquisition has already contributed to our portfolio with the approval of Jideytro, an pretreated ROS1 positive non-small lung cancer just last week.

Looking forward, we are updating our full year 2026 guidance with sales and operating profit now towards the upper half of the range with EPS now expected in the lower half of the range following the acquisition of Nuvalent. I'll now hand over to Nina, who is going to summarize how we're delivering this growth and she'll also take you through some color on Nucala and COPD, Exdensur and Blenrep.

Thank you, Luke. Hi, everyone. So commercial momentum continued in the second quarter, driven by key products across our specialty and vaccines portfolio. Growth was driven by Specialty Medicines, which grew 14% and vaccines, which grew 8%. Vaccines growth benefited from the global expansion of Arexvy, our RSV vaccine, strong performance from our meningitis vaccines and Shingrix in Europe.

Specifically, Arexvy benefited from a tender win for a 2-year supply in Australia. Specialty growth was driven by Nucala's continued COPD launch and our long-acting HIV treatment, Cabenuva as well as Dovato. General Medicines was down 9% in the quarter with declining sales of the older established portfolio. Also, there was a challenging pricing comparator for Trelegy in the U.S. due to a positive true-up that took place in the second quarter last year, also softer inhaled respiratory market demand, both of which we expect to improve in the second half of this year.

As Luke mentioned, we are focused on the products that drive the most value, including new launches and growth contributors. Next slide, please. Here, we have pulled out the 3 major launches of 2026. Starting with Nucala. We once again had strong global growth driven by the COPD launch and its halo effect on the other indications. In the U.S., new-to-brand prescriptions were up 69%, with COPD driving more than 70% of the growth. Internationally, sales were up 18%, primarily driven by our success in China, where Nucala gained majority share of bio-naive patients in COPD and already has NRDL listing in severe asthma and nasal polyps.

We are also continuing with the launch of Exdensur, our twice yearly IL-5 for severe asthma. The J-code went live on July 1, reducing the logistical burden on prescribers and providing certainty on reimbursement. We are continuing to build access and coverage with more than 50% of insured patients now being covered. The majority of new patients are coming from the bio-naive population, which we expect will continue as around 70% of patients who could be on a biologic for severe asthma still are not.

And finally, Blenrep, our community-ready antibody drug conjugate for multiple myeloma is building in line with our expectations. We now have approval in 49 countries. And recently, we have gained reimbursement for Germany and Spain. In the U.K., that's the country where Blenrep launched first, we are seeing a shift in second-line treatment, as shown in this very nice chart provided directly by NICE, with Blenrep now leading in new patient starts.

In the U.S., we are receiving positive feedback from physicians with strong intent to continue use. As we've said before, our approach is to go slow to ensure positive experience, helped by the J-code, which is now in effect for Blenrep as well. As we enter the second half of the year, we will continue to focus on unlocking the community opportunity where the majority of the patients are.

And with that, I will hand over to Deborah.

Thanks, Nina. I'm delighted to report another quarter of double-digit sales growth at 10%, reflecting continued execution of our strategy and sustained market growth for our long-acting injectable portfolio, which in Q2 represented 80% of our total HIV growth. In the U.S., we accelerated our market share growth, continuing to outpace the competition with sales growing 14%. Long-acting injectables contributed 35% of sales, underscoring strong execution in a competitive market and increased demand for our HIV medicines.

Cabenuva continued to convert patient preference into sustained growth with sales plus 33%. This performance was fueled by patient demand. And in the U.S., 77% of new prescriptions came from competitor products, reflecting increasing confidence among both health care providers and people living with HIV and the benefits of long-acting treatment.

Apretude sales increased 39%, supported by more than 4 years of real-world evidence and tolerability data. At AIDS 2026, 6-month follow-up clarity data further reinforced a more favorable injection experience versus lenacapavir after a single dose of each drug with 70% of participants rating CAB as very or totally acceptable compared with 37% for LEN.

In addition, fewer HCPs reported challenges with administration and patient management. Given our continued growth momentum, we are raising our 2026 sales growth guidance to high single-digit growth from mid- to high single-digit growth. I'll now hand over to Julie.

Thank you, Deborah. And I will now cover financial performance. So turning to the next slide. Starting with the core income statement for the quarter with all commentary at CER. Sales grew 5% and gross margin improved 250 basis points due to product mix benefits driven by the growth of specialty and vaccines, together with supply chain optimization charges that we took in Q2 last year.

SG&A grew 5%, driven by launch investments and phasing compared with the prior period, partially offset by continued productivity gains. R&D growth in double digits continues to be driven by accelerated investment in the pipeline with 3 Phase IIIs initiated across specialty in half 1. And the royalties decline simply reflects the RSV IP settlement that we received last year.

Operating profit grew 7% and EPS 9%, benefiting from a lower tax rate of 17.9% and the benefits of the share buyback. And then turning to the total P&L. Results were impacted by the impairment of Camlipixant following the recent CALM-2 readout.

Now turning to the first half cash flow. CGFO was GBP 4.3 billion, up GBP 0.5 billion versus last year, driven by operating profit, receivables and the CureVac settlement income. Free cash flow improved by GBP 1 billion with around half driven by the business and around half driven by one-off cash receipts relating to linerixibat and ViiV.

On the 15th of July, we completed the acquisition of Nuvalent at a net cost of GBP 7.1 billion, increasing net debt to GBP 22 billion, just under 2x net debt to 2025 core EBITDA. And the share buyback is now complete with an average price of GBP 16.13 over the 18 months.

Now turning to guidance. I will now cover 2026. And at the end of the event, I will cover the longer-term outlooks. So following the strong start to the year, we are pleased to be updating our sales and operating profit guidance towards the upper half of the range. Sales by product area has been modified with HIV and vaccines expectations improving to reflect the strong performance of Cabenuva and also Shingrix, respectively.

GenMed is downgraded to reflect the tough environment together with generic competition. Operating profit reflects the underlying strong business performance and is now expected to be in the upper half of the range with reduced SG&A and improved royalties, partially offset by increased R&D investments. EPS is now expected to be in the lower half of the range, and this is predominantly due to the additional interest of around GBP 160 million following the acquisition of Nuvalent.

Now to support your modeling with respect to phasing, we expect operating profit growth to be significantly Q4 weighted. And a number of factors lead to this, including productivity charges taken in Q4 last year, whilst Q3 is impacted by the consolidation and phasing of Nuvalent costs and the acquisition-related interest together with a tough tax comparator.

Thanks. And with that, I will hand back to Luke.

Thanks, Julie. Right. So coming back to the agenda, we'll now move to the accelerate portion of our event. As a reminder, we have allocated time for your questions halfway through and then again at the end of the presentations. Now at the start, I mentioned before that the focus of today is about products and growth. And we'd now like to take -- like to take you through our plan to do this.

So first, we'll give you more details on our products and why we're confident in our ability to grow the business. And then second, we're going to update you on how our late-stage pipeline is evolving. We're also going to talk about what we're doing to accelerate and expand our key late-stage assets as well as working hard to improve our ability to find and develop new competitive products and then finally, we'll update you on how we are funding all of this. And essentially, we will be reallocating capital and resources in a disciplined way to focus on what creates value. And hopefully, at the end, you'll have the same confidence that the team and I have in our plan and our ability to execute it.

Next slide, please. So what do we think our business is going to look like over time. Over the last few years, we have delivered considerable strong growth with commercial execution, and we will work very hard to maintain that growth in the near term, while we invest in the late-stage pipeline. In the midterm, we've identified key growth drivers. We think those growth drivers will compensate for the loss of dolutegravir exclusivity and allow us to push through this transition period that I'm talking about.

In the longer term, the changes we're making now to how we operate will accelerate the next wave of products to continue delivering top line growth. And finally, we remain very, very active in terms of BD. And here, we're looking for increment growth opportunities that make strategic sense for GSK.

Next slide, please. So the biopharma business, our biopharma business has changed over the last 10 years. Here you can see that operational execution has driven a move from being a company that was highly reliant on a genericizing business of largely primary care products and commoditized vaccines to a growth-orientated company with a broad mix of innovative products. And if we look at where we aim to be in 2021 and beyond on the right-hand side of this slide, GSK will continue to evolve to be more specialty focused -- and that means a much larger proportion of our sales coming from oncology, respiratory and hepatology, supported by a differentiated long-acting HIV portfolio.

Now right now, our portfolio is built around 5 core therapy areas. So today, our team will engage with you about the promising potential we see in each of these areas. And these are the 5 areas we're investing in. This is where we are focused. And whether they're walking into a lab, a manufacturing site, one of our offices or meeting our customers, every single one of our people needs to know how their role helps us deliver on these 5 priority areas.

Because in our business, and certainly with this audience, you'll understand this, a company's valuation is based on products and the core ability of management to recognize and deliver competitive innovation. And to do that, senior managers have got to be close to the products and the people leading the project teams. So we've taken material steps with the late-stage portfolio, BD and advancing our early stage to ensure that we are evolving to do just that.

Now I'll cover the mid and early parts of this slide shortly, but starting with the late stage on the top left-hand side. Every 2 weeks, a subset of the Executive Committee. So Tony and Nina as well as Regis. Regis you're there. I don't think many people know you, Regis, so that's Regis there. And Mondher, who everyone knows, Mondher Mahjoubi, who everyone knows, who's on holidays right now.

So we meet to look at the progress of our late-stage portfolio and selected assets every 2 weeks. These meetings are led by the product teams, the people running the projects. And this allows us to delayer the organization and it promotes accountability. And the aim is to keep us all on top of the internal, but also critically the external factors that influence our success.

Now since these reviews were started in January, we have identified acceleration opportunities across 7 assets, 18 indications and 25 studies. And you'll learn more about all of this today. Now as a result of these efforts by our team, we have over 20 Phase III starts this year. And that is more than double the expectations that we set out at the start of the year when we committed to 10.

You can see on the right-hand side of this slide that there is a good spread across our therapy areas. And you can also see the increasing importance of oncology. These Phase III trials are based on validated data with strong medicine profiles. And each opportunity has been thoroughly interrogated as part of the strategic portfolio reviewing process and in order to give us the confidence to invest right now.

This is a busy slide, but I love it. I think this slide does a good job of showing you how these elements come together in terms of the late-stage portfolio, the momentum that we have and the bolus that we've built up in Phase III starts. There will be attrition after we are talking about drug development, but that's why we have a broad portfolio. And our portfolio really is a set of assets that we are confident that is competitive and that can drive growth. For the mid-stage portfolio, we will continue to supplement our pipeline with business development, and we'll focus on products that address a validated target and where there is an efficacy or tolerability gap.

So far this year, we have executed 3 deals. Looking at this list, we missed with Bellus and Camlipixant in cough, but we've just got approval with Jideytro in lung. And overall, the majority of assets we've acquired with these deals have progressed to Phase III.

Next slide, please. In the early stage, we need to improve our output. And we've got to keep evolving how we work and who we work with. And I mean this slide shows we're putting our money where our mouth is. This is why we're closing Stevenage and moving our people up to Cambridge. I mean, having lived in Cambridge and worked at one of the places listed up there, I know the power of relocating to this environment, and it is designed to help Tony and his team drive change and to make us fundamentally better at discovering and developing new drugs. And Tony is going to take you through this in depth shortly.

So how are we making all of this happen and how are we paying for it? To realize the opportunities in the late-stage portfolio and R&D, we have announced today an accelerate growth program. This program is about reallocation within our existing P&L to fund these studies and labs. This is a 3-year program that will enable us to increase investment in R&D by targeting annual cost savings of GBP 1.9 billion by 2029. To do that, we will incur an expected onetime cost of GBP 2.4 billion, which will be GBP 2.1 billion in cash.

The majority of these savings we were making will be reallocated to the late-stage pipeline and some of that money will also go towards strengthening the margin through the dolutegravir loss of exclusivity period between 2028 and '30. Now this is fundamental to our strategy. We plan to evolve the company's cost base in line with its shifting product portfolio and to accelerate -- to deliver accelerated long-term growth and value to both patients and our shareholders.

Next slide, thanks. Finally, this is how we see the late-stage portfolio. As you can see, the portfolio will evolve over time, accelerating growth to drive long-term value for patients and shareholders. Now with that, let's get into the nuts and bolts of how we're going to make this happen as a team. And to get that started, it gives me enormous pleasure to hand over to Tony. Tony?

Hi, everyone. Delighted to be here with you, and thanks, Luke. As Luke highlighted earlier, accelerating R&D is a key priority for us, and this means focusing on 3 important areas: maximizing the value of the late-stage portfolio, supplementing that portfolio through business development and of course, accelerating the progress we've been making in changing the way we work in R&D.

I'm pleased with the progress we've already made. Starting on the left-hand side of this slide, you can see the value of our pipeline is increasing. In fact, we've more than doubled the number of Phase II and Phase III assets with blockbuster potential since 2022. Our pipeline is also moving 25% faster, meaning we're now in the upper quartile of our peers based on recent CMR benchmarks. We expect this trend to continue to improve.

Together, this means we can do more. And as you can see, we significantly increased the number of Phase III starts this year compared to the past. 2026 will be a bolus year for Phase III starts based on our acceleration decisions, which I'll cover in more detail in a moment. Much of this has been achieved through our use of data and technology. It enables faster decision-making with greater confidence, something we continue to embed in all aspects of R&D.

As Luke mentioned, we're taking a new approach to reviewing the portfolio. And this means experts from project teams present directly to myself, Luke and Nina, so we can make quick decisions, resolve issues promptly and provide support to advance exciting programs. The approach ensures we have the right alignment across R&D, commercial and medical to make the most informed decisions possible. It's fully cross-functional, data-driven and has already allowed us to confidently make a number of acceleration decisions, which you can see on the right-hand side of this slide.

These are the assets and programs you'll be hearing more about today, so you can understand why we're excited about them based on their differentiation and potential benefit to patients. In oncology, our ADC portfolio has been significantly accelerated. This is supported by data from our partner, Hansoh as well as our own global clinical program.

Our decision to accelerate 5 Phase III studies for Mo-rez in gynecological tumors and 4 for Ris-rez in lung and prostate cancer demonstrates our confidence in these assets. In respiratory, we'll start 6 Phase III -- sorry, Phase III trials across indications for our ultra-long-acting TSLP GSK'283. This is a significant acceleration of its development path.

Kaivan will describe emerging data, which support the use of the 6-monthly regimen for treatment of diseases like COPD. For efimosfermin data suggests a best-in-class profile for the treatment of MASH. The program has recently been accelerated against our original time lines and now includes F4 in addition to F2 and F3 patients. And I'm pleased to announce that the F4 program recruited its first patient only last week.

As you can see on this slide, the changes we've been making in R&D, particularly in development have led to a transformation in our late-stage portfolio, which is now much more focused in areas with greater patient benefit and value. Overall, we're significantly increasing the number of Phase III starts significantly this year. We expect this trend to continue to be above that as a past, although not at the level we're seeing at this year.

Importantly, these are in high-value areas with a major driver of this being a significant increase in the number of oncology Phase III studies. 2026 will see the start of pivotal trials for Mo-rez in gynecological cancers, Ris-rez in genitourinary cancers, Velzatinib in first-line GIST, efimosfermin in F4 MASH and our 3x yearly treatment for HIV.

External innovation and business development have been and will continue to be an important part of accelerating R&D. Luke's highlighted the deals we've added important assets to our late-stage pipeline, most recently, of course, Nuvalent. We'll continue our approach of bringing in assets with validated targets that address efficacy or tolerability gaps to complement our mid-stage pipeline.

We use the same data-driven scientifically courageous approach I just described for our BD decisions as well. It's true for both clinical and earlier platform deals. And in the latter case, means R&D is increasingly externally focused. You'll hear more from me on the early-stage R&D later in the year. Now as we become more externally focused, we're also making sure we co-locate our key laboratories with major external innovation hubs containing leading academic institutes.

We have 4 key locations, the East Coast of the U.S., U.K., Europe and China, each with important academic partnerships, and I've highlighted the major ones on this slide. The partnerships span a portfolio of interests aligned to our core therapeutic areas and forge deep connections with leading researchers that expose us to groundbreaking innovation. The majority of these projects focus on human health data, giving us unique insights that derisk our target identification and translational efforts and allow us to advance faster with greater confidence.

We continue to actively look to expand our partnerships on the East Coast of America and in China, and I look forward to sharing updates with you in the future. In Europe, we already have a significant presence with very strong partnerships like the one we have with Oxford University. The announcement today that we're establishing a hub in Cambridge, U.K. shows our commitment to ensuring our people are in the right places with the right partners to accelerate innovation. Our new Cambridge site will accelerate the changes we're making within R&D, reflecting the new way of working we've built to discover and develop medicines.

CBC is one of the leading integrated biomedical campuses in the world and as such is a perfect location for us. We'll be beside one of our key academic partners, Cambridge University as well as with internationally recognized research hospitals and clinical infrastructure. Our scientists will be able to work in state-of-the-art technology-enabled labs with an ecosystem of innovative AI and biotech companies. This move is part of a broader transformation of R&D, which I'll continue to update you on.

Finally, I want to reiterate the strength of our late-stage portfolio, which has been delivered from the momentum we've been building over the past years through business development and most recently, our acceleration decisions. We have a number of exciting milestones ahead of us, and I look forward to updating you on these in the future.

With that in mind, I'm now going to hand over to the team to take you through these programs in more detail, and we're starting with Hesham and our oncology portfolio.

Thank you, Tony, and good afternoon, everyone. I'm Hesham Abdullah, Global Head of Oncology R&D at GSK. Today, I'll highlight the significant progress we've made in oncology, building on our strength in gynecological and hematological cancers and expanding into new tumor types. Given the additional R&D investment we're announcing today, I'll also discuss how we'll focus this investment to accelerate development and bring our pipeline of clinically meaningful medicines to patients faster.

Let's start with why oncology matters. Oncology is a large market opportunity, defined by significant and persistent unmet need. Cancer incidence continues to rise with many tumor types projected to see double-digit growth in incidents through 2030 and beyond. Despite meaningful advances over the past decade, driven by precision medicine and new modalities, many cancer diagnoses continue to have very low 5-year survival rates. There remains a substantial opportunity to improve patient outcomes. Our pipeline and team are well positioned to address this growing unmet need.

We've built a portfolio of competitive, high-potential assets and critically, we have a talented team with a proven track record of execution in oncology. This combination of high unmet need, a high potential portfolio and a proven team will make oncology a key growth driver for GSK. We've been deliberate with how we've rebuilt the oncology pipeline at GSK, starting with strong franchises in hematology and gynecologic malignancies and now expanding into lung cancer, propelled by the recent Nuvalent acquisition as well as gastrointestinal, prostate cancer and other solid tumors. Building on our marketed anchor assets, we're advancing a deep clinical stage pipeline across multiple modalities, including ADCs, next-generation targeted small molecules, immune cell engagers and novel precision oncology medicines.

We're focusing on developing a better understanding of cancer biology, generating unique insights from deep phenotyping, novel nonclinical model systems and foundational models for patient identification and stratification. These differentiated oncology technologies enable sustained growth and innovation with a quality portfolio of assets in our research pipeline. End-to-end, our GSK oncology portfolio is designed for scale and sustained leadership.

Turning first to our 2 lead antibody drug conjugates, Mo-rez and Ris-rez. Both ADCs utilize a proprietary TOPO1 payload with a proven linker technology designed to deliver enhanced stability and tumor penetration with a potentially differentiated safety profile. For example, in our BEHOLD interim study results presented at SGO, we observed a 3% incidence of ILD pneumonitis, and we'll share further evidence of these potentially differentiated outcomes at ESMO with Ris-rez.

We've already advanced both ADCs into pivotal programs based on an extensive range of clinical data spanning across ovarian, endometrial, small cell and prostate cancer with data generation ongoing across other solid tumors. Early access to extensive Hansoh clinical data sets in large patient populations, combined with competitor insights and our own data in global populations allows us to rapidly incorporate learnings, design competitive Phase III trials and optimize our strategic positioning.

At the same time, we're evaluating novel biomarkers to potentially further enhance activity with a multipronged translational strategy. Across both programs, we're delivering at pace, striving for flawless execution while making smart, disciplined choices along the way. Mse mocertatug rezetecan, or as we call it Mo-rez builds on the strong foundation of ZEJULA and Jemperli to drive GSK's next wave of innovation in gynecologic cancers. Strong clinical data in both ovarian and endometrial cancer position Mo-rez in the top tier of a competitive and emerging class of antibody drug conjugates in gynecologic malignancies. Mo-rez delivered numerically higher antitumor activity, combined with manageable safety with a 62% response rate in platinum-resistant ovarian cancer and a 67% response rate in second-line plus endometrial cancer.

Importantly, this activity is independent of B7-H4 expression level with no unique toxicities. For example, none of the TROP-2-specific stomatitis. Supported by an extensive data set, we've moved at pace to initiate a scaled Phase III development program, initiating 5 Phase III studies during 2026, including 3 ovarian and 2 endometrial cancer studies. Driven by a strong signal observed with Mo-rez in early clinical trials, the BEHOLD clinical program has recruited over 600 patients, and it has taken just 15 months to move from Phase Ib to initiating Phase III. Expect further safety and efficacy data updates from Mo-rez at ESMO.

The second asset from this class-leading ADC platform is Ris-rez, our B7-H3 ADC, which is effectively an oncology pipeline in a single asset. B7-H3 is widely expressed across a large number of solid tumors. Across these potential indications, we're prioritizing early entry into small cell lung cancer and prostate cancer, where proof of concept has already been established.

In parallel, signal confirmation in a global population is underway in non-small cell lung cancer and sarcoma, now that PoC has been established in China. And we're also exploring additional opportunities across multiple other solid tumors. With already more than 930 patients dosed across in both trials globally, we have established a strong foundation to further accelerate Ris-rez development and maximize its potential.

Similar to Mo-rez, robust early clinical data provides conviction to move our Ris-rez program with pace and at scale. In the second-line small cell lung cancer setting, FDA granted Ris-rez breakthrough therapy designation based on the initial data presented by Hansoh at the World Conference on Lung Cancer in 2024. The updated data published in cancer cell this year showed an objective response rate of 60% with a 6.3-month median progression-free survival and a 14.9-month median overall survival in the TOPO-1 naive cohort.

Earlier in July, our partner, Hansoh, announced that Artemis-008, a Phase III China study, met its primary endpoint, demonstrating a clinically meaningful and statistically significant improvement in overall survival for patients with second-line small cell lung cancer. This marks a significant milestone as the first positive Phase III overall survival data for a B73-directed ADC in any tumor type. Our global GSK Phase III study in second-line plus EMBOLD Small Cell Lung Cancer 301 is actively recruiting, and we plan to initiate a first-line study later this year.

And at China non-squamous non-small cell lung cancer, second-line plus population, Ris-rez has demonstrated meaningful activity, both as a monotherapy and in combination with a PD-L1 inhibitor. Our ongoing Phase II combo study EMBOLD PanTumor-101 will aim to confirm the signal in PD-1 exposed patients in a global population.

Prostate cancer is a key growth opportunity for Ris-rez, and we will initiate a number of Phase III studies in prostate cancer before the end of the year. The EMBOLD program includes 2 Phase III monotherapy studies in late-line and chemo-naive metastatic castrate-resistant prostate cancer as well as a Phase III combination study in metastatic hormone-sensitive prostate cancer. These accelerated investments are supported by the response data shown here on the left, a 37% confirmed objective response rate in metastatic castrate-resistant prostate cancer patients, supported by 9 months landmark PFS rate of 56%.

Ris-rez is complemented by a growing pipeline of early-stage prostate assets that position us for future expansion with different modalities. Highlights for the remainder of 2026 include the Artemis-008 data set, which look like Ris-rez in second-line treatment of small cell lung cancer. This trial met the overall survival primary endpoint and data will be published before the end of the year. These data are significant because this is the first pivotal trial to show a survival benefit for any B7-H3-directed ADC in any indication.

In addition, our partner, Hansoh, has just announced positive results from a second China Phase III study, evaluating Ris-rez in osteosarcoma patients that have received at least 2 prior lines of therapy. The trial demonstrated a clinically meaningful and statistically significant improvement in its primary endpoint, IRC-assessed PFS with consistent benefit observed in key secondary endpoints. Osteosarcoma is an area of high unmet need, and Ris-rez has secured breakthrough therapy designation from FDA in this tumor type. Data from the Phase III study will be presented at a scientific congress later this year.

Additionally, at ESMO, we'll share the first Ris-rez data from a global population alongside ILD analyses that will further characterize the asset's potential differentiated monotherapy safety profile. This momentum is expected to continue into 2027 with Ris-rez data being presented at major medical congresses throughout the year. Together, this represents a rich multiyear data cadence across one of the broadest B7-H3 development programs.

Turning to our recent Nuvalent acquisition, which provides assets in precision oncology lung cancer. Neladalkib and Jideytro have the potential to transform treatment in ALK-positive and ROS1-positive non-small cell lung cancer. The potential to improve efficacy and tolerability in ALK-positive and ROS1 positive patient segments will support extended treatment duration and in turn, drive market growth.

The ALK and ROS segments of the non-small cell lung cancer market represent around 2% to 4% of the overall population. But these segments are typically younger. They are more frequently women and fitter than the broader lung cancer population. Patients are usually diagnosed with metastatic disease and typically have a higher rate of CNS involvement at diagnosis. For patients with ALK ROS non-small cell lung cancer, next-generation agents like Jideytro and Neladalkib may extend median PFS beyond 46 months in ROS1-positive patients and over 84 months in ALK-positive non-small cell lung cancer patients.

While the majority of first-line lung cancer patients will be treated for around 9 to 10 months, the duration of therapy for a first-line -- the duration of therapy for a first-line ALK patient may be greater than 7 years. Jideytro was recently approved by FDA for the second-line treatment of ROS1-positive non-small cell lung cancer patients. We're also working with FDA to support Neladalkib approval with an FDA decision for second-line ALK-positive non-small cell lung cancer expected by November 27.

First-line studies for both Jideytro and Neladalkib are still ongoing and enrollment in Neladalkib's first-line ALKAZAR Phase III trial is already more than 30% complete. In the cross-trial comparison shown here for ALK-positive non-small cell lung cancer post second-generation TKI, neladalkib shows 14.5 months median PFS compared with 6.6 months achieved with lorlatinib, with 91% of patients maintaining a response for more than 12 months versus 70% with lorlatinib in a TKI-naive population.

In ROS1-positive non-small cell lung cancer post TKI, Jideytro shows 23.8 months median PFS compared with 9.7 months for taletrectinib with 96% of patients maintaining a response for more than 12 months versus 74% for taletrectinib in a TKI-naive population. Acknowledging the caveats that exist with these cross-study comparisons, these data appear to suggest the potential to meaningfully prolong median PFS with Nela and Jideytro. These are best-in-class efficacy profiles, and I will review safety and tolerability data on the next slide.

Data from the neladalkib clinical program indicate Nela is well tolerated with the lowest rates of dose reductions and discontinuation when compared with other assets in the class. Nela is a highly selective ALK inhibitor, which is reflected in the adverse event profile observed in clinical studies. Nela does not appear to be associated with the long-term metabolic and neurological adverse events seen with other TKIs in the class. While Neladalkib does show higher liver enzyme elevations, physicians' feedback indicates these are largely clinically asymptomatic and manageable with routine monitoring. In short, a tolerability profile designed for long-term first-line use.

Velzatinib is another asset in our precision targeted therapy portfolio. It's in Phase III development for the treatment of GIST or gastrointestinal stromal tumors, a rare type of cancer, which develops in the digestive tract, most commonly in the stomach or small intestine. The first-line standard of care for GIST patients has not changed since the introduction of imatinib over 20 years ago. While this first-line therapy has improved the outlook for patients over time, GIST tumors will ultimately become resistant to imatinib and patients typically progress to a second-line treatment strategy.

The standard of care in second-line treatment is not well tolerated with variable efficacy. Velzatinib is the only agent in the TKI landscape, which targets all primary and key secondary KIT mutations with a lower rate of adverse events when compared to other available treatment options or standard of care.

At ASCO this year, we presented velzatinib data, which showed a 61% confirmed response rate and a 65% unconfirmed response rate for velzatinib in the first-line setting with every patient on the trial demonstrating a reduction in tumor volume. These data were used to inform the StrateGIST frontline study, which recently started recruitment. We now have 2 Phase III studies underway, StrateGIST-3 in second-line GIST and StrateGIST frontline and first-line GIST, both exploring velzatinib as monotherapy.

Recruitment for both studies is progressing strongly ahead of schedule. This momentum underscores the pace at which we're advancing this asset and velzatinib's potential to redefine the standard of care in GIST. Finally, I'd like to provide a short update on Blenrep, our ADC for the treatment of multiple myeloma. Blenrep's clinical development program is targeting all patient segments of newly diagnosed multiple myeloma.

The DREAMM-10 study is designed to investigate a Blenrep combination, which is appropriate for the majority of first-line or newly diagnosed patients. These patients are described as either standard risk fit or high-risk frail patients. DREAMM-10 investigates a Blenrep triplet versus a daratumumab triplet, and we anticipate preliminary MRD negativity data in the first half of 2028.

For high-risk non-frail newly diagnosed patients, the Phase III PRECOX study will investigate a quad regimen of Blenrep plus VRd versus a CD38 combination of daratumumab plus VRd in a high-risk enriched population, addressing the need for deeper myeloma control through higher treatment intensity. Together, these 2 pivotal studies should support blenrep use in a large proportion of the first-line multiple myeloma patients. Blenrep's projected median progression-free survival of 101.8 months from the TERPOS data presented at EMN is competitive versus 100 months for a CD38 quadruplet regimen and 62 months from a CD38 triplet.

Next, real-life burden of care. BRd offers a meaningfully lower burden of care with dramatically fewer infusion days. This has real-world implications for patients. And then finally, the Grade 3/4 ocular event rate is significantly improved and matches first-line expectations. This is achieved with 1.9 mg per kg dosing on a once every 12-week dosing schedule in the maintenance setting. This is a regimen designed to optimize benefit risk in this newly diagnosed patient population.

Now let me close with the big picture. Our GSK pipeline and team are well positioned to address the growing unmet needs in oncology. We have a highly competitive oncology pipeline, and we're continuing to apply various acceleration levers. Starting in lung, we have a near-term acceleration opportunity into second line with Jideytro now approved and Nela on its heels with first-line expansion for Jideytro planned in first half 2027. Both address clear efficacy and tolerability gaps.

With our 2 ADCs, extensive clinical data sets provide conviction to progress multiple pivotal programs at pace with Mo-rez in Gyn-onc and Ris-rez pipeline in a single asset. Ris-rez brings the first positive Phase III OS data for any B7-H3 directed ADC with 2 positive Phase III trials to be presented in the second half of '26.

Continuing with our pipeline of differentiated precision oncology medicines in areas of unmet need, Velzatinib has the potential to redefine a 2-decade-old standard of care for GIST patients as a well-tolerated monotherapy with potential superior activity and tolerability profile.

Finally, we will continue to see upside with Blenrep. The ongoing clinical development and evidence generation program aims to ensure success in newly diagnosed patients while creating broad access for community-based BCMA therapy. Taken together, this is a high potential competitive oncology pipeline and one we're advancing with real pace and conviction.

I'll now hand it back to Luke to commence the Q&A session. If I can also ask Julie, Nina, Deborah and Tony to join me on the stage as well, too.

Great. Thanks, Hesham. And as you said, we'll open the floor -- open the floor. [Operator Instructions] So Matthew, I think you were the first. I think you get a job as a Formula 1 driver with those reflexes. So Matthew.

It's Matthew Weston from UBS. One question really about -- and it's about the financials before we get into all the detail because there's more time to dig into the detail later. Slide 24, you gave the illustrative picture of the impact of the new GBP 1.9 billion savings program. And it showed the cost base today and then it showed a smaller cost base in the future. And I think you're on track to deliver about 31% margin based on guidance in '26.

So one of the most significant questions I've received today over and over is, does the new cost saving take that margin target higher? So am I right in interpreting Slide 24 that, yes, you are now aiming for margins up at the end of the 2031 period relative to where we are today.

The reservation in the slide that we shared was basically saying it was the cost base as a percentage of sales, first of all, as a result of accelerate growth. We are guiding to more than 31% margin in '26. And what we've said previously before today was that the margin will be stable through dolutegravir LOE, which is 28% to 30%. And we feel confident of that because the portfolio is pivoting more and more towards specialty, #1.

And as you've seen over a number of years now and with this program, we are driving productivity and improvement in the business. So that brings us to date. Now what we've said is as a result of accelerate growth, we will also drop some of those savings through to the margin in the period of dolutegravir. So it builds in the dolutegravir LOE period, 28% to 30%. We've not given a specific percentage, but what we have done is changed the margin guidance through dolutegravir now to say it will be stable to improving. So we're giving a range and recognizing the drop-through from the Accelerate growth program.

I think, Luisa, you are next, right?

Luisa Hector from Berenberg. I wanted to check on the asset accelerations. So you've highlighted 7. What are the criteria for accelerating? Is there some new decision-making in that mix? And then I don't think Nelo is an accelerated asset. Is there a reason for that? Maybe it's in flight too recent?

And if I can also ask on probabilities of success and linking that to the validated targets. So you have this awesome selection now of pipeline. Is there a reason for probability of success being higher with the '25 Phase III starts? You talked about the validated targets. I don't know how much of those -- what percentage of those are with validated targets and what that really means validated target.

Thanks, Luisa. I'll start, and then I think this is very much going to be a bit of a tag team answer. So maybe a little bit of heritage, a little bit of background. I mean, Nuvalent wasn't in there because it was running on a similar track with the deal and the programs are more advanced. But if we can go faster, we'll certainly look to do that. But essentially, we wanted to sit down and look at the portfolio, benchmark it versus external parameters, not just marking your own homework, but if you look at a classical program in lung, what are the appropriate time frames, what's a typical white space that's a fair comparator? And then what can we do to compress that obviously applying common sense that we didn't want to go so fast that you increase risk.

The other thing is, of course, as this portfolio is evolving, if you do have a validated target, you are removing elements of the risk, and therefore, you've got more confidence. I think just fundamentally, we want to look at ways that what were the things that were stopping us from making the decision to go faster. Was there any biological risk? Was it a resource risk? Was it our own process? And really compressing all of those, and each program had different combinations. And then we ended up -- we ran up against Julie, who said, that's lovely. And she's doing her job, she said, this needs to be paid for. And that's what then triggered the second round of the process, which is to say, okay, well, then how do we effectively use our shareholders' money appropriately to try and unlock that.

And clearly, moving it from historical areas of the business or areas where, frankly, we could partner or we could do things more simply and moving those monies to Phase III programs and to BD, we felt it's a better return and a better use of our shareholders' money. So that's the high-level answer.

I don't know, Tony, if you want to give a bit of color, Nina and then Julie, just sort of how that flows through. But clearly, at the end of the day, it's a benefit of -- a combination of benefit risk that we're looking at with these programs, classic portfolio management. Tony?

Why don't I just start a little bit with what data underpins confidence here. And you're going to hear a lot more about that from Kaivan, for example, and you already did from Hesham. And so I think you start with the fact that our portfolio now has a significant number of assets that have broad potential associated with them.

And what we've been doing -- and by that, I mean, a number of potential indications that carry significant value as well. And we've been integrating data from one end human causal data from genetics all the way through clinical characterization of patients to individually detailed molecular data. And what that allows us to do is, if you like, draw lines of confidence in underlying biology across different indications. So that's one aspect of it.

You'll hear some nice examples from Kaivan after the break on that. Couple that then with the opportunity to be able to execute a clinical study in both an effective and shall we say, appropriately gated way when we're going with relatively strong data, as I've just described, but perhaps the absence of a Phase II. And what you have is a set of ingredients that allow us to then put confidence behind the 7 assets that we described.

And that's why we've described it as 7 assets with 18 indications and I think 25 studies. All of that, coupled with having my friend here sat beside me telling me whether or not she thinks it's worth anything, really helps us to pull together a very different approach that we have now to accelerating the portfolio. I'll hand over to you.

Yes. Thank you, Tony. Not much to add, but Luisa, to your point about the confidence, I'll use some examples. Velzatinib, we have seen -- we have ongoing second-line study, right? When you see a study recruiting at 200% rate, that gives you a bit of confidence that there is actually genuine interest and desire to use the program, to use the asset. And then we try to accelerate, obviously, starting first line and support to make it possible to hopefully repeat the same. I'm not promising it, but there is high confidence that, that is -- that study will recruit.

Other examples are the 2 ADCs. We have this massive benefit of having a Chinese partner who generate a huge amount of data very quickly. We are all aware that sometimes data generated in specific Asian population might not be repeated. So the question here is which level of confidence we need to have in the global Western population to then embark very quickly into a Phase III study. And some of these, we -- for some of these, we feel very confident already.

So I think it's based to what Tony said, it's underpinned by data, definitely. And also, you can imagine that we have -- we ask the teams to come bottom up with proposals. If you have a blue sky scenario, what would you bring as acceleration? We had more than 100 opportunities that were brought by various teams. And we obviously looked at how big are certain opportunities and what does it mean for our 2030, what does it mean for post-2030 growth.

And I think we are very confident that at this point, we are -- our kind of cutoff is blockbuster indication. So that plays a role as well, together with how much does it cost, operational execution? Is it feasible to do it and so on.

And we -- just to stress something Luke said right at the beginning, we keep a very close eye on what's going on competitively. Particularly, for example, Kaivan, I'm sorry if I get ahead of you, but the TSLP's a nice example. We got a hint that our friends at Generate Bio are getting ahead of us, which we didn't like the idea of. So that was something that then went very quickly through this process, and you'll hear more about that program later.

And I think, again, we want to build a culture that's obsessed with products. Graham?

It's Graham Parry from Citi. On the accelerating growth post 2031, can you just help us understand what you're assuming for cabotegravir IP protection there? So you've talked about protecting through dolutegravir, but the cabotegravir LOE is 2031. It would be pretty major if you actually lost it there. So you can detail how you're expecting to protect that.

And then secondly, on zidesamtinib, what's your confidence in the ability to get approval on the first-line data given I think it's only a 35-patient cohort and you've already got Taletrectinib approved from TRuST12, which actually had more patients. And have you had any discussions with regulators regarding the filing yet?

Great. Thanks, Graham. Deborah, do you want to give some color on that? And then Regis, if you could just step through the process of making cabotegravir because I think that's -- it's quite interesting is what I would say. And then we'll come back to zidesamtinib first-line Hesham.

Sure. So thanks for the question, Graham. So we've got a robust approach to intellectual property. You'll see on Charlotte's slides later, a little more detail on this, but I can talk about the additional intellectual property that we have in our hand today and potentially we will have in the future on cabotegravir. So let's look at 6x yearly treatment for Cabenuva that's in the market today. We've got additional protection now granted through to 2040 for that asset. We've then got 3x the yearly treatment.

Again, we've got additional protection pending through to 2047. And then when we come into 60 early prevention, we actually have the patent granted to 2031. We don't have an additional coverage for that asset. And then 3x the early prevention, we've now got secondary patents pending, which takes us out to 2045. So it is an incredibly difficult medicine to make and to bring rilpivirine and cabotegravir together in the treatment space. Enables us to have quite a moat of intellectual property either available today or patents that are pending, which are broad and cover both the combination of the 2, how you make it and obviously, the original composition of matter patents.

So we feel really confident in the future of our IP to protect the assets that we have in our hands and in our pipeline. Just so we don't leave because we're on the topic of IP, VH184 and 499 out, the base patents there run until hopefully, when they're granted 2040, but we have additional patents that will again take us out to 2047. Regis, do you want to just talk a little bit about how challenging it is to make these medicines?

Yes. I had no idea. I would be describing the process this afternoon, but fasten your seat belt. We make the API in Singapore, quite a standard process, long chemistry, synthetic chemistry. Then after you bring it in U.K. where you do nanomilling. When you have finished a nanomilling, you will do gamma irradiation. When you have finished the gamma irradiation, you bring it back, you're going to feed it as a sterile product. You're going to gamma irradiate again and you're going to inspect it and then you're going to inject it. So if we do it, we are not the only one to be -- someone else can do it, but not everyone.

Thanks, Hesham, first line. And maybe just build on some insights we've got as part of the due diligence process talking to physicians. And again, we had insight into the regulatory exchanges as well. So over to you, Hesham.

Yes. Thank you, Luke. Yes, I'll start off first by saying, of course, that the Phase I study has actually been recruiting additional patients in that first-line cohort as well, too. I think the key really when we think about first line is the fact that we need the additional follow-up to be able to show that duration of response and that durability of response, which I think is really critical for regulators as well, too.

With that in mind, I think probably what I would probably focus on and point to is really when we look at the comparisons of the efficacy, especially in this TKI-naive patient population, you look at the duration of response more than 12 months, it's really at about maybe 96% for zidesamtinib versus 74%, of course, for taletrectinib.

And then, of course, to Luke's point, really had a lot of insight into physician experience with the drug, especially from a tolerability profile perspective as well, too. When we look at, for example, the GI side effects, including the diarrhea, the nausea, the vomiting. And then even, I would say, when we look at some of the CNS side effects as well, too, just given how selective and TrkB sparing the drug is, including on dizziness, where we see, of course, with taletrectinib about the 22% incidence versus 12% only with zidesamtinib as well, too. So I think we feel pretty confident about the first-line approach from a regulatory standpoint. We're expecting a filing probably before the end of the year and then hopefully, a regulatory decision in 2027.

Great. Konstantin, I think we'll take one online and then we'll go back to the room.

Our next question comes from Steve Scala at TD Cowen.

Relative to the General Medicines guidance decrease, it was in part attributed to the soft environment. I'm curious what emerged in the last 3 months that led to this softness. Specifically, the company signed the agreement with CMS on June 15. So were there any details of that agreement, which were negative surprises?

Nina, could you hear that?

I think...

A little bit of an echo.

Yes. Okay. So I think -- so look, this is a portfolio of mature, older assets that continue to be in many regions under pressure, under pricing pressure and generic medicines coming on board. That's one element. The other element is Trelegy. And I think you have seen -- we spoke about this in the first quarter already. We do see increased abandonment rates in the U.S. for Trelegy and Trelegy is not the only one. It happens to actually all the assets in the SIT (sic) [ sitagliptin ] class. That is easing definitely. But overall, that level of abandonment, the trajectory is going down, but it's at a higher level than what we have seen in the previous years.

And to some extent, that is contributing, we mentioned that we expect this to now be removed in the second half. We expect the growth to come back, but it influences the whole year. And I would just ask Julie if she wants to add anything.

I think that's a perfect summary. We've obviously seen Gen Med under some pressure in Q1 and the pressure increased slightly in Q2. So the full year view reflects that. I think very importantly, we knew Trelegy would be under pressure in the first half and Trelegy has been the asset that's been growing double digits. So it's taken away some of the strength in Gen Med that we had before.

So in the second half, we're anticipating there'll be less abandonment going on, and we haven't got a tough comp like we had in Q2 because of the rebate and return adjustment. So I think that's the summary.

Yes. And there's a little bit of mix, of course, as the COPD component becomes more. Peter.

Pete Verdult, BNP. Just a few for Tony. Just what time lines are you working to ballpark to get your people into Cambridge? When it comes to this new accelerated R&D strategy, have there been -- and I don't mind if it's not, the answer is no, but have been any notable leadership changes to your team in the last 12 months?

And then just specifically, when it comes to your B7 targeting ADCs, they are competitive, we agree with you. But there are a lot of others out there. And in many cases, they're ahead of you. So as part of this accelerated change in late-stage development and the 9 studies you're doing, are there any indications you'd call out where you think you could be first to market as a B7-H3 or 4 targeting ADC?

Okay. Let me start and Hesham, I'll give you a chance to have a think about where the B7-H3 and 4 question might go. First of all, in terms of Cambridge, remind me, there was 3 questions in there. The first question was...

Yes, time frame became...

Time frame, early '29. We want to move the whole group and the first building is up. There are 2 more to go up, but early '29 is the plan for that. No immediate changes to my team. I've elevated one person. Our Head of Clin Ops now reports directly to me, and that's all consistent with the way we're operating the business in R&D. She is an experienced leader and somebody we acquired actually from AstraZeneca. So she knows how to find the Cambridge Biomedical Campus.

And in terms of what you -- where you will see changes, and we will probably introduce you to some of these folks in the second half of the year when we do some of the earlier updates on research are the folks who report through to my colleagues who are here with us today. We continue to hire really exciting new leaders in MD PhDs who are still clinically practicing individuals. These are the folks who are helping us, for example, to integrate across different data layers. So I'm delighted with the progress we're making in really bringing the patient right to the center of our thinking in early research.

In terms then of the ADCs and with regards to acceleration, look, before I give Hesham the opportunity to talk about which of the programs we see as coming first, I think it's worthwhile underscoring what we see as an emerging picture for both molecules, both in terms of their overall quality for response rate and now the first OS data, as you heard from Hesham for Mo-rez, together with an emerging, not yet fully qualified, but I think advantageous selectivity profile.

And since Regis is in the room, I'll also mention the fact that our experience with Blenrep has set us up very well with regards to ensuring manufacture of these molecules, which is not the most straightforward proposition. But Hesham, you might talk about some more specifics on where we see acceleration.

Yes, I'm happy to, Tony. And I think probably starting off first to say -- it's not always about being first. I think there are a number of different variables when we think about these ADCs that we have to take into account. I think the first one really is the type of technology platform that you have. I think we're pretty confident about the fact that we have a well-validated linker payload technology. We're seeing that in the data sets that we're generating.

I think the second is, you heard me talk a little bit about the fact that we've got -- and Nina touched on this as well, too. We've got different sources of data that not everyone has access to. We've got large amounts of data that have been generated in China with both H3 and H4. And then we're complementing that with the data that we're generating across our own development programs, more than 600 patients for H4, more than 930 for H3. And that gives us unique insight in terms of not only which indications to pursue, which ones not to pursue.

And I think the third really is more around how we're thinking about translational strategy. To me, at least, probably, it feels like the most differentiated ADCs across different patient segments or tumors are going to be the ones that could better enhance the treatment effect relative to the ITT, and that comes through a really good understanding of the biology, but also how the drug actually works in the context of not only target expression, but also the linker and the payload and their importance in terms of how sensitive the tumor is to them.

And so we've got a multipronged strategy where we're actually looking at a number of different technologies and platforms for biomarkers that we think will certainly be important in that regard. And then, of course, the execution is clear in terms of the pace and the scale, which is important. But I would say probably maybe for B7-H3, the one maybe tumor type that I'd highlight that could be of potential interest and could be differentiated is actually non-small cell lung cancer. We're seeing the data, of course, that was presented at AACR, 47% response rate in combination with PD-L1 in a PD-1 pretreated patient population.

Again, it's data from China. We have to validate it. We've got ongoing Phase II to do that and help confirm it, but it could certainly be an interesting opportunity that maybe is more unique at least in the short term.

And that's probably worthwhile just quickly, particularly for Mo-rez where the data is more advanced. I think it serves to take a look across the various patient characteristics and dose use for our molecule relative to our competitors there to get a sense of what Hesham was talking about in terms of the emerging properties of Mo-rez relative to others.

Yes. And I'd also add, we've got a team, the layers below that has a fantastic track record across a number of companies in terms of navigating programs. All right. We've got time for one more question. Simon, then we'll go for a break.

Simon Baker from Rothschild & Co Redburn. I'll try and be quick. A big picture one on R&D. It's clear that R&D at GSK in 5 years' time will be in a very different place in every sense of the phrase. But I just wonder if you could give us an idea of the moving parts between the additional resources that's going in, productivity changes.

And really, the key question is, how are you going to measure that change in improvement? And how will we see that measure improvement beyond simply looking back in 8 years and thinking GSK accomplished more than it did in the previous decade. Where sort of where are we now? Or where were we? Where are we now? And where could we be by the end of the decade?

Tony?

Well, that's certainly another 1-minute answer, Simon. So look, I mean, where were we was a very distributed portfolio pointing to opportunities of little value. And you saw that we've transformed that substantially in the past 4 years. Also that we have a portfolio in which there are a number of meaningful life cycle innovation opportunities so that I'm getting more out of each asset.

They're moving quicker. We're 25% quicker than we were. We're in upper quartile as far as that's concerned. The decisions that we make about that portfolio and in terms of BD as well are made by exactly the same people who make the decisions on the early-stage portfolio. So you should expect to see the same discernment in terms of highlighting and accelerating assets to that as well. I will share with you at some point in time, if you want, the scorecard on how we evaluate individual areas of the business. I don't have time to go through that in detail right now.

What you will see, hopefully, is continued momentum towards the areas of significant opportunity and competitiveness in terms of either pace and for first-in-class or careful decisions for best-in-class agents. And the best way I can illustrate that is through the portfolio that we'll be sharing today. In early stages, I could pick different examples across all of the parts of our business, looking, for example, at how we execute our clinical programs. A case in point might be as we apply more data there, for example, we're expecting to be able to half our study start-up time by the time we get to 2028.

So it would take me the next half an hour, Simon, to go through each one of the segments and give you the simple KPIs that we're using to judge progress there. But I can assure you they are in every single group. They're a relatively small number because I don't like to give people the opportunity to hide behind long lists, and it's extremely data enabled.

So the good news, Tony, is you've got 20 minutes at the coffee break to do exactly that. That concludes our first Q&A. If we didn't get your question, please obviously know the people to find, and we'll make sure that we get to your questions in the second round. And of course, we've got time at the end as well.

I just want to get -- make sure we capture and get your questions. So with that, we'll have a break. Thanks, guys. We'll see you back in 20 minutes, at 3:35. It's a less than 20.

[Break]

So welcome back, and I now get to introduce Kaivan, over to you.

Thanks, Luke. Good afternoon, everyone. My name is Kaivan Khavandi. I'm the Head of R&D at GSK for Respiratory, immunology and Inflammation. GSK is well recognized as the leader in respiratory medicine, having pioneered multiple products across indications, notably asthma and most recently with the launch of Exdensur, the first ultra-long-acting biologic to be launched in airways disease.

However, when we think about the largest remaining unmet need and the sheer scale of opportunity, this is undoubtedly in COPD, which is an area of enduring growth and represents a core focus of our future portfolio. Similarly, in hepatology, we have an important product launch planned with bepirovirsen for chronic hepatitis B, a rare opportunity to impact population health and where, of course, we're committed to realizing the full breadth and value of that product through its life cycle, including potential combinations, but it's steatotic liver disease, secondary to MASH and alcohol, where we see GSK continuing to innovate with efimesfermin and beyond.

What's underappreciated, though, is that these 2 areas are much more connected than at first apparent, serious chronic diseases with shared underlying inflammatory and fibrotic as well as vascular risk, which frequently coexist. Patients with primary disease of the liver, heart and lung are also at risk of developing secondary pulmonary hypertension, a serious and much more expansive area than idiopathic PAH, for which there is largely no approved treatments.

Together, these 3 areas form an unaddressed comorbid access that carries a very high risk of mortality and for which GSK is strongly positioned to lead. So with that background, when we look at recent product developments at GSK, success has been demonstrated really as a consequence of mechanisms that stop the core inflammatory risk relevant to each disease.

In areas like asthma and nasal polyps, these are primarily driven by T2 pathways identified by eosinophils and very well served with products like Nucala. Future innovation in these diseases will not come from marginal gains with new mechanisms, but from practical real-world innovation from modalities that can help patients comply and persist on their medicines, enter our ultra-long-acting portfolio with Exdensur and ultra-long-acting TSLP.

There is one overlooked T2-driven disease, and that's food allergy, where IgE targeting has only recently been shown to be effective and where we rapidly build on that observation and early commercial success with an improved long-acting and potentially best-in-class approach with Ozareprevast. And that takes us to COPD and non-CF bronchiectasis. Whilst an important subset of COPD is T2-driven, most of it is not and a different set of risk factors with distinct inflammatory metabolic and vascular drivers are responsible for disease progression.

Here, we do need mechanistic innovation, and we apply our deep translational insights directly to late-stage product developments, notably with IL-33. This bridges us to pulmonary hypertension that can, of course, result directly as a consequence of COPD, but is a pulmonary vascular disease by definition with mechanisms of risk overlapping with COPD on the left and MASH on the right.

So with COPD really at the center in terms of the greatest burden of disease, GSK's competitive advantage and bridging these 2 worlds of inflammatory risk, let's take a moment to consider the scale of the problem. And it's substantial. You might have heard these stats before, but when you see them contrasted versus enormous established markets like rheumatology, it becomes evident that we're only scratching the surface with only 2 advanced therapies in one subtype of COPD reserved for late-stage disease.

But with 400 million patients affected globally, over 20x more patients than RA and 100x more deaths annually, it becomes very clear that multiple product solutions are needed. So what do things look like for a patient with asthma or COPD today? The orange line in the top figure shows exacerbations and with them, the step changes in lung dysfunction, which in asthma leads to disease progression and in COPD brings irreversible loss of lung.

And as seen in the red line below, these are associated with surges in mortality. Short-acting biologics today are started late with poor persistence leading to disease progression in asthma and unfortunately, hospitalizations and premature mortality in COPD.

So what's the solution? Well, start biologics sooner and stay on them for longer. If we were able to move from 24 injections a year to just 2 and provide sustained coverage and protection, that would surely be the way to achieve this. And that's precisely what our portfolio is designed to do with Exdensur launched in asthma and shown in the graph, how we're approaching COPD, a development program that seeks to sustain persistence, but not just at the conventional point of treatment, but with these unique characteristics of the medicine, we have the confidence to start a third Phase III study, VIGILANCE, enrolling patients after just 1 exacerbations. That's unprecedented for a biologic.

So the prior slide showed how Exdensur achieves greater coverage and clinical benefit in patients with T2 inflammation through earlier management, and that's illustrated in the rubric here by extending across the grid horizontally. But I mentioned that in COPD, we do need more mechanistic innovation to achieve greater coverage across different populations who have different types of inflammation, and that's illustrated by extending vertically up the grid.

Nucala was the first biologic to achieve a broader label owing to metrics, which studied lower eosinophil levels, while MATINEE came in and showed efficacy for the most clinically impactful events, emergency department visits. TSLP is a mechanism that by design is able to extend into intermediate T2 inflammation and where data indicates efficacy in those with eosinophils as low as 150 but not lower.

And that takes us to IL-33, where we probably need to ignore eosinophils altogether as this mechanism cuts COPD in a fundamentally different way, and that's easier to visualize. All patients with COPD have innate immune dysfunction and a propensity to T1 and T17 inflammation. These patients are older than those with asthma, they're sicker and they have a high burden of vascular and metabolic disease represented on the right-hand side of the slide.

A proportion of these patients have truly high T2 risk and a further group have mixed intermediate levels. This is the orange and middle overlap segments of the slide. And this risk is well addressed with IL-5 and TSLP biologics, respectively. But how do we get to the backbone of pathobiology in COPD, the blue plane in the slide?

Well, a single, dual or even triple cytokine approach won't be the answer if they're targeting the wrong biology. This is where we need to get to the tissue, vascular and structural damage that results from repeat injury at the root of COPD.

IL-33 is expressed primarily on lung epithelial and vascular endothelial cells, the dynamic barrier lining the airways and blood vessels. These are the first tissues to be exposed to and then attempt to respond to inflammatory injury and our translational insights reveal how and when IL-33 governs this therapeutically untapped space. And so we're very excited to have a potentially best-in-class long-acting and Phase III-ready products, which will be deployed with the benefits of this deeper understanding.

We predicted the early success now shown clinically for anti-IL-33 when stratifying based on mucus score. With the luxury of what we believe to be the most complete set of respiratory data anywhere in the world, over 1,000 randomized controlled trials, several million patients with deep genetic and cellular profiling and of course, clinical interventional data in COPD with our product, we've designed pivotal studies based on patient profiles most likely to respond to IL-33.

These will include factors related to stage of disease by which I mean lung function, distinct from disease severity defined by exacerbation history and other traits and tested against new clinically important outcomes that can differentiate the product. Without disclosing too much, what I can share is that one of these pivotal study starts includes a cardiorespiratory outcome study, which we will start next year in partnership with a major cardiovascular academic research organization.

In parallel, we will complete our Phase II study in non-CF bronchiectasis, an enormous market with no approved biologics and where we're positioned to be best-in-class with IL-33 as well as testing combinations with TSLP, which our AI-enhanced models predict could provide synergistic efficacy. So we're looking forward to coming out of IL-33 stealth with conviction and material differentiation.

Our ultra-long-acting TSLP program has been significantly accelerated by 9 months across 3 indications, now positioning this asset to start 6 pivotal Phase III studies, the PERSIST program integrating data from a GSK-sponsored Phase II study in asthma, the NASER study, alongside data from our partner, Hengrui, who studied nasal polyps.

This gives us dosing and pharmacodynamic data to confidently advance the first ultra-long-acting TSLP across all major indications, asthma, nasal polyps and COPD. Our BD strategy to access derisked mechanisms with a high likelihood of success allows us to jump directly to testing for product differentiation rather than mechanistic relevance. And this is reflected in our deal since January.

Ozarepubart builds on the proven efficacy of IgE in food allergy and CSU, but provides materially broader eligibility for those 25% of patients contraindicated for Xolair because of their weight or high IgE levels and an optimized solution for all with 3 monthly dosing. This will be transformative for the prevalent adolescent population and children. This class has had a remarkable first launch within the first 2 years with Xolair, now Roche's fastest-growing product and ozure is positioned to provide an objectively improved profile whilst benefiting from that momentum.

This overlooked space has understandably garnered interest and activity since our deal, but Ozure is the most advanced next-generation product with clinical efficacy data in CSU, which importantly included an active arm with Xolair, which didn't perform as well as Ozure. The program is rapidly enrolled in Phase II and has now recruited the sample size necessary to progress to an interim analysis, which will enable Phase III start in both food allergy and CSU by the end of 2027.

For HS235, we build on a new and transformative class of activin traps in pulmonary arterial hypertension, but with an improved molecule that can both remove the liabilities of the incumbents in group 1 PH, namely bleeding, but what's equally exciting is the potential to unlock the full value of the mechanism, which extends to reducing inflammation, insulin resistance and reducing visceral fat, all of which are substantial drivers of risk in Group II and Group III pulmonary hypertension secondary to chronic heart and lung disease.

Whilst this program is relatively earlier than other products being presented, we've seen evidence to support both the safety and efficacy profile described in the Phase Ib study. And I can share today that we've rapidly converted this post deal to Phase IIb starts that have now been initiated for both Group 1 and Group 2 pulmonary hypertension.

And that takes us to our hepatology portfolio. Put succinctly, our portfolio is pointed to the 3 major causes of liver-related cirrhosis and mortality, chronic hepatitis B, metabolic dysfunction-associated steatohepatitis and alcohol-related liver disease.

All of these diseases have poor outcomes and inadequate standard of care. There's no approved treatments for alcohol-related liver disease, one liver-directed treatment for MASH and no therapies that can drive cure in hepatitis B. Let's start with bepirovirsen, our first-in-class ASO for hepatitis B. Our program was ambitious, designed with the primary endpoint of functional cure, the very highest bar. This is best illustrated in the comparator arm in B-well, where what's labeled as placebo actually represents the standard of care, 48 weeks of treatment with a nucleoside or nucleotide analog.

And in that group, we saw 0 patients achieved the primary endpoint, functional cure in the ITT population. 0 patients achieved functional cure in those with baseline surface antigen levels less than 1,000 and 0 patients achieved an effect with surface antigen levels under 100, which will be consistent with the definition of partial cure.

In comparison, bepi achieved 19% cure in the ITT population, 26% in those with surf antigen at baseline less than 1,000. And importantly, when you include partial cure, a response that's been reported in population studies to improve long-term outcomes, almost 1 in 2 patients studied in the ITT population received a response that would predict clinical benefits. And that increases to 62% in those with surface antigen levels less than 1,000 at baseline.

Of note, this opportunity consolidates in 3 key markets: China, U.S. and Japan. You can see the epi and scale of the opportunity on the slide in the bottom left, which is vast. So a very exciting opportunity reflected in a suite of expedited regulatory designations setting up near-term expected marketing authorizations and product launches. And then efimosfermin, our potentially best-in-class FGF21 analog in an area of major unmet need in steatotic liver disease.

Let's start with the class. On the left, in F2-F3 MASH, you can see greater benefit on improvements in fibrosis with FGF21 analogs when compared indirectly across studies with GLP-1 agonists, such as semaglutide and thyroid hormone agonist, resmetirom.

Moving to the right in cirrhotic MASH, where currently there's no approved treatments, you can see placebo adjusted changes that are unprecedented with this class, showing the ability to reverse histological fibrosis and move the patient from cirrhotic to non-cirrhotic disease. In contrast, semaglutide showed directionally worse effects versus placebo.

And then within the class, we selected efimosfermin over other products, all available at the time of acquisition based on its best-in-class credentials with monthly versus weekly or biweekly dosing regimens. And since the deal, efimosfermin has reported the fastest observed signal for an antifibrotic benefit of any in the class with fibrosis biomarkers improving as soon as 4 weeks after treatment and for which we've designed our pivotal program to substantiate as a potential additional differentiator.

For all these reasons, we're committed to realizing the full value of this potentially transformative product, seeing us initiate the ZENITH studies to F2/F3 MASH, both recruiting since earlier this year. And we have now initiated the F4 cirrhotic MASH program, the NEBULA studies only in the last 2 weeks.

And our Phase II study in alcohol-related liver disease, ALL-STAR has just had IND approved and will start this year. So a portfolio of specialty products pointed to serious and prevalent diseases with renewed discipline to truly focus on areas of greatest commercial value and in turn, prioritize and accelerate those programs. Unprecedented data for bepirovirsen, which resets the bar of efficacy in chronic hepatitis B with functional and partial cure where the standard of care fails to achieve either.

A portfolio in COPD that will provide modality and mechanistic innovation providing greater coverage and protection for a disease that's the third leading cause of death globally and with material acceleration of programs like ultra-long-acting TSLP and with both molecule and potential evidence and claims differentiation for our best-in-class long-acting IL-33.

Efimosfermin advancing at speed across a comprehensive Phase III program, which will capture the unique breadth and potential for this mechanism across all stages and etiologies of steatotic liver disease, F2 and F3 MASH, cirrhotic F4 MASH, alcohol-related liver disease and actually potentially beyond with a molecule that has best-in-class properties.

And a portfolio enhanced by BD deals that bring best-in-class products, derisked mechanisms and which all fits within an axis of disease that physicians recognize that has yet to be applied to drug development. And that's a gap that GSK is uniquely positioned to address. With that, I will hand over to my colleague, Sanjay, to cover vaccines.

Thank you, Kaivan. Good afternoon, everyone. My name is Sanjay Gurunathan. I head the Global Vaccines and Infectious Disease Unit in R&D. Vaccines have a massive impact on public health. That's not new. We've known that for decades that preventing disease takes real pressure of health systems. But here's the thing. The science and economics around vaccines are shifting. They are pointing to something much bigger than we give them credit for.

So let's dig into why this is the case. Here's a stat that always surprises people. Vaccines make up a tiny slice of our health care spending, less than 1% of the health care budget in high-income countries. And yet that investment -- return on investment is roughly 19x of what you put in. We already know how valuable it is to prevent an infection. What's missing in the economics is the big picture. The benefits that go beyond preventing the disease a vaccine was designed to stop.

And let's think about that. That could be worth a lot. But if it's not on the label, it doesn't count towards how a vaccine gets assessed or reimbursed. The science is starting to catch up. We used to think of an infection as something that happens and then passes. It turns out that's not the whole story. A lot of infections go dormant in the body, and some of them seem to be tied to long-term health effects, even chronic disease down the road.

So preventing that initial infection might do a lot more than we thought. It could lower your risk of things like heart disease and dementia later in life. So the opportunity here is simple. We need to build the evidence that turns this potential into something that's recognized and reimbursed.

And GSK is in a great spot to lead on this. We have already a broad, well-established vaccine portfolio, Shingrix, RSV, flu vaccines, a strong meningitis franchise and a deep lineup of pediatric and travel vaccines. But more importantly, there's real room to expand beyond what these vaccines can already achieve. Shingrix is our best example of this. We have a huge amount of real-world experience. Over 116 million adults have been vaccinated with Shingrix since it was launched nearly a decade ago.

This growing body of evidence that herpes viruses, including herpes zoster, the virus that causes shingles can influence cognitive decline. So why would that be the case? Well, the shingles virus doesn't actually go away after a chickenpox infection. It just goes dormant hiding out in the brain neurons. When it wakes back up, it can start local inflammation, and that inflammation seems to play a role in cognitive decline over time.

So by keeping the virus from reactivating in the first place, Shingrix may end up slowing down that decline. But there's likely more to the story. We think Shingrix's adjuvant AS01 might be doing some extra work behind the scenes beyond just blocking viral activation. it could possibly be dialing down inflammation more broadly, including the kind of age-related inflammation that builds up in the brain.

If that's right, it could mean Shingrix is nudging the whole trajectory of neuroinflammation in a healthier direction. We've now seen through several observational studies, risk reductions of dementia symptoms up to 50%. This signal is now being put to test in 2 big pragmatic studies in Finland and Denmark, covering around 200,000 people with results expected from 2029.

We're not only seeing this as how Shingrix affects neuroinflammation, but as we go to the next slide, when we look at cardiovascular risk, it gets even more interesting on Shingrix's broader protective effects. real-world data from several independent sources, Veterans Affairs, Kaiser, Optum, TrNIDEXX, all point the same way.

Older adults who got Shingrix saw about a 25% drop in major adverse cardiovascular events or MACE. So why should that be? It turns out the shingles virus itself isn't exactly harmless to your blood vessels. It can damage them, spur up inflammation and even trigger clotting, all of which nudge up your risk of stroke and heart attacks. We think Shingrix, thanks to our AS01 adjuvant, might also be doing some quiet work behind the scene, calming inflammation and potentially bending the curve on chronic diseases in older adults. So what does this all mean? This matters a lot.

Cardiovascular disease is expected to nearly double by 2050 with costs in the U.S. alone set to top over $400 billion a year. We believe the real-world evidence you're seeing on this slide is compelling enough that we are launching a formal Phase III randomized controlled trial this year to nail down whether this is actually causal, not just correlation. We expect the study to start soon.

Another opportunity to improve outcomes in older adults is to prevent influenza infection. This disease burden of influenza is significant in adults -- in older adults with the majority of hospitalizations occurring in older adults. It's a segment we have not previously competed in. We know from published literature that influenza vaccination reduces cardiovascular disease burden and respiratory complications, underpinning the theme of broadening the protective effects of vaccine, especially in older adults.

As you can see from this visual, currently available flu vaccine effectiveness has varied from 20% to 60% over the past 15 flu seasons, illustrating why there's a true unmet need to improve flu vaccine effectiveness. We believe there's an opportunity using our mRNA technology to establish benefit over current standard of care. We can optimally leverage this technology, its differentiating characteristics to develop our next best-in-class flu vaccine.

We will present our positive Phase II results at the Options meeting next month, where you'll hear the exciting data. So let me conclude. What's our focus and where is our focus? Our focus is expanding the role of vaccines, the vaccines play in helping older adults living a longer and healthier life. If you can back that up with strong clinical outcome data and a real understanding of the biology behind it, it could support future labels that reflect these broader benefits. And that changes things. It gives health care professionals more confidence to recommend vaccination and give more people reason to get vaccinated no matter what their current health status is.

What really excites us is the growing signs connecting infection to chronic disease. It makes an already strong economic case for vaccination even stronger. Opens up new opportunities across our portfolio. And thanks to Shingrix, it gives us a real working example of how to unlock that value and help shift the trajectory of chronic diseases for older adults. It's now my pleasure to hand over to Charlotte, who will talk to you about our HIV business.

Thank you, Sanjay. I am Charlotte Allerton, Head of R&D and CSO for ViiV Healthcare at GSK. Despite decades of progress, HIV remains a major unmet public health challenge. More than 40 million people are living with HIV globally. And in the U.S., around 30% of people diagnosed with HIV are not virally suppressed, equating to approximately 400,000 people, the majority of whom are still taking daily oral antiretroviral medications as their standard of care.

Real-world barriers such as adherence and stigma continue to negatively affect health outcomes, quality of life and transmission risk, reinforcing the need for long-acting medicines that address these challenges while delivering public health benefits and significant revenue growth. Treatment represents 90% of the current HIV market, the largest unmet medical need and remains our priority. By 2035, we expect this market to be worth approximately GBP 25 billion, with growth driven by uptake of new long-acting regimens despite daily oral generics entry and pricing pressure.

For prevention, we expect this market to be worth approximately GBP 6 billion by 2035. Across both treatment and prevention, long-acting injectables are the fastest-growing segment, and we are leading this market transformation from daily oral to long-acting HIV care that improves patient experience, supports adherence and drive sustained competitive growth. We have been at the forefront of HIV innovation for nearly 4 decades, leading transformational changes in patient care through the first 2 drug oral therapies and then Cabenuva and Apretude, the first-to-market long-acting injectables for treatment and prevention.

Our current portfolio and future pipeline are built on the foundation of integrase strand transfer inhibitors, or INSTIs, which are trusted by health care providers worldwide due to their superior efficacy, long-term tolerability, high barrier to resistance, and they form the basis of over 80% of treatment regimens globally.

Today, we will focus on our near-term growth drivers, 3 times a year treatment, 2 times a year treatment and 3 times a year prevention. However, as you can see beyond these transformational opportunities, we will continue to innovate to address the health of people impacted by HIV for many years to come. This includes best-in-class long-acting orals, which we see as an opportunity to reach the around 30% of patients who our market research suggests may not choose injectable treatment.

We have initiated a Phase I study for VH359, a capsid inhibitor and have multiple potential weekly oral INSTIs and capsid inhibitors in preclinical development. Our leadership in long-acting will continue to fuel our growth with each innovation building on our expertise to shape the future standard of care and reach more people impacted by HIV. Given our lead, we will have launched our second and potentially third long-acting injectable treatment before anyone else enters the market.

Cabenuva is the first and only complete long-acting injectable HIV treatment. More than 5 years' worth of real-world and clinical evidence continues to validate the strength of Cabenuva, showing robust antiviral effectiveness and barrier to resistance comparable to daily oral medications with strong persistence out to 2 years and substantial patient preference compared to oral therapy.

In addition, Cabenuva demonstrated superiority over oral standard of care in the LATITUDE study, delivering nearly 2x lower regimen failure and 4x lower virological failure, leading to early study termination due to overwhelming efficacy in this suppressed high-risk HIV population with adherence challenges. The real-world data in viremic patients is also compelling, and we look forward to seeing data from our CROWN study in the second half of '26, assessing Cabenuva in viremic patients with adherence challenges to daily oral therapy.

The entirety of this data shows the power of Cabenuva to lead the -- to lead the market growth in long-acting injectables through addressing preference, stigma, adherence and reducing the burden of daily oral therapies, supported by a robust IP strategy with cabotegravir NCE patent protection into 2031 and addition no patent protection now granted into 2040.

As the first mover in long-acting treatment, we have built the market from the ground up, establishing the evidence, infrastructure, provider experience and patient confidence needed to accelerate the adoption of future long-acting injectable innovations. We are now focused on franchise growth, continuing to address stigma and adherence challenges while meeting patients and health care provider preference for less frequent administration.

The profile of our 3 times a year treatment constituting novel formulations of cabotegravir and rilpivirine is compelling. It builds on the proven efficacy and trust experience with Cabenuva, takes 365 oral daily treatment days down to just 3 injection visits per year, doubling provider capacity compared to Cabenuva, enabling clinics to serve more patients without increasing infrastructure. And this competitive profile is underpinned by a robust IP strategy with additional patent protection pending into 2047.

I am pleased to share that QUATTRO, our 3 times a year Phase III registrational study in suppressed switch patients has begun, supporting potential approval in 2028. We remain confident that 3 times a year treatment will be transformational, not incremental, making long-acting treatment easier to choose, deliver and sustain, unlocking substantial switch opportunity from both oral therapy and existing Cabenuva, which will drive long-acting injectable market growth.

Having set a high bar with our 3 times a year treatment, we are driven to keep innovating for people living with HIV by delivering a 2 times a year long-acting injectable treatment. Our preferred regimen is the combination of our third-generation INSTI, VH184, with our novel capsid inhibitor, VH499, a combination with NCE patent protection into at least 2040 and additional patents pending into at least 2047.

We believe this regimen can set a new standard of care for a broad HIV population, bringing confidence in efficacy and a high barrier to resistance while further addressing adherence challenges. VH184 is currently in a Phase IIb clinical study, where we have seen rapid patient recruitment, reflecting the community's interest in its third-generation INSTI profile. Our differentiated capsid inhibitor, VH499, will commence its Phase IIb study in the second half of 2026. And we have a bold plan to get to Phase III in 2028 and approval by the end of the decade, combining operational insights from our ongoing 3 times a year QUATTRO study and utilizing the entirety of our Phase I and II data to select optimal doses and formulations to achieve what we believe will be a practice-changing profile.

The data on this slide represents a subset of evidence of that practice-changing profile. The chart on the left shows VH184 retains superior potency over second-generation INSTI bictegravir against the majority of second-generation INSTI resistance mutations from the DAWNING clinical study. Its high potency and enhanced resistance profile positions it to transform HIV treatment, and we plan to determine its clinical efficacy in an in resistant population to further inform our Phase III plans.

The graph on the right shows VH499 does not cause the CYP3A-mediated drug-drug interactions that can lead to safety concerns for patients taking common concomitant medications or recreational drugs. It shows that VH499 had no effect on the pharmacokinetic profile of midazolam, the FDA recommended probe for exploring CYP3A drug-drug interactions.

This data, combined with 499 and 184's strong efficacy and encouraging tolerability gives us a combination that is not just less frequent, but clinically and commercially differentiated, maximizing patient reach and transforming options for people living with HIV once again.

Now moving to HIV prevention. The unmet need is significant. Despite the 2.2 million people in the U.S. that could benefit from prevention, only 25% use it. Daily oral persistence remains low, creating a major opportunity for long-acting options that better fit people's lives. Our 3 times a year prevention candidate, which contains a new formulation of cabotegravir builds on Apretude's greater than 99% efficacy and extensive real-world experience and is protected by a robust IP strategy with additional patents pending into 2045. 6 months after a single dose of cabotegravir and lenacapavir in our CLARITY study, follow-up data reinforced cabotegravir's highly preferred injection profile with fewer, less visible and shorter-lasting injection site reactions, whereas 90% of participants continue to report lenacapavir-associated modules at 6 months with 20% being reported as severe over that time period.

Delivered through a single intramuscular injection, our 3 times a year prevention has the potential to combine strong tolerability, a favorable drug-drug interaction profile, a dosing schedule aligned to routine sexual health visits and the fewest maintenance injections per year, reducing treatment burden and supporting long-term persistence.

With registrational study data from EXTEND4M anticipated in the second half of 2026 and approval in 2027, we remain confident it represents the optimal prevention option for both patients and providers. To close, HIV remains a significant, persistent and unresolved public health challenge. The market is moving towards long-acting the innovation we have built and lead with [Instantly] at the core to drive the market transformation.

Cabenuva demonstrates the power of long-acting treatment and creates the foundation for continued innovation and a pipeline that keeps raising the standard of care. Our near-term long-acting injectable growth drivers are clear. 3x a year treatment to unlock the next wave of growth targeted for '28 approval, 2 times a year treatment, novel molecules designed for differentiation plan for Phase III start in '28 and 3 times a year prevention optimized based on patient and provider feedback targeted for '27 approval.

As HIV care continues to evolve, we are uniquely positioned to shape where the market goes next, combining scientific leadership, long-acting innovation and deep patient insight to deliver the next generation of treatment and prevention options. That brings us to the end of the R&D part of the presentation, and I will now hand over to Julie to share more on the funding of accelerate growth and our outlook.

Thank you very much, Charlotte, and also to all my R&D colleagues. So as you've seen, GSK has a broad and rich portfolio of opportunities. And the purpose of this section is to show you how we plan to fund it. Moving on to the next one. So one of our 3 priorities is to simplify the way we work. And this will be enabled by the Accelerate growth program. We've identified GBP 1.9 billion of cumulative annual benefits to be delivered by 2029. And the majority of these will fund the investment opportunities outlined by Tony and his team today, accelerating 7 assets across 18 indications, and we have more than 20 Phase III trial starts in 2026.

Now a proportion of the savings will also drop through, strengthening the margin through the dolutegravir loss of exclusivity period, which is 28 to 30. The program will deliver incremental sales from 2030 -- it has a very strong IRR, and it will be implemented with financial discipline as usual, ensuring we retain capacity for business development.

Turning to the details of the program. We expect 90% of the cumulative annual savings to be delivered by 2028. And we have undertaken an enterprise-wide review to identify opportunities with processes redesigned and enabled by tech and AI. Support functions and key processes across the organization will be streamlined for efficiency and impact. Procurement will be enhanced further to deliver maximum value. And we will also be reallocating resources from mature brands towards the key specialty growth drivers.

And finally, there will be further automation and simplification of the supply chain and the network to align with the evolution of our portfolio. The program will cost GBP 2.4 billion to be reflected in adjusting items, of which GBP 2.1 billion is cash and the payback is 2.5 years before the reinvestment. We have a compelling track record of deploying cash in line with our capital allocation framework.

First, invest for growth; and second, shareholder distributions, all underpinned, as you know, by a strong investment-grade balance sheet. Since the start of 2021, we have delivered more than GBP 40 billion of cash generated from operations. We've deployed GBP 18 billion to invest for growth by way of capital expenditure and business development. We have distributed GBP 16 billion to shareholders through the dividends and the buyback. And we've reduced net debt through this period by GBP 6 billion, decreasing net debt to core EBITDA to 1.3x.

This represents a considerable transformation of GSK and considerably improved cash generation and a significant reduction in net debt has led to the strengthening of our balance sheet, affording us the optionality to execute BD and further strengthen the pipeline, as you've recently seen through the acquisition of Nuvalent.

We also have a strong track record of delivering profitable growth and increasing returns whilst continuing to increase the investment we've placed in R&D. So from '21 to '26, we are on track to deliver yearly sales growth of 8%, operating profit growth of 13% and more than a 540 basis point improvement in the margin. Now this is all whilst R&D investment has stepped up, increasing more than 50% to now more than GBP 7 billion and supporting a doubling of the Phase III starts in 2026, as Tony outlined.

So looking ahead to our longer-term outlook and the impact to accelerate growth. We remain committed to our outlook of more than GBP 40 billion of sales in 2031, with more than 50% of our business in Specialty Medicines. Our operating margin is now expected to be stable to improving through the dolutegravir, a loss of exclusivity period, supported by a number of things.

First, specialty continues to grow as a proportion of the portfolio. Second, we were driving increased productivity gains across the business. And third, part of the savings from the program overall will drop through to the margin in that 3-year period. Growth is then expected to accelerate from 2031 onwards, given the portfolio of products and the opportunity for further BD, the latter of which would be incremental to our commitments.

This program allows GSK to build on the strong foundations we've laid over the past 5 years and accelerate growth from 2031 onwards. Thank you, and I will now hand back to Luke for final words.

Thanks, Julie. Next slide, please. So today, I open by saying that our focus was on products and growth. And this slide here shows the pathway we are building with our products to drive growth and with it, delivering long-term value. So the presentations from the team today were designed to give you greater insight into how we're actually going to make that happen.

And to reanchor you, at the start of the day, I outlined that we would demonstrate to you the following: Firstly, confidence in our ability to drive the business now and beyond to 2031 by showcasing our late-stage pipeline and our focus on defined value propositions and by providing some detail on how we are reallocating capital and resources to change and invest in R&D.

With that, I think we're going to go to questions. I'll ask, Guys are quick. I wouldn't want me get a gunfight with you. So we'll bring the team up. So Julie, Nina, Charlotte, Kaivan and I think Sanjay as well.

And as we said earlier, raise your hand, you guys clearly remember that. So Zain, I think you were -- do you want to go first? And then I'll just wait while everyone sits down.

Zain over to you.

Zain over from JPMorgan. First question is just on the 2031 target and beyond. I think Julie sort of ended with a comment on it in terms of 2031 now sounds like it's organic, but just to confirm that Nuvalent included in the 2031 are greater than $40 billion. And then the target or ambition for accelerating growth beyond 2031, you mentioned that it's organic in terms of delivery on your commitments, but how much of that is dependent on BD in terms of the ambition beyond 2031. That's the first question.

The second question is just a follow-up on 2027 margins because I think the path on 28% to 30% is relatively clear. And you have the cost savings that will help offset some of the dolutegravir. But next year, you've got the Gilead royalty going in Q4 IRA impact potentially and R&D, you've mentioned will significantly outgrow sales. So just how should we think about '27 in terms of margins? I think consensus has got margin expansion. So what are the other drivers that could get towards margin expansion?

Okay. So in terms of the first question related to Nuvalent and so we've emphasized that we are totally committed to more than 40%. Obviously, the Nuvalent acquisition happened recently, and we've now got accelerate growth. Accelerate growth for sales start in 2030, but they're quite minor in 2030. It's more of a longer-term play. But net-net, we just -- we'd like to emphasize that we are saying we will deliver and we will deliver more than 40 but we didn't want to get into minor increments each way along.

I think as Luke mentioned, it is a portfolio. We obviously had the camlipixant news just over a week ago, but it is a portfolio, and we believe we will deliver more than 40% overall when you take it asset by asset. Everything we do as well. I think as most people know, is PTRS adjusted probability of technical and regulatory success. But inevitably, you get movements in the portfolio now that we've built to build that optionality.

And then none of it at all is dependent on what you might call new BD. So if we do further deals, which we do intend to do, we've got capacity to do them, as Luke outlined, they would be incremental on top, if that answers that question. And then in terms of the margins, I got this question in the break actually from quite a few people. So we have guided the margin to the end of 2026, which is more than 31% at 25 average exchange rates.

We then guided the dolutegravir period because we knew and appreciated that investors were quite concerned about that period because of the profitability of HIV. So we did an extensive amount of work as a team to basically understand how we could underpin that margin through that period. But we did not want to get into guiding a margin every year.

So we gave the assurance based on a whole series of factors that we could hold the margin stable through the dolutegravir loss of exclusivity. What we're now seeing because this program then generates the additional savings, which total GBP 1.9 billion by 2029, it allows us to drop through some of those benefits to give not just a stable margin, but the optionality to also have an improving margin through that period. And it builds 28 to 30. So the period when dolutegravir hits the most, it's most protective.

I'm trying to pick the rest of you. Have you had a question before? And then we'll go to James and then anyone in the back.

Naresh Chouhan from Intron Health. Just one on vaccines. It seems that the pharma business and the vaccines business are going to have increasingly different outlook in terms of innovation growth rates, capital requirements. So how wedded are you to continuing to own vaccines, which presumably, if they are separated would unlock quite a lot of value and would further simplify the business.

Short answer is very wedded. I mean the capital intensity really is in Regis' shop. I think the main challenge with vaccines, frankly, is the paucity of novel targets of innovation. But again, we're trying to capitalize on that and some of the signals that we've observed there. But I mean, it's a fantastic business. It's very hard to get into. Okay, it's under short-term pressure, frankly, because of politics in some locations and post-COVID hangover.

But frankly, I think if you look at the medium to longer term, it's a very durable business with very high barriers to entry. The question is what can we do to be more operationally effective? How do we make this plant more productive? And then when we do see innovation, how do we make sure that we're participating in it faster and more aggressively than others.

So yes, long story short, we like the business. But again, the hierarchy for us in terms of capital allocation, you can see is specialty. And again, that's why we're highlighting that from 2031 plus. And then James, and then I think Sean will go to you. Is that Sean up there? I think Yes, Sean and then I promise we'll get to everyone.

So James Gordon at Barclays. Two on HIV and one quick one on R&D. So on HIV, I think the previous plan was to have a 6-monthly prevention product. I think it was in 2028, but I couldn't see it on the slide. So are you not doing 6 monthly prevention anymore? And on treatment, I think it was 6 month treatment, 28 to 30. So I could see that you're -- I think starting the Phase III in '28, but when do you think that launch is that beyond '29 so post dolutegravir LOE is when you'd have a 6-monthly treatment? And then also just a clarification on orals, I think you also talked about, but when do you think you could have a weekly oral or a monthly oral in the market, please? And then the final one, just squeeze R&D spend. I think before you said R&D would grow faster than sales is the way you put it. Should we assume that's the assumption that effectively you spend less on SG&A, but R&D keeps on growing faster than sales? How should we model that, please?

Yes. Sure. I mean, long story short, yes, we want to drive R&D as the portfolio changes. When I joined GSK, we launched Trelegy and a few thousand people in the U.S. You look at zidesamtinib, we're talking 10, 20 people. So Charlotte, over to you. And then, Julie, if you want to add anything on that one as well, if I May.

Great. Thank you for the questions. I'll start with the 2x year prevention. So our market research and prevention says to us that really 3x yearly is the optimal. I updated on the 3x yearly today with -- we hope data in the latter part of this year to support approval next year. It aligns very well with Medic's preference in terms of bringing people into the clinic and wellness checks and sexually transmitted disease checks.

That said, we know there will be a subset of the market that we'll still seek for twice yearly. And so we remain committed to that as a line extension. And we have actually a prodrug of cabotegravir that will take into the clinic during the latter part of this year. We will look to develop that using PK bridging approaches, and we'll update on time lines on that more in due course. the twice yearly treatment, you asked about potential time lines for that. We have a bold plan. We have a bold plan looking to get to approval in the latter part of 2030.

And we have a bold plan because we like the profile of it, and we want to take it out to the community as quickly as possible. It's too soon to be getting the details of our Phase III plans. We need to keep working those through and obviously discuss them with the agency. But I can tell you how we're thinking about it, which is, firstly, we're very focused on Phase III start in 2028.

That will be using the entirety of our Phase I data on different formulations as well as our Phase II data for 184 and 499. For the Phase IIbs, as you heard, 184 is underway, 499, we will start soon. And then for the Phase IIIs, what I would say is that we're going to learn a great deal from our 3 times a year treatment trial, QUATTRO that we have started. We started mid-'26. We're looking to gain approval in 2028. And we will be taking those learnings into the Phase III development of our twice yearly. Your last question was on... Orals.

And the markets that we're leading in, and we just talked about one long-acting injectables. We know 70% of patients from our market research are saying they prefer a long-acting injectable, but we definitely want to cater to those who would rather avoid the injections, and we know others have been leading in that space.

However, there remains a strong opportunity for a long-acting oral weekly that's in based, and I've talked about why today in terms of the superior efficacy barrier to resistance and also it's so familiar and highly trusted by patients and providers. So we will be focusing on a true best-in-class INSTI-based oral weekly and moving at pace. We have VH359, which we believe has the potential to be a best-in-class oral weekly capsid inhibitor in Phase I.

And we have multiple other INSTI and capsid inhibitors in preclinical development. And I would also say we have a long relationship in INSTI design with our other stakeholders, Shionogi. And so we will update more on time lines regarding the oral weekly in due course.

Great. So we do Sean, Sarita and then Sam. How about that? So Sean, have you got a microphone up there...

Sean Conroy from Shore Capital. Just firstly, I will pick on the one Phase III trial in vaccines that you announced of the 34 that you're planning. Is the ambition with this MAYA study to ultimately get a labeling change for Shingrix? And could you give us some idea of what that might ultimately mean for progressing the pricing over time?

And then maybe for you, Julie, in terms of this restructuring program and this steer of capital into specialty medicines, is there a risk -- you've talked about this being for mature products. So presumably, the bulk of this is coming from GenMed. Is there a risk that you end up underinvesting in some of these brands and this general medicines becomes diluted to the growth story? And if so, how open would you be to divesting some of these brands in the future?

Thank -- so Sanjay, and maybe Kaivan, feel free to give any color around some of the signal finding work and just the basic hypothesis that is there. I mean I think with MACE, clearly, the regulatory pathway is more robust than dementia, and that's why that's being prioritized. But Sanjay, do you want to get into that and then we'll come to you, Julie.

Yes. So the answer is the ambition to get a label is an emphatic yes, right? So how do we get there? And why are we so confident? So first, I showed you 7 studies, real-world studies where what is remarkable about the effect size, it's fairly consistent across these 7 studies. So despite all the limitations you have with real-world studies, the fact that the signal is so consistent gives us a lot of confidence.

Second, we have some unique insights into biology that we're exploring that might give a little bit of credibility to the biology and the mechanism of action. So if you take these 2 things together, the confidence that we are going to be successful in this study remains high, and that's why we're embarking on this. We are in discussion with regulators and the reception so far has been very favorable.

So we are progressing and hope to finalize those discussions over the next few months to really move forward with the MACE study. And as Luke said, the pathway and the road map for MACE is relatively well established. The endpoints are fairly standardized, and I think Kaivan can speak to them the way we conduct these studies and the benchmarks are available already. It's much more of a difficult discussion with dementia, which is a much more heterogeneous condition, and we are in discussions with the regulators to try to solve that.

Yes. Just to add that my organization has significant experience in cardiovascular outcomes trials. And so the design that's being implemented for Shingrix is adequate and well controlled to support a registrational label. But as Sanjay said, this is a fairly unique setting where clearly, the data in support of Shingrix's cardiovascular benefit appears to be working through inflammatory mechanisms rather than through lipids, blood sugar or blood pressure. And so we've done a lot of work to ensure that there's understandable mechanistic plausibility that would go in concert with that large outcomes trial, and we've engaged the appropriate experts to make sure that's an integrated package.

Can I suggest for George, maybe just...

Pricing. I didn't...

The impact on the physicians and patients...

Willing population.

Yes. Maybe to talk a little bit more broader about what we think the benefit of such an indication would be. Just to take a step back, when you get an additional indication for a vaccine like Shingrix, it's not to get a license for a broader population, but to increase the motivation of people to be vaccinated.

And we've got extensive research that shows that when there is a strong recommendation from a physician, the willingness to be vaccinated increases from 40% to 8%. And we also know from research that an indication such as MACE or dementia for that matter, increases the confidence of the physician to provide a strong recommendation from 50% to 90%. So that gives you, I think, a very good understanding of what the benefit is of such an indication.

But also, it's a major driver in the short and midterm ahead of such an indication of why we are focusing so much on comorbidities and comorbid patients to be considered for vaccinations for Shingrix. And in fact, more than 70% of the 50-plus population that Shingrix is indicated for are suffering from these comorbidities.

Obviously, Sanjay spoke about how this proposition improves the economics. And if the study is positive and we have the data, we will be looking obviously at what that means in terms of price.

Julie?

Yes. Okay. GenMed, the GenMed question. The GenMed business is an invaluable part of our portfolio. A number of reasons for that. But one of them is that it's synergistic with the other parts where we sell respiratory. So vaccines, obviously, with Arexvy, together with specialties such as Nucala Exdensur. And so there's an ability to use the field force across multiple parts, GenMed vaccines and specialty.

The other point about GenMed is that although it's under some degree of pressure, it is significantly a cash-generative business. So it's part of the portfolio overall. Very importantly, the reason we're choosing to invest behind specialty more so -- and it's actually of the 7 major assets that have been chosen to be accelerated, specialty is 6 of them.

It's just because of the longevity, the future of that business and the growth and the profitability from that business as time moves on, as you go out of the investment phase into major launch and thereafter. Oncology, in particular, people probably know the margins that you get in oncology products. So that's essentially why.

Yes. And we've signed a series of deals in emerging markets across multiple geographies with companies like Zuellig, where there's basically revenue targets and profit sharing to obviously put some ballast with that. So I think, Theresa, your hand was up and then session.

It's Theresa from Morgan Stanley. So the later-stage pipeline appears to be weighted to assets as you've highlighted that are derisked mechanistically and clinically. But how should we think about the commercial risk of entering markets with potentially entrenched competitors? And are the convenience advantages alone, so for example, with IL-33 wrapped enough to drive meaningful share? And then just a quick one on Neladalkib and ALK+ lung frontline. Is it possible to get an earlier look versus 2030? So could it come at interim in '28? And what percentage of the overall value or peak sales opportunity is contingent on frontline?

Sure. Okay. So Nina, do you want to cover that? I'll resist adding to my because we hear from the team today, and then we'll go to Hesham.

Yes. Let's -- just with the last one, is it possible to read out early? Yes, it's possible. It's event-driven. So events will determine how early we get there. In terms of competing with long-acting specifically, I think I want to be Kaivan can definitely add, but I want to be very specific. Long-acting is the first thought that comes to mind is it's convenience.

It's actually not -- it is convenience, but it's a feature of the drug that ends up in better persistence or longer persistence and earlier use. So it's a feature of a drug that changes potentially benefit for patients and the willingness of the physicians to prescribe the drug earlier. So that -- both of those things are translating into patient benefit and outcome.

And I think one core component of success of long-acting formulations is to position it like that and profile it like that rather than just convenience. And then on Nella, I'll...

First line is the bulk of the value, as you'd imagine. But we did an enormous amount of due diligence with physicians who are empirically exposed to the drug, and it's recruiting incredibly well. So -- that's always a good sign. Hesham, anything you want to add?

And maybe just Sachin and I were actually talking about this a little bit at the break as well, too. Just a few points to highlight. The first, of course, is as we think about the comparator in the study, of course, different comparator versus the lorlatinib trial. So this is against a second-gen TKI. So just something at least to take into account.

The second, of course, to Luke's point, recruitment rates are really important in terms of how these event-driven studies actually read out as well, too. And then the third, of course, is how early does that separation actually take place. I mean when we look at the data with Nella, especially in the TKI-naive patient population, we look at these 12-month duration of response, 91% versus 70% with lorlatinib, the response rate, 86% versus 76% as well too.

So I think these are all variables that we have to take into account. But in addition, we're always going to be opportunistic in the context of how the trial was designed. And specifically, again, like I said, how early that at least separation occurs and possibly when certain interim analyses could potentially read out as well, too.

Yes. And I'd just add -- just to build out on the commercial differentiation. I mean, use the example of the WAP transaction. I mean we had been following Xolair for multiple years. And I can remember back at Roche, this product was expected to be finished, kept growing. And initially, we thought it might have been driven in asthma, of course, it's not. It's being ablated in that population.

Then we identified Chris' team identified RAPT and then we started to do market research and talk to physicians using it. And it was pretty clear the barriers there in terms of dosing, the 25% population with obesity, et cetera, and just the frequency of having to treat children in particular. Then we characterized the BTKs and the safety profile of BTKs. And it was pretty clear from pediatricians that they would be reluctant to use those drugs in kids, plus the half-life is pretty short.

So how much coverage if they're away, away from supervision, et cetera. So it's always a combination. And then you had the target, obviously, derisk and the learning from Novartis there. So it's always -- it's a combination of things that we do. So thanks, Theresa. Sachin?

Sachin Jain, Bank of America. A few questions, please. So firstly, on Bepi. I know we've got a bit of time post these. I wonder if you could just update us on your thoughts as to how you think about the speed of launch. So 2 deltas. Any sense on speed of payer uptake, both commercially and in government channels given the government is a big section? And then you commented to a bolus of patients. Again, I wonder if you got a better sense of that.

So you listed today 50,000 patients in the U.S., less than 1,000. Of that population, do you have a sense how many could be fast adopters? So just to sort of start thinking about the cadence of launch as we think about the back end of this year, early next year.

On the IL-33, do you have a target exacerbation reduction profile that sort of puts together all of your sort of internal data, mucus, et cetera, relative to existing biologics of 20% to 25% that sort of builds on the just duration? And then just one follow-on for Hesham, which we didn't get to touch on earlier.

Just it's the first disclosure of 35% of patients recruited in the study, which I know you said it's in line, but given, I don't know, the 300 KOLs or whatever you've spoken to are very excited. It seems to me that maybe a little bit slower than anticipated given the study has been running for a year, but just any sense there? And can you accelerate it?

Great. Do you want to cover that one first Hesham? Then I'll go on IL-33 and then we'll do Bepi. And Pedro, feel free to add in anything as well. Pedro has joined us from AbbVie has quite a bit of experience in that area.

Thank you, Luke. I'll start off first maybe Sachin by saying, of course, that recently at ASCO, we just saw the first-line TKI-naive data for Nella as well too. And prior to that, I'd probably say the data that had been communicated was probably relatively limited in its scope. So I think we're starting to see now, certainly in terms of recruitment picking up quite significantly, especially with the communication around the data, the potential of the asset itself.

And of course, how we're seeing the -- not only the medicinal chemistry design of the drug itself, but also the pharmacology playing out especially the fact that it has this activity against both single ALK mutations and compound ALK mutations as well, too. Getting to the question specifically around recruitment. What I would say is, no doubt, are there opportunities to accelerate it? There is. We're actually engaging and Nuvalent has been engaging, of course, with patient advocacy groups, certainly investigators. There's a lot of excitement about the drug itself.

And I think when you add to it the potential in terms of scale that GSK brings in terms of clinical operations and execution as well, we see a lot of potential for that. I mean, Luke talked about and touched on the fact that as well, too, that we're seeing at least with Neladalkib, more than 200% ahead of recruitment on our second-line study.

So we see the same potential here, especially in these areas of high unmet need. And we think that certainly, that could pick up, especially over the next 6 to 12 months.

Yes. So I think the question was effectively the product profile we'd be targeting with IL-33. And as Nina said, per the entire portfolio, long or ultra-long acting, we don't have to trust our intuition. That's a good thing. Exdensur is going to qualify and substantiate why that translates to clinical benefits in a real-world setting. With IL-33, we additionally have a mix of mechanistic and trial innovation. And so exacerbation reduction target sizes, we're accustomed to seeing those for T2 elevated disease.

In T2 low disease, there's no approved therapies. So the types of reductions we've seen with Nucala, for example, I think, would be transformative in T2-agnostic target medicine profiles. But what I would say about IL-33 is very different from the mechanisms we've seen previously. So I wouldn't expect it necessarily to work on spirometry, but you might see an enhanced effect on severe events, hospitalizations, -- and as I've described, the biology also potentially is having a direct effect that's protective on the vasculature. And so for us, the types of effect sizes you've seen previously, but extending into all types of COPD, additionally, in particular, for severe events and the cardiopulmonary hard endpoints, I think, will materially differentiate our program.

Nina, take bolus.

Yes, definitely. So on Bepi and then Pedro, please, as Luke mentioned, Pedro has history of working in hep C, so a pretty good idea of where we might go. So bolus, yes, we expect basically that patients who are currently on treatment, and you know that these patients are on lifelong treatment are the first patients who will start therapy.

When we talk to the physicians and centers that treat hep B patients, they will quote frequently number of patients that they expect. They will start on therapy as soon as available. Testing in different geographies is at different stages. So in Asia, testing is very present and part of routine care.

As it doesn't determine diagnosis or treatment in the U.S., it's definitely less present. It's a relatively simple test. It's just not used because it doesn't help at the moment in the treatment pathway. We are working on that as well, supporting centers to implement or start having testing available.

What we -- we have pretty good idea on price. where -- what is going to be acceptable. And obviously, we will see the price once the drug is approved. I think we made the comment before, we do expect to be in the scale of hep C. Now that has been quite some time ago. We will see where we end up.

Pricing then negotiations and specifically enabling access will happen as after the approval, so end of '26 and '27 discussions with the payers in the U.S., which we expect to then unlock. In terms of barriers, we do expect the testing will be required for -- as part of prior authorization. I don't know, Pedro, if there is anything else you want to add.

Yes, to add to that... Just to add to that one that there was like in the ACV space, there was kind of a bolus of patients, and that's what everyone has in mind. With Bepi, we are expecting a different approach. We are very pleased with the way the medical society has taken the data in the functional cure, but also beyond functional cure. But what was driven the ACV uptake was mainly the cirrhotic patients that were waiting to get that cure.

Here, the treatment is not on the cirrhotic patients. So we are expecting the patients really to be willing to be treated. Actually, there is a segment, quite sizable segment that in the market research are coming really willing to start the treatment as soon as possible. But that will be basically going to the doctor when they need to go. We are not expecting what happened in ACV that basically there was a massive pressure to the doctors, but also to the payers to get the product reimbursed, mainly because the cirrhotic status.

So -- but we are expecting really a fast uptake in that population that is really willing to be treated. Medicare, these patients basically are all over the commercial and Medicare. So we are expecting Medicare to come a little bit later due to access situation, but there is a lot of these patients that are with the commercial.

And relatively high geographical concentration in the U.S., typically vertical, as you'd imagine. other questions, we'll do around and then we'll go online.

Michael?

It's Michael Leuchten from Jefferies. Two questions, please. Just on HIV, the IP for cabotegravir up to 2040, maybe longer. What are you assuming in your revenue estimate? So when we look at your indicative revenue chart, what's in those assumptions?

And then just maybe, Kaivan or Nina, back to IL-33. If I heard it right, you're going to do the cardiometabolic endpoint with a partner. I think you said academic. Is that not going to slow you down given that this is going to be a competitive space?

Do you want to go with that one first, and then we'll come to Julia and Deborah on the assumptions.

Yes. To be clear, it's not an academic alliances with a professional ARO, which are the organizations responsible for running most cardiovascular outcome trials. So the opposite. We're going to be partnering with an established entity that has delivered multiple MACE-like studies over the last 20 years. You can imagine there's a list of them that are familiar in the Boston area and beyond.

And maybe just to clarify, that's not the only outcome we would look at -- so yes, if that's your question about slowing us down. We will have the...

Sorry, apologies. in terms of the study time lines. Yes. So this will be additional to a more conventional exacerbation endpoint study. And you're right, it won't be dramatically shifted exacerbation studies and this type of cardiopulmonary composite endpoint. It might be that study is a year later than the exacerbation study, which obviously we would file off the exacerbation study if it came sooner.

Logically, we're trying to aggressively exploit differentiation and disrupt the targets been derisked for us. Okay. Julie and then Deborah? -- and then we'll take one online.

Yes. So in terms of cabotegravir, the new chemical entity patent protection is into 2031. Obviously, 3-year patents, 3 times a year patents are then pending, and they would take you into the mid-2040s. I mean just in the way in terms of how we take these things into our forecast.

Until we get an extension or until we get a new combination, we would always -- in the forecast we do, we would use the earlier date of expiry until we have extensions available to us, et cetera. Deborah?

Yes. Just to build a little bit on how we're thinking about this. So we've got patents granted for the 6x yearly, so current Cabenuva to 2040, and we've got a number pending. So there is a robust intellectual property strategy that's playing out. The other way I think about it is how quickly can we cannibalize one product into another. So it took us 12 months to cannibalize the once monthly into twice monthly, about 70% in the first year and then everything else pretty rapidly afterwards.

Our expectation is that we would rapidly cannibalize the 6x yearly into the 3x yearly. And obviously, that's coming in 2028. And then we would rapidly cannibalize a big chunk of the 3x yearly into the 2x yearly because in treatment, there is a really strong value proposition for the twice yearly because of the unique assets, VH184 and 499 in the way that Charlotte's described.

So in our model, we are modeling a very rapid cannibalization in treatment product by product as you get further and further through the pipeline. PrEP is a little bit different. It's a much smaller opportunity for us market size-wise, but also we absolutely prioritize treatment. So in PrEP, I think you will find a coexistence of the 3x yearly and the 2x yearly because some physicians really, as Charlotte described, really want that 3 times yearly.

They want people to come in and have their sexual health kind of dialogue rather than just leaving people unprotected for too long. So I think it's the way of thinking about it would be IP and cannibalization. And as you bring it together, the pipeline really is very, very sustainable from a value perspective.

Thanks, Deborah. Okay. Last question is a phone one. We've got 3 on phone. Okay. Is there 3 people with 3 questions or Okay. 3 people. All right. Well...

Our next question comes from Seamus Fernandez at Guggenheim.

So I wanted to ask a little bit more about the accelerated approach on the respiratory side, particularly with the long-acting TSLP. It says on clinicaltrials.gov right now that there is an ongoing kind of formulation study, but you are planning to move forward in the second half of this year. I just wanted to get a little bit more color on your confidence that this formulation will have a true kind of full 6-month coverage all the way through the sort of end of treatment.

And then the second question is just your conviction in the TSLP mechanism having a robust result in COPD. I think that's one where I think there's still some questions and whether or not TSLP should be targeted to patients with elevated eosinophils.

Great. Thanks, Seamus. I mean I would start the answer and then we'll go to Kaivan. We looked at every long-acting TSLP out there. And this was one that we clearly had the most confidence in, in terms of its durability. Programs and context, Kaivan?

Yes. So very confident indeed because we've run a Phase II study. We now have interim pharmacodynamic data that supports the Q6M profile in asthma. And as I said earlier, we also have data in nasal polyps from our partner, Hengrui, which has allowed us to have confident discussions with regulatory authorities for end of Phase II. We've actually now submitted all 3 Phase III indications under the IND, and we will be starting those 6 studies by the end of the year.

So very confident in terms of our ability to select dose confidently across all 3 indications, which I think is unique in the ultra-long-acting space for TSLP. Mechanism-wise, I think that the data we saw with Tezspire demonstrates a best-in-disease profile for nasal polyps.

In asthma, clearly, the differentiator is that it's truly eosinophil-agnostic in asthma. But you're right, in COPD, we don't expect it to work in true T2 low disease in contrast to what I described for IL-33. So the COPD study will enrich based on either eosinophils, pheno or a combination thereof so that we're in that sort of intermediate high T2 space.

Next question?

Our next question comes from Kerry Holford at Berenberg.

Thank you for the full review of everything today. The one thing that stood out to me, I think, is very clear, business development is increasingly central to your pipeline. And the commentary today suggests it will remain so going forward.

So really, my question is, following the failure of camlipixant that we saw recently, are there any key learnings that you can now take from the BELLUS acquisition? Anything you would highlight here, particularly in the context of more recent business development decision-making post that deal with BELLUS thinking about your recent round of BD, but also your decision-making when you are looking at future targets going forward?

Right. Thanks. I mean I think and feel free to add guys or Tony as well. And I think with BELLUS, again, we approached it, we tried to integrate the lessons from Jeff Dupixent in terms of target selectivity, dysgusia, taste disturbance, the cough counter, all of these elements. And in the end, we had one study that worked and one that didn't.

But then we looked at the totality of the data, we just thought, okay, this is not going to shift care. And so we took that decision to reallocate the resources. I'm not sure what else we could have done different. I mean, in the effect -- the effect was disrupted by a Hawthorne effect. Obviously, people changing their behavior when observed. And that's always a challenge. We knew that was a challenge in that program. So I'm not sure it would drive a main shift, but you are correct.

I mean, we are very committed to BD. We're very active with BD. We see it as an integral part of the strategy. But again, disciplined. And the deals that you've seen us done this year already, I think, are a good framework to employ for the types of transactions that we would be looking to execute in the future.

And at the end of the day, this is drug development. We have a portfolio for a reason. Typically Phase III programs, 75% probability. So you are going to have situations like we had. I don't know, Tony, do you want to add anything else?

Yes. Just to report, Hi Kerry, by the way. Look, for camlipixant, we took it on because we saw a significant unmet need in an area of adjacency. If we learn anything from it, and you can now see it entirely reflected in the portfolio that you've seen this afternoon, which is where we can. We're focusing on hard endpoints. You heard that in the MACE versus dementia conversation that was going on around Shingrix as well.

But again, I mean, let me just reinforce, this is an area that we saw was an adjacency for us. It had high unmet need. Obviously, we're disappointed and particularly disappointed the patients with refractory chronic cough. They have no medications. The study read out in the 3 dimensions that we were anticipating, the Hawthorne effect overwhelmed the outcome to a greater extent than we anticipated.

Thanks, Kerry. Was that your only question?

Well, if I can squeeze another quick one in, as I have been online for two hours I promise. HIV, I wonder if you can just talk briefly to how Apretude is faring in that PrEP market. I know you referenced it being less important than the treatment. But how is that faring in PrEP relative to Gilead? And what do you expect for market share evolution in that space if Merck succeeds with a once monthly pill?

Great. Thanks, Kerry. So Deborah, over to you.

Thanks, Kerry. So I think what you're seeing is a reshaping of the PrEP market. It's continuing to grow rapidly. And as more options come in, less optimal daily treatments are being replaced by longer-acting ones. And I think the Merck once monthly, our own long-acting injectables and obviously, our competitor long-acting injectables are all going to serve patients and protect them from acquiring HIV in a way that the daily orals had not done because people just did not adhere to them in the way that they needed to.

So I think that it's a really good story for innovation. In terms of what's happening at the moment, so you will have seen that we grew Apretude 39%. The market continues to grow. We're holding share in a fast-growing market. And you will see YoY has had a relatively good uptake.

Long-acting injectables are growing fast in the segment. But I think we're holding our own, and I'm really delighted that versus our competitor, we're holding our own, and we're continuing to grow in this part of the HIV market. But as I say, more choice is good when what's there today is suboptimal. That's why only 25% of people who could benefit from PrEP are currently taking PrEP. So I think it's going to be a good news story for those that are involved in that market.

Great. We'll take one more question, and then I think we'll close because it's very sunny outside.

Our final question comes from Steve Scala at TD Cowen.

And I have 2 questions. First, given that GSK seems to be an industry leader in organizing decades of in-house data, why was the term AI spoken, I think, only twice today and certainly wasn't a focus?

And then secondly, I'm curious, why is enlarging R&D presence in a country that is so difficult on pharma and you might not launch new drugs, some new drugs in the future anyway. Why is that a good idea? As one example, GSK employees won't even have access to the latest innovation.

Is there some aspect that we're not seeing? I think you'll answer that the talent is so rich in Cambridge, but there are certainly other parts of the world where that's the case as well.

Thanks, Steve. So I mean, on the AI one, my rule of thumb is the more people talk about it, the less they're doing. So we are very, very active. But again, I think we're quite selective in terms of what we disclose because I think it is so fluid right now and these people are very difficult to attract and retain. We're quite cautious about how much we disclose.

But clearly, the effort we're putting is really on the frontier of Tony's organization. I mean, do you want to provide a little bit of color? And then I think, Steve, your second question is very fair. And you will hear the answer for Tony exactly as you've just suggested it may be, but I'll let Tony answer and then we'll close.

So look, AI is at the center of everything we do. We don't talk about it so much because of what we feel is a competitive position. It's pointless without data. So we focus very heavily on the acquisition of data, and that really underpins the approach that we've taken. I'll tell you more about it, Steve, when we talk about early R&D and how we're applying AI, not just to the idea of matching targets and patients and opportunity, but designing molecules and ultimately making clinical trial execution more effective.

We've got 150 people in our AI group. These folks have PhDs in maths. We don't unwrap other people's shrinkwrapped AI products. We have access to token windows through our collaborations with Cerebrus, for example, that leave us stable for the coming 2 to 3 years where GPU utilization is going to be a really big question.

But I'm keeping what we do pretty close to my chest. We'll share more of it. But as I say, it's all about the data. And in fact, indeed, just -- Steve, I don't want you to misinterpret. We are continuing to underpin our presence in the U.K. I don't think we said we were increasing it in terms of -- and again, there again, it's all about a focus on data, the relationships that we have with Cambridge University that I mentioned. We also have relationships with Oxford University and with King's College.

And we'll continue to deepen that type of relationship elsewhere in the world as well. I mentioned in the deck that we'll be looking to do more on the East Coast of the U.S. You'll hear more from us on that in the near term and indeed in China.

So I'd say what we focus on is where we can access unique patient-related data that helps us make the sorts of decisions that you've heard illustrated throughout the afternoon. And we apply AI/ML where it enables those decisions in an effective way based on the nature of the data and the iteration that's available within it.

Great. Thanks, Tony. So I think we should close now. Firstly, I wanted to thank you all for participating. Again, very thoughtful and fair and challenging questions. So I appreciate that. Thank you to the IR team -- well, firstly, thank you to the presenters. I mean, yes, I personally couldn't be more proud, and there's a massive amount of thought and effort that's gone into this. And it's a privilege on my part, frankly, to moderate this today. For the IR teams, thank you. There's a huge amount of work, particularly to Joanna, who had to pull all these slides together and also the LSE Group and the Conn's Group, India has been coordinating it and everyone else that helped out.

So thank you. It concludes it. If you're in the room and you would like a drink...

A warm welcome to this GSK call on our agreement to acquire Nuvalent. My name is Constantin Fest, Investor Relations. I'm delighted to have here today with me Luke Miels, CEO; Nina Mojas, President, Global Product Strategy; Tony Wood, Chief Scientific Officer; Julie Brown, our CFO. Also for the Q&A part of this call, we'll be joined by David Redfern, President, Corporate Development; as well as Mondher Mahjoubi, our Chief Patient Officer. Please go with me to the next Slide 3, for our disclosure statement. Also note our cautionary statement on Slide 4. With this, please turn to Slide 5, and I will hand over to Luke to start this presentation.

Thanks, Constantin. Good morning, and thanks for joining the call at short notice. Look, I'll start here first. As a reminder, this is the framework that we're using to drive value for patients and shareholders. It's got 3 components, so driving top line growth, accelerating late-stage assets and combining this with simplification. And this deal is a disciplined continuation and acceleration of that strategy. Next slide, please. Now we've been following Jim and the team at Nuvalent and their impressive medicinal chemistry work for some time. The deal is a consideration of USD 10.6 billion. It's accretive to EPS in 2029 and is expected to close in Q3 of 2026.

This acquisition critically will bring multiple products. with the 2 lead assets already filed and expected to launch in 2026, immediately impacting top line growth. Next slide, please. So here's the logic for the deal. Simply, it's on strategy and helps us deliver top line growth and accelerate R&D. It accelerates our planned entry into lung via 2 well-defined subpopulations, which have clear unmet needs. Both products work via validated targets and are designed to address these established unmet clinical needs. These are small molecules in oncology.

So, the deal combined with measures to offset costs is accretive to sales and operating profit in 2027 and EPS in 2029. And through discipline, we are maintaining the 70p dividend and the progressive policy. Next slide, please. Finally, just at the start, I would add, this is our type of deal. The difference is that it's a multiproduct deal versus a single asset, single company deal. Zidesamtinib for ROS1 mutations and neladalkib ALK1-driven tumors are the types of products we like. And they're an extension of our BD strategy, which you can see on this slide, which is to acquire external innovation that works via established targets that addresses unmet efficacy or tolerability needs. So with that, I'll hand over to you, Nina.

Thank you, Luke. As Luke mentioned, Nuvalent is a company that has been very successful in developing precision medicine assets with its clinical stage assets focused on specific well-defined patient segments in lung cancer. ALK+ and ROS1+ mutations affect about 3% to 5% of all non-small cell lung cancer patients with about 80% of patients already diagnosed at Stage 3, so metastatic stage. These patients are often younger in their 40s and 50s, unlike typical lung cancer patients who are normally diagnosed in their 70s. These patients are more frequently women and in general, have high rates of central nervous system involvement, so brain metastasis.

What's very characteristic about this specific defined patient population is that they are one of the most engaged lung cancer communities and are actively shaping their treatment. Established treatments have been transformative for these patients, and they frequently remain on ALK and ROS1 tyrosine kinase inhibitor therapy for years. As an example, treatment duration in first-line non-small cell lung cancer patients treated with PD-1s, majority of cancers of patients in non-small cell lung cancer patients. They are treated for approximately 10 months. For EGFR-mutated cancers, patients are treated for up to 2 years. And for ALK+ first-line patients, current median PFS is longer than 7 years and hopefully further increasing.

Next slide, please. Acquisition of Nuvalent is going to strengthen our overall oncology ambition. And specifically, it will accelerate our efforts in lung cancer, supporting both development and commercial efforts for our ongoing Ris-Rez program in lung cancer. After this acquisition, we are looking at a number of milestones from 2 approvals this year, potential approval for ROS1 naive patients next year, ongoing trial in first-line ALK mutated segment and the ongoing trials for the early-stage HER2 asset. On the other hand, GSK's global footprint will maximize the opportunity for Nuvalent portfolio of precision medicine assets.

Next slide, please. We are moving to the ALK-specific segment. Over the past decade, we have seen an improvement in the outcome for ALK+ non-small cell lung cancer patients as innovation focused on solving unmet needs such as blood-brain barrier penetration to address CNS metastases, which I have mentioned before are very frequent in this patient population and then broader coverage of resistance mutations. The current third-generation ALK inhibitor, lorlatinib, recently had 7-year update of its CROWN study, where the median PFS still has not been reached. Despite strong efficacy, unmet need remains as tolerability issues significantly limit potential quality of life and therefore, adoption in first line.

These limitations stem from the lack of selectivity for ALK and involvement of TRK kinase, which Tony will describe in details in a moment. Neladalkib is a next-generation ALK tyrosine kinase inhibitor designed to improve on lorlatinib's profile, sparing TRK engagement with first-line pivotal study ongoing. Next slide, please. So how did this development impact the evolution of treatment practice in ALK+ non-small cell lung cancer space. Most commonly used medicines to treat ALK+ lung cancer are second- and third-generation ALK inhibitors.

Alectinib continues to have a significant use in first line, driven by its acceptable tolerability profile. Despite best-in-disease efficacy, lorlatinib adoption is limited by its tolerability issues, central nervous system events impacting cognition, speech and mood and then metabolic issues like hypercholesterolemia, hypertriglyceridemia requiring co-medications and then significantly weight gain. These issues are attributable to lorlatinib's off-target activity.

And I'll now hand over to Tony to talk more about neladalkib's differentiation and supporting clinical data.

Thank you, Nina. On this slide, you can see the evolution of the -- of the ALK family inhibitors. Neladalkib is a fourth-generation inhibitor, is designed to pair third-generation ALK potency with strong CNS penetration while retaining activity against both single and compound ALK-resistant mutations. This, alongside its Trk-sparing profile, underpins its potential for superior efficacy and tolerability compared to previous generations of inhibitors. Each of these characteristics is critical to maximizing the amount of time a patient can potentially benefit from therapy.

Next slide, please. Okay. Taking a more detailed look, we believe that nela has the potential to be a best-in-class ALK inhibitor as it delivers strong performance against the 3 basic pillars of precision medicine. Firstly, and as you can see on the left-hand side of the slide, it's important to hit the driver of disease hard to control the original tumor. Secondly, and also on the left-hand side of the slide, it's important to address or prevent the emergence of key drivers of disease progression to extend the durability of response. This specifically includes designing molecules, which maintain inhibition in the presence of on-target resistance mutations as well as optimizing for brain penetration to address metastatic disease.

This is illustrated on the right-hand of the slide and is critical because of the high incidence of brain metastases at diagnosis for ALK+ non-small cell lung cancer patients. And thirdly, it's important to address selectivity to avoid off-target adverse events, which can be treatment limiting. You can see this in the selectivity index calculated on the left-hand side of the slide. This is critical to minimize discontinuations and dose reductions and to maximize potential therapeutic benefit while removing barriers to adoption. This differentiation is important as it allows nela to improve on the significant cognitive, psychiatric and metabolic adverse events associated with lorlatinib, which severely impact patient quality of life.

Next slide, please. With these design principles in mind, data from the ALkove-1 study support a best-in-class profile for neladalkib based on cross-trial comparisons. In TKI pretreated patients, nela produces encouraging response rates, including for intracranial disease when compared to lorlatinib. As you can see on the left-hand side of the slide, in the second-line plus setting, a median duration of response is not yet reached. And encouragingly, 60% of patients achieved a duration of response greater than 18 months, which is a meaningful improvement compared to 9.6 months for lorlatinib.

Based on these data, the FDA has granted nela priority review with a target PDUFA date of November 27, 2026. In TKI-naive patients nela produces promising response rates compared to lorlatinib and importantly, shows a 12-month duration of response for more than 90% of patients, exceeding the historical benchmark from lorlatinib in the Phase III CRAM study. A Phase III registrational study for nela in the first-line setting, ALKAZAR, is ongoing and recruiting well.

Next slide, please. ALK+ non-small cell lung cancer patients are typically younger non-smokers who are otherwise fit and healthy. This is a highly motivated and informed patient population and as such, a manageable safety and tolerability profile is a key consideration. Nela spares TRK binding, and this is reflected in its adverse events profile, which shows avoidance of the long-term metabolic and neurological adverse events seen with lorlatinib. Importantly, the liver enzyme elevations seen with nela are typically asymptomatic, transient and manageable through monitoring and dose modifications as is consistent with routine practice for TKIs. Overall, they do not result in increased drug discontinuation rates and compared to other ALK inhibitors.

This is also supported by physician feedback, which highlights a more manageable safety profile for nela compared to the intensive monitoring and caregiver burden associated with lorlatinib's cognitive impairment, mood disorders and metabolic side effects.

Next slide, please. On this slide, you can see the ongoing clinical studies for nela. ALkove-1 is a Phase II study in ALK+ solid tumors with several cohorts. It was designed to have registrational intent of TKI pretreated ALK+ non-small cell lung cancer patients. In 253 TKI pretreated patients, nela delivered a 31% overall response rate and a durable response was 64% and 53% of responders estimated to remain in response at 12 and 18 months, respectively. Notably, 78% of patients had received 2 or more prior ALK TKIs, of which 91% had received prior lorlatinib. So a heavily pretreated population for which no approved therapies have demonstrated meaningful activity.

This pivotal data was presented last week in Chicago at ASCO. As mentioned, based on these data, nela has been granted breakthrough designation with a planned PDUFA date in November of this year. ALK is an ongoing Phase III registrational trial in the first-line setting using the current standard of care alectinib as a control arm. This study is enrolling well.

Now let me hand over to Nina.

Thank you, Tony. We are moving now to the ROS1 space. Consistent with the evolution of ALK TKIs, zidesamtinib is strongly differentiated through its significant improvement on safety profile and strong efficacy compared to previous generations of ROS1 TKIs. Repotrectinib carries notable TRK-driven neurological and metabolic side effects that drive dose discontinuations. Taletrectinib, a third-generation ROS1 TKI improves on tolerability, but still brings meaningful dizziness, GI tox and side effects like diarrhea, nausea and vomiting. Based on the large clinical data sets generated across over 900 patients, zidesamtinib shows a class-leading safety profile.

Its ROS1 selective and Trk-sparing design allows for a differentiated safety profile avoiding the CNS and GI side effects historically associated with the class. Ability to stay on treatment for longer has potential to translate into improved median PFS in first line compared to current treatment options. Back to Tony again.

Thanks, Nina. Next slide, please. As with nela, zidesamtinib has a compelling profile. It's a highly potent Trk-sparing ROS1 inhibitor with broad mutational coverage and improved selectivity profile. Importantly, the G2032R resistant mutation coverage supports durable activity in heavily pretreated patients and improved outcomes in early lines of therapy, including in the TKI naive population. G2032R is a common resistance mutation arising following crizotinib and next-generation TKI treatment.

Once more, high TRK selectivity allows for CNS activity, which is demonstrated in patients who received more than 1 prior brain penetrant TKI as well as in the naive population. Overall, this profile translates to a low rate of serious or severe CNS events with significant improvements in problematic adverse events associated with earlier generation TKIs, including dizziness and GI toxicity. Next slide, please. Moving on to the clinical setting and looking at cross-trial comparison to [existing data], you can see a substantially improved duration of response in both heavily pretreated and TKI-naive patients as evaluated in the ARROS-1 study. Based on these data, the FDA has granted zidesamtinib breakthrough designation with a target PDUFA date of September 18, 2026, in TKI pretreated patients.

These data support best-in-class efficacy with comparable response rates and response durations exceeding that of taletrectinib in both the TKI pretreated and naive settings. Next slide, please. Finally, this slide shows a summary of the ongoing studies. The ARROS -1 Phase II study recruited patients with ROS1 positive solid tumors with a specific cohort focused on ROS1-positive non-small cell lung cancer, including those previously treated with TKI inhibitors as well as TKI-naive patients. As mentioned, clinical efficacy supports a best-in-class profile. And importantly, this extends to safety where zidesamtinib demonstrates considerable improvements in rates of dizziness, GI and liver toxicity that is seen with previous generation TKIs.

The pretreated indication carries an orphan drug designation with an upcoming PDUFA date in September, while filing of a supplementary NDA for the TKI-naive setting is planned in the second half of 2026.

I'll now hand over to Julie.

Thank you, Tony. So to summarize, the acquisition of Nuvalent includes 2 launch-ready best-in-class -- potential best-in-class assets with blockbuster potential with PDUFA dates later this year and will further strengthen our oncology portfolio, building on our exciting development pipeline, which includes Ris-Rez, our ADC for lung cancer. I will now cover 3 main areas, and all my commentary will refer to core results at constant rates. So first, the transaction details. We have agreed a purchase price of $124 per share, a 40% premium to yesterday's closing price and a 26% premium to the 30-day VWAP, equating to an aggregate consideration of $10.6 billion or net of cash, $9.4 billion, which is GBP 7.1 billion.

We will commence a tender offer for the shares within the next 10 business days, and subject to regulatory approval, we anticipate closing the deal in Q3. Second, the financial impact. We expect the acquisition to support GSK's revenue growth from 2027 onwards and be incremental to our existing ambition for sales of more than GBP 40 billion by 2031 and to strengthen sales, operating profit and margin through the dolutegravir loss of exclusivity period.

We expect the deal to be accretive to operating profit in 2027 and earnings per share in 2029 onwards, inclusive of synergies and reprioritization. Assuming completion in Q3, we expect a low single-digit dilution to EPS in full year '26 to 2028, but remain confident in our current 2026 guidance range for earnings per share growth of 7% to 9%. Third, capital allocation and the balance sheet. This transaction is aligned with our investor growth priorities and BD strategy. Our capital allocation priorities remain unchanged. Post the transaction, we will retain our strong investment-grade balance sheet with no impact expected on our credit rating. We remain committed to our dividend of 70p this year and our progressive dividend policy. And lastly, the transaction will be funded from existing and new debt facilities and existing cash resources.

And with that, I'll hand back to Luke.

Thanks, Julie. So to summarize, we think this deal is a strong strategic fit for GSK, and it represents a continuation and acceleration of our strategy. We get 2 potential best-in-class products that can launch this year, driving growth and operating profit in 2027. And as you've just heard from Julie, we have applied financial discipline to ensure that we manage the cost of the deal and that we've recommitted to the dividend and the progressive policy. So with that, let's turn it over to Q&A, please.

Thank you. With this, we're ready for Q&A. [Operator Instructions] The first question comes from Matthew Weston.

It's about the split of the value or the potential, I should say, by asset. So I think consensus has 2 billion peak approximately for Nuvalent, but that's heavily skewed to ALK over ROS1. I'd be very interested in your view on the relative contribution of [zidesamtinib] versus nela. And then also about the speed of launch. I think [zidesamtinib] has an expanded access program with over 500 patients on it. Does that mean that we should expect a rapid launch on approval as we convert those patients to commercial drug?

Thanks, Matthew. So I'll answer the second one and then maybe, Nina, if you want to characterize that without too much color because we'd like you to do your work on your own modeling, Matthew, but I appreciate the question. I mean the speed of launch, absolutely, and that's -- if you look at our heritage working with Sierra and other biotechs that we've acquired, this is a very important component. We're already planning to pivot and execute that launch, and we're in a good place.

The access program, the recruitment for the programs, the first-line ones are very strong. So again, it's a targeted population we can wrap that up. And it was something that we were going to do for B7-H3 anyway. So thanks for that question. And Nina, the split of the asset and $2 billion, Matthew, I assume, again, we won't comment on that, but it's obviously not the time frame that we're looking at over the life of the deal.

Yes. I was just going to mention the $2 billion. I'm not sure that's the peak reference to peak sales, which are clearly higher than that. The -- in terms of value split on sales, I would say ROS space is probably between 1/4 to 1/3 of the total value.

Next question comes from Sarita Kapila.

Just on nela and in the TKI naive cohort that you have in your original data, are you actively discussing with the FDA whether a frontline label expansion is possible? Or will we have to wait for the ALKAZAR Phase III PFS readout for approval in the earlier line setting? And then if I could just squeeze in another one, please. Are you sure that doing a head-to-head in the frontline setting versus alectinib is the right comp, particularly when we've seen 7-year PFS data for lorlatinib from the CROWN study?

Thanks, Sarita. We certainly have looked at those questions in depth. Tony, did you want to cover the first 2? And then maybe Mondher, if you can comment on the standard of care -- on the second question, Nina, feel free to jump in.

Yes. And look, I'm obviously not going to get into the details of regulatory interactions, and it's a little early in terms of the Phase III study. The points you raised are all ones that we have taken into consideration, and we very much see this molecule as being one which has the credentials that will support a first-line indication.

Just to add actually, today, the standard of care in terms of market penetration is still alectinib with almost 45% market share and tells you about how important it is for us to pick the right control arm. Just as a reminder, lorlatinib Phase III trial, the CROWN data that were presented at ASCO used crizotinib as a control arm. So very low bar in the third-generation TKI. So the fact that we are choosing alectinib, I think it's the right thing to do. Having said that, I believe the community will certainly look at other setting of the disease and also other options to have head-to-head data with lorlatinib to try to figure out actually the best benefit/risk ratio.

Thanks Mondher. Nina, do you want to?

Yes, I just realized that we didn't answer Matthew's question on early access program and the number of patients. Yes, actually, Nuvalent did a great job with early access program for both assets, and there are hundreds of patients on early access program, which gave us confidence for multiple reasons because feedback from the physicians who have hands-on experience with actually all TKIs in this space, and we're able to compare the experience of patients and the physicians was a really tremendous benefit. When we launch the drug, the assets, we do expect early access patients to be transitioned to commercial source.

Actually, that's an important point, Sarita. Because there's such broad experience and empirical experience with both of these products, we were able to do a massive amount of due diligence, frankly. So we had over 300 interactions, quantitative, qualitative, in-person interviews, online interviews with physicians, a large proportion of whom have direct experience utilizing these drugs in these subpopulations. So again, that's what's behind the confidence and why we think there's a pathway there. We've also spent a lot of time characterizing the profile of lorlatinib in particular, and have some insights there that we will disclose at a future date. Next question, please.

Next question comes from Kerry Holford.

One for Julie, please, for the financials in the context of the accretion that you cite from next year for revenues and profits and EPS from '29, you referred to synergies and reprioritization. So just intrigued to hear what that involves both in terms of the deal, but perhaps also internally, anything additional to add there?

Thank you very much, Kerry. So as Luke mentioned, obviously, we wanted to be very disciplined about the way we approach the deal generally, appreciating that this was going to be on the face of it dilutive to shareholders. So taking each of those in turn, and I've worked very, very closely with Tony and his team on this, -- the first one is relating to synergies on the integration. We expect some synergies through SG&A, and then we also expect synergies in R&D, including through the discovery portfolio and integration and also contracting synergies for activities such as CMC and clinical study design.

This is exactly what we found with other deals that we've embarked on recently. And then the second thing relates to the just prioritization in the business generally across all areas together within R&D. And as far as we're concerned in R&D, approximately twice a year, we do a very thorough review of the portfolio. We are constantly assessing the internal portfolio and reprioritizing assets to really optimize the return on investment and the probability of technical and regulatory success. So net-net, we believe we've been very responsible in terms of exercising discipline around the dilutive impact of the deal.

Next question comes from Emmanuel Papadakis.

It was just a follow-up on ALKAZAR. I'm not sure if I -- apologies if I missed it. Is the frontline approval predicated on PFS readout? Or is there any scenario in which you could get that approval sooner? And maybe a quick question on ROS1. Back in the day, the original commercial optimism around that landscape is predicated on better diagnosis, unlocking clinical and commercial opportunity that hasn't really happened. Do you harbor any greater hopes for a diagnostic transformation, unlocking the patient opportunity there?

Sure. Thanks, Emmanuel. Nina, do you want to cover the second question? -- then Tony? A quick one.

Yes, the frontline study is based on PFS.

Do you hear that, Emmanuel? PFS. And Nina, on the ROS1 testing and opportunity.

Again, both ROS and ALK are now standard part of testing. It's part of the panels that are done on lung cancer tissue samples when -- at the diagnosis. That's probably less of a barrier. But as we have seen, the product profile so far actually had significant limitations.

And Nina, do you mind expanding on this? Because I think the more you look at these products and particularly you look at these subpopulations with these particular mutations, what we found is a very interesting relationship in terms of innovation price, small molecule, -- you've got a defined population, but you've got these very, very long tails, which the better tolerated profile that you can get, you're more able to sustain this. So the mathematics start to look very, very interesting. But you really have to stop and look at it and just work your way through it, which is what we've spent a long time doing. So Nina, do you mind expand on that?

Yes. So again, to repeat what Luke said, there are a small number of patients, that's definitely true. But if you look at the totality of non-small cell lung cancer in terms of value, it's disproportionately higher because for each patient that you start on ALK or very likely in the future on ROS, you have a multiple duration of therapy for these patients. So CROWN data update 7 years, PFS rate at 7 years is still 55%. So median has not still been reached. It's very likely that, that tail will continue at 50% or above 50%. And these are metastatic patients. They are not stopping their treatment.

It's very difficult for mutation-driven cancer to stop treatment because what we have experienced from all these TKI areas, so EGFR ALK as well as soon as patient stops therapy, the cancer usually comes back. So in terms of value, they are proportionately significantly bigger than what the number of patients would indicate.

I would just add, as Luke mentioned, we spoke to probably about 300 or had interactions with about 300 physicians. Very positive thing is that they had hands-on experience and they could compare the effects of all these TKIs. I will share some of the comments that were made. One is lorlatinib is a drug that everybody loves to hate. But because of the efficacy, it's frequently the first drug that they will offer to their patients. What comes with the use of lorlatinib is CNS-related side effects. So serious conversations with the patient, with patient cares because they have to be aware of these side effects that go into a psychiatric area.

So one of the physicians said using lorlatinib, I became both a psychiatrists and metabolic expert. One of them mentioned that he became a target for sales reps that sell GLP-1s because the patients gain weight, and these are younger patients, it's very relevant for them. One of them described a patient who was a younger woman. Her income was coming from being an influencer on social media. And after gaining weight, she actually stopped therapy and progressed. So these are all issues that you need to address over the years while you're treating patients.

And therefore, it was a very, very clear feedback that tolerability is the main barrier. While we were doing due diligence, just a comment between ROS1 and ALK. -- while we were doing due diligence, I have to say ROS1 space was probably what physicians refer to as slam dunk. There is no way that they would not use this drug over other inhibitors ROS1 inhibitors. So there, our confidence is actually very high that this is going to be the best in disease, best-in-class drug.

Thanks, Nina. And we can expand on that. Again, we've been spending a lot of time on this before breaking cover. And have really been very thoughtful and rigorous in profiling these assets and the team that's developed them.

Next question comes from Sachin.

I'm on dial-in apologies. So 2 quick questions, please. One, just big picture for you, Luke. This is one of the largest deals Glaxo has done in a while and is focused on launch assets versus mid-stage, early-stage pipeline for '29, '30. So just what's driven that, in inverted commas, strategic shift? I know you frame is consistent.

And then second one for Nina, a follow-on to prior. So thank you for giving the split on ROS versus ALK. I wonder if you could just give us a bit of color on second line versus frontline across both, acknowledging that frontline is bigger. So 2-part question. One, how comfortable are you with consensus on the launch in later lines before frontline comes through? And then how much of the deal valuation is frontline out where there's some perceived risk around that data delivering differentiation?

Thanks, Sachin. So I'll answer the first one, and then we'll go to Nina. Look, I think -- and that's what I tried to outline with that slide in my introduction. We have a methodology to our BD. We like validated targets because essentially, the clinical scientific components are heavily derisked. And then we're really relying on our regulatory clinical execution and commercial launch capability, which, again, we have to validate it every quarter, but I think the -- it would be fair to say there's a high degree of -- a strong track record there.

What we had with Nuvalent was unusual. Basically, it was a little bit like London buses session, right? Suddenly, 2 or 3 come along at once. And each one of these products, we would have acquired as a separate deal. We just had the attractive element of having them all embedded in a single company. And importantly, this was very much a bottom-up driven deal. Some deals have driven top down. I might come to the office and say, I really like this company, let's go for it. This was very much a deal that was driven by Chris Sheldon, who you all know from his previous time at AstraZeneca. We had the individual involved in designing Tagrisso on the team.

There was a number of other AstraZeneca and [indiscernible]. I'm sitting next to Tony, who was deeply involved in lorlatinib's design. And so this built momentum inside the organization over quite a long time. And in the end, we reached the conclusion that this was a really smart deal to do and it was a good use of our shareholders' capital. And again, if you take the components apart, it's more consistent with what we've done before. But also there's attraction in critical mass because essentially, we're pulling forward our entry into lung, but in discrete populations to build our credibility there, which positions us very well for B7-H3.

So there's a method to this, but also critically, as we've said, there's financial discipline here to maintain capacity for future accretive deals. But this was just too attractive to let pass by. Nina, over to you.

Yes. And Sachin, I'm not sure I fully understood your question. So I will try and maybe either you need to help me or my colleagues. So first and second line, ROS1, as I think we communicated, second line has been filed. PDUFA date is in September this year. In ROS space, all -- this is really ultra-orphan indication. So a number of patients is very small. All the assets are approved on single-arm studies. Second line -- so the first line is -- filing is expected in the second half of this year, so approval next year.

Again, this is extension or additional -- based on the additional data from TKI-naive patients from the ongoing study. As I mentioned, there is a very, very clear feedback that this is going to be easily standard of care in the ROS space. I'm not sure I fully -- was there a question on ALK as well for.

Maybe reframe the question. So 2 parts. One, are you comfortable with consensus on launch in the later lines across both ROS and ALK in the next couple of years versus yourself framing upside to peak midterm? And then the second was how much of the deal valuation is on front line out for that data '28, '29? And how do you assess the risk around differentiation delivery?

Yes. So Sachin, pretty confident, again, to a previous question about number of patients on early access program and the extent of experience that physicians community had so far. So I would say, again, not going to guide on the year annual sales, but we are quite confident that consensus is not too optimistic or unrealistic. And then the value of first-line ALK, yes, clearly, first-line ALK carries majority of the value of the deal, no doubt.

You are looking at the highest number of patients with the highest duration of therapy. Based on the data that we have seen and the profile of the drug, we actually have very little doubt that this would not be successful. Question is time, which also we actually have a pretty good idea when it's happening because the recruitment in the study is actually going exceptionally well.

And Sachin, I would say, look, 3 things to consider in the context of confidence in the duration of response data in the first-line setting. And this is not only true for nela, but also in the ROS1 setting. If you look at the improved resistance profile, that is important in maintaining response because it prevents the emergence of compound resistant mutations as well as taking care of already existing cases.

Obviously, tolerability plays into that as well and in particular, in the context of dose reductions or dose holds. Nela has a very favorable profile in that context and also in the context of when reductions are necessary, what we see is mostly only single step-down reductions in the case of nela and its intrinsic properties, its PK favor a more reliable outcome in that context. And in case anyone is going to ask me the question, we've looked into the impact of dose reductions and holds on the efficacy, and we can see very little to suggest that there's any significant impact there. So it's a combination of features underpinned by the profile of the molecule, which gives us confidence in duration of response.

I can't resist jump in. And Sachin, you may remember this. 10 years ago, I think a few people believe that EGFR market will become what it is today. And actually, second and third generation of drugs have turned this disease into a chronic one. I think we have with ROS1 and the opportunity to turn those metastatic patients to really a patient who can live with their cancer for many, many, many years. And the key word here is really tolerability. I think we know that second and of course, third generation and this asset hit the target hard, have a broad coverage of the different driver mutation, penetrate the CNS, has definitely a very good efficacy in terms of tumor shrinkage, but the key word is tolerability and durability.

And I think what we have seen so far in the Phase I/II and the momentum that Nina described around clinical trial and expanded access program from the community of oncologists, but also from patients is telling us that this is the right drug for them to stay longer on treatment, even in second line, but definitely more in first line in order to live with this disease more than 10 years. Of course, everyone is excited about the CROWN. But remember, I mean, half of the patients stop their treatment already. And we know what will happen for this patient when you stop treatment.

Next question comes from [Victor].

And so maybe starting with the comment we've made on ALKAZAR. So you've mentioned that recruitment was progressing well and that you have good visibility on completion. So can we ask whether there is an interim analysis planned on ALKAZAR? And what would be the trigger for that potential interim analysis? And then on Nela's hepatic toxicity signal, can you walk us through how you think about managing this signal in clinical practice and why you believe it won't ultimately undermine its tolerability advantage?

And maybe last one for Julie. You've indicated low single-digit EPS dilution for 2026, but guidance for 7% to 9% remains unchanged. So can you just help us reconcile this?

Great. Thanks, Victor. So Tony, do you want to cover the interim? Mondher, you cover clinical consequences and management of nela, which we've learned a lot about and Julie last on that question.

Look, obviously, I'm not going to get into the details of the ALKAZAR study. But yes, an interim is planned, and you can get a clue from that if you look at the landmarks from the Phase III CROWN study.

Right. And Mondher, we've seen the full data set?

Yes. So maybe a quick reminder that one of the challenges that we have seen with third-generation ALK inhibitors is essentially the off-target side effects and the fact that inhibiting the tyrosine-related kinase, there are 3 of them. And actually, the A, B and C, the B is the one that basically is driving the whole CNS side effects. And now actually, it's really disturbing because not only we have somnolence, we have cognitive effect, we have really even mood transformation that basically prompt patients and physicians to stop treatment.

This is the most critical actually side effects. Of course, there are other side effects, in particular, peripheral neuropathy that occur in more than 34% of the patients that sometimes actually are of Grade 3 and 4. These type of side effects are leading to the discontinuation. What we have seen in the 1,500 patients treated so far, both in clinical trial and expanded access program with nela is basically no side effects of this type.

The only thing that was noticed is an elevation of transaminase that is truly asymptomatic. There was no hepatic failure. There is no fatal events. It's only biochemical asymptomatic elevation of transaminase that can be monitored very easily. Physician -- oncologists are used to this because it's not the first time that we have this in tyrosine kinase inhibitors. And the approach is to stop treatment for a while, test until it goes back and then rechallenge with a slight dose reduction. And we have seen that patient can completely be rechallenged without any compromise with the efficacy.

And I will just add that other ALK inhibitors have the same monitoring for liver enzyme elevation already as part of their management clinical practice and the label. So we don't expect that this is going to come as a surprise to the physicians because that's exactly what they are doing with other ALK inhibitors already.

Great. And Julie?

Yes. Thank you very much for the question. So obviously, the EPS is affected mostly by the interest that comes through together with the Nuvalent profile in its own right. And we are assuming for '26 that we've got a Q3 completion of the deal. And clearly, when we've guided, we've guided an EPS range of 7% to 9%. So it does mean that we move within that range to manage the dilution, but we stay within the range on a net basis.

Thanks Julie. and thanks [Victor].

Next question comes from [David Evans].

So just a question, if you could just clarify or give us some more information on the level of discontinuations that you see in the ALK space. I thought your slide said that on lorlatinib, well, only 7% discontinuations versus 5% on nela. Is that a like-for-like comparison? It doesn't quite seem to stack up with your sort of commentary about wildly different tolerability profile. So just anything in the lorlatinib proposition, if you could just flesh out much less well tolerated in theory than those figures would indicate.

Yes. Sure, David. Thanks for your question. I mean these are distinctly different profiles. Tony, do you want to cover that and Nina add any market commentary, physician commentary?

Yes. And the data you've picked are indeed relating to discontinuations associated with tolerance. What's important, though, is to look at the complete picture for treatment discontinuation because as Nina mentioned earlier, with discontinuation and dose reduction, you do see disease return and the data for Lorlatinib at 2 years, I believe, is a 38% progression rate based on the combination of those things. Nina, you want to add anything?

Yes. Again, David, so I think if you look at the discussion that happened at this year's ASCO post CROWN 7 years presentation, I believe there was a slide from the discussant, which something along is the crown the price. or something along that where the focus of the whole discussion was exactly the tolerability profile and is the benefit that comes with such a long PFS actually worth the adverse events that patients are going to. I would probably say if there is an interest to -- for you to talk to some of the physicians who have used the drugs and hear the experience because that probably tells you more than the numbers in the tables.

Great. Thanks, David. And we can certainly do that for anyone who's interested.

Next question comes from [Naresh Chauhan]

Just interested in the ex U.S. development plan, please. 2/3 of Alecensa sales come from outside the U.S. and China is a big part of that. It looks like about 1/3 of the sales. There seem to be no Chinese sites in any of the Nuvalent development program as far as I can see. Can you just help us understand the ex-U.S. development plans, please?

There is a plan to bring Chinese sites. Tony, do you want to.

That's basically it. It is a global plan than just opening Chinese sites.

Thanks for your question. Next one, please.

Next question comes from -- is a follow-up from Matthew Weston.

Lots of dialogues. Can you hear me?

Yes, we can.

Amazing. It's a quick follow-up for Julie. Julie, in your opening comments, you said, I think, that the deal strengthens margins through dolutegravir's LOE. Now I think the previous comments were that margin was going to be flat through the dolutegravir LOE. So does that mean we all need to sharpen our pencils and start taking the margin up?

Or this just gives you incremental confidence that you'll be able to keep those margins flat, particularly because it looks like there may be some incremental pressure in HIV from guideline changes and other things.

Okay. Thank you, Matthew. So just in terms of -- just to recap for everybody, in terms of prior margin guidance, we've said that in '26, we'll be above 31%. And then we've said we will be -- have a stable margin through DTG LOE, which is the '28 to '30 period. What we're referring to when we say the deal strengthens is it will improve. Obviously, it's very accretive to sales during this period as the team have talked about. It's high profitability assets, so it brings through benefits to the profit. And therefore, we would expect the margins during that period to be higher than before the deal. As we know, we've managed the dilutive period to be a very short period with accretion quite quickly. So therefore, it does give us a benefit to profit and margin through the DTG years.

Thanks, Matthew. Appreciate the other questions. We've got time for a couple more if people have them.

Next question comes from Zain.

It's another follow-up for Julie, just on the dilution over the next couple of years of low single digit. I think the color you provided earlier was helpful in terms of the expectation for synergies, and it sounds like there's internal portfolio rationalization goals for CMC costs within Nuvalent that you can potentially unlock to manage at a low single-digit dilution. But just stepping back, I'm still struggling a little bit to fully get that because I think Nuvalent consensus is about $100 million revenues for next year.

OpEx, they've got about $400 million in terms of spend. So what's the key disconnect as you see it? Do you think that the maybe consensus top line is a little bit on the conservative side given your bullishness around zidesamtinib and what the uptake could be there? Or do you think that maybe there's a portion of your R&D effort rationalization that helps you get there that we might not be appreciating?

Thanks, Zain. I mean I think the short answer is it's a combination of those things, but I'm not sure we want to give too much color at this point beyond the commitment. But Julie, feel free to expand if you want.

Yes. I think we've covered it. I mean we wouldn't go into specific projects in the R&D portfolio. And I would emphasize that we're looking at prioritization across the company, not just within R&D, but across the company and driving that hard to be very disciplined, as Luke mentioned. I mean we wouldn't normally also comment on consensus models. But in our view, the R&D cost in consensus models for the target are reasonably high. So I'll just leave it at that.

We have time for one more question, probably also a follow-up, and that is Kerry.

Just a quick one. Anything you could say on the IP for the 2 late-stage assets that you're acquiring here? And just to confirm, you expect both to be exempt from IRA?

Yes. So yes, on IRA because they're orphan and 2040s plus, Nina.

Yes, early 40s.

Thanks, Kerry. Very grateful to everyone joining at short notice. I'll conclude by saying, again, to reinforce, we think this deal is very much the type of transaction that we do. It's a great fit strategically for us. It's consistent with our strategy in lung cancer and actually forms an accelerant for that. And we're getting a number of very, very attractive assets, which, as you've hopefully heard today, have deep exposure amongst the clinical community and patient exposure.

And I think there's a clear pathway for both of them, the late-stage ones to best-in-class as well as some earlier-stage assets like the HER2 and a stable of preclinical medicinal assets, which are also very accretive. And finally, I hope you've seen that we have applied financial discipline here in terms of selecting this transaction, pricing and then integration of it.

So thanks again for your very thoughtful questions at short notice and look forward to following up with you.

It's my pleasure to introduce GSK. We've got Hesham, he's the Head of Oncology R&D at GSK. Exciting times just coming out of ASCO. I guess, Hesham, thank you for joining.

Thank you, Michael.

I guess to start, if you sort of think about GSK's Oncology R&D, what are the 2 or 3 decisions you're most proud of that shaped current portfolio? And is there anything you deliberately stopped doing to focus resources?

Yes. It's interesting because I think one of the first things that I think about just in terms of the journey that GSK has had coming back into oncology is really how the field continues to evolve. During one period of time, probably early on, there was a lot of interest in immuno-oncology and checkpoints as well too. And I think in many ways, if you look across the industry, at times, we may have actually over-indexed on checkpoints.

And I think it's one of the areas that probably as I took on my role, I tried to really strike the right balance of thinking about precision oncology, a focus on what are probably much more well-validated platforms and molecules and a move more towards precision oncology and a bit away from checkpoint exploration. And I think probably, if anything, that was probably the first decision that I think is really important and helping shape at least the oncology portfolio at GSK.

The second really was at a time when I think, maybe early on, there were certainly some mixed feelings about BLENREP, especially after the results of the DREAMM-3 study early on which was the first Phase III study that didn't meet its primary endpoint in a late-line multiple myeloma population. Again, mixed reviews, I think not everyone believed in the asset at the time.

And we kept moving forward with DREAMM-7, DREAMM-8, really optimizing the design of those studies. And ultimately, they really led to successful outcomes, including DREAMM-7, which demonstrated statistically significant PFS and overall survival benefit and DREAMM-8 with a statistically significant improvement in PFS.

The third really is around dostarlimab. I think at the time, if you look at certainly the landscape and opportunities to help differentiate its development program, given how competitive the PD-1, PD-L1 landscape was and identifying opportunities like first-line endometrial cancer, a space where the standard of care hadn't necessarily evolved, and for quite a lengthy period of time, about maybe 15 years or so with platinum-based chemotherapy. A space like, for example, dMMR/MSI-high, locally advanced rectal cancer, where we've seen, at least through the Memorial Sloan experience, 100% clinical complete response rate and initiating a pivotal development program in that space in GI malignancies.

I think those were certainly also decisions that I feel like we're really the right ones to help us start to build the pipeline and then expand. And then probably, I would say like the last one is really business development. A lot of collaboration with Chris Sheldon's team on the BD side, that's really helped enable us access, not only the right technology platforms, but the right assets. And you look at, for example, acquisitions like Sierra Oncology with momelotinib or IDRx with velzatinib as well, too, as another means to complement the pipeline.

So overall, I would say the decisions that I'm really proud of are the ones that, one, really helped us address key unmet needs for patients. Two, helped optimize the probability of success for GSK and its pipeline and rebalanced its risk profile. And then three, this focus on moving towards precision oncology and higher positive outcomes for our assets.

Excellent. And if we stick with BD for a minute and sort of try to link that to internal. So coming out of ASCO, we said it in our note, I think GSK maybe a little bit surprisingly came out as somewhat of a winner out of ASCO for us because we didn't quite expect the IDRx data. And I think what we've seen with other ADCs and PROC, your B7-H4 looks pretty good. Their licensed asset or externally sourced assets. So when you think about that internal versus external mix, what's the ideal mix?

Yes. Michael, it's a really interesting question. I would probably say like all big pharma companies are struggling and grappling with this. I don't know if there is a specific split that I would say is most optimal, right? But what I can say is, I don't think any company could sit here and say, hey, by the way, we are going to source innovation purely from an internal standpoint. Like it's not realistic. It's not possible. Each company has unique strength, unique capabilities.

Like for us, for example, I think our antibody engineering, our small molecule engineering are focused on, for example, functional genomics, immunology, like those are all areas of expertise for GSK. But for us to say, hey, we're going to like -- have like the broadest expertise and the deepest expertise across all areas of platforms, it's not realistic.

And I think we have to really think broadly, like so one, we have to think about where to source the innovation from, right? So historically, it's been much more like from the U.S., from Europe. Now, of course, we're seeing it emerge in Asia and certainly in China as well, too. And the bottom line is making sure that there is an openness towards what can be done externally and what can be accessed externally.

Once you've prioritized like and clearly delineated what you're interested in, and I think to me like that's a like fundamental fact of like what's defining -- what's your strategy? What are your prioritized disease areas? What are your prioritized technologies or platforms? And what are the best out there? Do they exist internally? Do they exist externally? And can you benchmark them in their performance as well, too?

And there's -- to be honest, there's an element of like what are you looking for? Are you looking for first-in-class? Are you looking for best-in-class, right? And then you can think about, is it developed internally and in-house? Or do you try to kind of access an iteration or a best-in-class asset externally as well, too.

But at the end of the day, even now and as we think about discovery research organizations, I think the biopharma space has to really look at it and say, what is the right-sized research organization for this day and age, given where we are and given the open source innovation that exists as well, too, right? Do you have to have an internal presence for a research organization? Of course, you do, right? But at the same point in time, like, does it need to be like tremendously large. I think that's a separate question and very debatable as well, too.

Perfect. And could we maybe briefly try to layer into that sort of the technology angle, everybody talks about AI. There's digital pathology. There's tumor modeling. Like how does that feature into that mix?

Yes. A really important question, Michael. I mean for us, it really starts everything from discovery, right? And I think data and technology go hand in hand. So it's everything from accessing proprietary data sets from either external partners or collaborators or academic institutes to help us with antigen discovery to certainly medicinal chemistry design and how AI/ML can certainly help enable that and is embedded within GSK.

Two, basically, and I think to me, this is fundamentally the area that where I try to spend a lot of time is prosecuting and better characterizing disease biology, right? I mean if you think about the challenge that we have in oncology, and I would argue probably across different disease areas is oftentimes, we're only looking at one singular piece of the pharmacology in the context of the biology of the disease without better understanding what's happening around it.

And for us, we focus really right now on building what our foundational models, right? And these foundational models help us get a better understanding of the disease biology in terms of progression, resistance, relevance of different targets and combinations. And at the same point in time, they have to be powered by data. How are they powered by data? They're powered by data that we access externally. So multiomic data, so everything from, of course, clinical outcomes annotated data. to genomic, proteomic, transcriptomic deep immune profiling data, at a tumor microenvironment level, at a spatial level, right?

And at the end of the day, the ability to be able to, again, use AI/ML to generate these biological models is really important. And you also have to keep them up to date because there's new data that's continually emerging as well. And then basically link them to, not only discovery, but also your translational strategy and hypotheses.

For example, we acquired sometime in early 2025, a company called CELLphenomics, and this company focuses on developing novel in vitro model systems. What do they do? They're called organoids. And basically, they try to replicate what happens within a patient's tumor, but outside of the human body. And you're able to, not only do that through the lens of better, for example, replicating what happens in the patient's tumor through unique knowledge, insight and culturing but also be able to visualize it in 3D fashion and collect all of the data that's being developed in this living model system, right? And then see if you can replicate what happens in the organoid from the patient.

And then follow the 2 in parallel to see is the drug predicting, for example, in the organoid what's happening in the patients. And can you predict the resistance mechanisms that are likely to occur, response, lack thereof, et cetera.

So to me, I think fundamentally, like that's equally important. And then finally, maybe the third piece is we're talking about like predictive biomarkers and also diagnostics. Computational pathology is really critical. The ability to be able to once again start looking at biomarkers through a different digital lens and start to move the diagnostic discussions away from just simple testing to more probably slide and AI/ML assessment is also something that we're evaluating and assessing as well too.

Fantastic. So we start talking a little bit more about the ADCs. I guess that -- so to me, the SGO data -- at SGO, you show data for Mo-Rez that look really good and look very clean. So it seems to me that ADCs are still poorly understood, and they're complicated. There's the payload, there's the target, there's the chemistry. It looks like with your B7-H4 that could be quite differentiated. So if I take a step back, what do you think ADCs are still misunderstood? And if I could link the next question into that, how do you decide whether to go single agent or combo with ADCs?

Yes. It's interesting because I know like -- we think back to maybe like 10, 15 years ago. And the only thing that, like, with the first iteration of ADCs that we thought about was, hey, like the therapeutic index, that's the issue that -- like they seem to be really difficult. I think we've moved like beyond that.

And you're absolutely right. Like, I think now, we're looking at ADCs through the lens of like there's 3 different components to them, and they all matter and they matter in different ways. So is it the antigen and not only its expression but also selectivity, of course? Because that matters in terms of on off-target effects. Is it the linker and its stability? And again, because of the toxicity, but also the efficacy as well, too. And also as we think about like things like bystander effect, right?

And is it the payload? Where is it on the spectrum of like potency, toxicity, right? And its mechanism of action because you're also thinking about combinations. What types of synergies could there exist, right? Could it be combinations? I'm just saying like, with like, let's say, DNA damage response agents with, of course, checkpoints and others as well, too. Like does it -- does the payload causing, for example, let's say, DNA damage, elicit an immune response through new antigen or neoantigen generation.

So all 3 components matter. I think we're still following a space where we're trying to optimize dosing, if I may say, because I think it becomes much more important to patients. At the end of the day, we're trying to basically deliver what our targeted chemotherapy to tumor cells. I think the biomarker space is still one that is, I would say, important to consider. I think we've moved beyond target expression. It is no longer a target expression game. It is actually one where we have to think about multivariate biomarkers that incorporate the targets, the linker and the payload and sensitivity to all 3.

And I think there is an element of, we have to think about what's to come in the next 3 to 5 years as these patients start to progress on more commonly used payloads and we identify what the resistance mechanisms are, so novel payloads are going to be equally important as well, too.

Fantastic. And maybe this is unfair, but if I get you to rank B7-H4 versus B7-H3, I think my impression in the past has been B7-H3 was maybe just slightly more interesting asset to you with the data that we've seen, it seems like it's flipped a little bit. Is that a fair interpretation or not?

So I look at the entire portfolio, and I get these questions often like even internally, by the way, like what's your favorite asset? What are you most excited? I'm going to say both of them to me are equally important and for the following reasons. I think you look at B7-H4 and because of its expression profile, it is highly directed towards gynecologic malignancies, broad expression in ovarian, endometrial cancer, a lesser extent, maybe in cervical, a little bit in triple-negative breast and biliary tract cancers. But ovarian and endometrial, very clear, right?

And the way that the ADC is designed as well too. It's a [ dara 6 ], it's cleavable linker, it's a Topo-1 payload and the activity that we've observed, the data that was presented at SGO you alluded to, 62% confirmed response rate in platinum-resistant ovarian cancer, 67% in second-line endometrial cancer, 5 Phase III pivotal studies launched. The drug is active irrespective of H4 expression. And the safety profile, I think, certainly, it's very consistent with that of the Topo-1 payload, just the heme tox, which is quite manageable because of how familiar medical oncologists are with it as well, too, the neutropenia and so forth. And so I think about it through that lens and the drug has got a really interesting efficacy profile.

On the other hand, B7-H3 as well, too. I would say what's unique about it is this broad expression profile of the target. And not only is it expressed across thoracic malignancies, lung, head and neck, GI malignancy, CRC, GU, prostate, bladder and also sarcomas.

But also, I think maybe this is something that's common to both of them. Not only our -- like not only is the target differentially expressed on tumors versus normal tissue. Both B7-H3 and B7-H4 are checkpoints. So there is this like dual role that they have, right, which I think is an area that we're focusing on better characterizing because I think it plays a really important role in how we think about combinations and combining with checkpoint inhibitors as well, too.

And so we're learning a little bit more about that in small-cell lung cancer, where we have a breakthrough therapy designation, but also in osteosarcoma. And we've already initiated a Phase III study in second-line small-cell, but stay tuned. I'm going to say, Michael, for 2 things. One, several more Phase III studies that will be starting with B7-H3 over the next few months. Two, data, multiple data sets from our own development program and from the Hansoh development program that will actually be presented at a key scientific congress in the second half of this year.

Fantastic. One that I didn't have on the list, but I hope you don't mind, just thinking about the combinability. There's data that suggests that Jemperli better than Keytruda in trials. What you just said about the combinability is that ADC approach and ability to bring that out more that you actually have a checkpoint inhibitor that is actually very competitive, but it's just been difficult to do the trials in a conventional way now that the ADCs are there, you can -- that's more enabling to get that through?

Yes. I think it's an interesting question. And I think you're referring to the PERLA data, of course, which is looking at -- it was a Phase II study designed to really just benchmark the clinical activity of dostarlimab to pembro. So dostarlimab plus chemo versus pembro plus chemo in first-line non-small cell lung cancer and what we saw was, at least, again, the study wasn't formally powered for superiority or noninferiority for that matter, but it was just a relative comparison. And what we saw was the response rate were relatively similar and some positive trends for PFS and OS that favored dostarlimab. And I think for us, the key was basically benchmarking the activity of dostarlimab to the market leader in pembro. And I think that was really helpful context for us.

How we think about the B7-H3 and B7-H4 programs? We're thinking about it through the B7-H4, B7-H3 development hat. And so we think where it makes most sense to combine with our already approved PD-1 inhibitor than -- or PD-L1, then we'll do that because, of course, there are clinical, regulatory and certainly commercial considerations.

And the clinical and the regulatory ones involve, of course, investigator use, physician use. They involve having maybe data or not in a given tumor type. They involve what we call contribution of components from a regulatory standpoint and the need to generate that. And then there's the commercial kind of element as well, too, like I said, around uptake and so forth. And where there's opportunities for us to combine with dostarlimab and it makes sense to do that, then we're going to try to do that to help the dostarlimab program out as well, too, from its development strategy.

Now bear in mind, there's 3 pivotal Phase III studies ongoing for dostarlimab. So not only did the Ruby Part I and Part II studies read out positive, but also we have ongoing Phase II pivotal study in locally advanced dMMR/MSI-high rectal cancer. We have a Phase III study in dMMR/MSI-high colon cancer, and we have a Phase III study in locally advanced head and neck post chemoradiotherapy as well. So those components remain ongoing, and I think we're continuing to identify ways to maximize the value of dostarlimab, which has become a blockbuster medicine as well, too, recently.

And then maybe IDRx, which now is a different name, which I always forget. I still call it IDRx.

Velzatinib.

So the data at ASCO looked really interesting certainly in the first-line setting. You've gone into Phase III head-to-head versus Gleevec. That's a punchy trial. It's going to take a little while for that to come through. Should I think about that as the main path to first-line? Or is there a fast forward that could get you there quicker?

Yes. No, I think it's an interesting question. And you're right, you saw the data at ASCO, very encouraging. In second-line confirmed response rate, 38%, unconfirmed 40%, median PFS about approximately 14 months. Well tolerated, I think especially as you look at the second-line data with other agents that have reported data recently as well, too. Like I think probably the Grade 3 event rate is about maybe 30%, 33%. Other agents, it's like 2 drugs, combination regimens, 72% Grade 3 event rate. It's difficult for this patient population that is typically, I would say, more used to well-tolerated, gentler at least treatments like imatinib.

And I think for us, second-line is a starting point. So we've had a Phase III study start in late '25 head-to-head against Sutent in second-line patients. And then we're starting this first-line Phase III study head-to-head against imatinib and again, the ASCO data set, 61% confirmed response rate, 65% unconfirmed response rate. We're very encouraged by it, and we're going to continue to identify ways to accelerate that trial. Let me leave it at that.

Fair enough. I tried. Maybe in the last minute, 2 questions. One, a little while ago, I was sitting somewhere, I think it was in France, and you said look at the ADCs and luckily I did. If I were to ask you, in the next 12 to 18 months, what's the data set that I should be focusing or investors should be focusing at that sort of show that continuity of look at what we've done with the ADCs, look at what we've done with IDRx?

Yes. I'm going to say probably like for B7-H3, multiple data sets coming out over the next 6 to 12 months from our own development program from the Hansoh program, starting with the second half of this year at a key scientific congress. So stay tuned. So I think that's maybe the first one.

I think the second is really more of like continued follow-up from the first-line cohort for velzatinib, which was presented at ASCO, which I think is going to be very helpful.

And then the third, continued data maturity for the B7-H4 data across ovarian and endometrial as well, too. And then finally, maybe just one more point to put out there for BLENREP. Interesting data that was presented from DREAMM-9 at ASCO, looking quadruplets. But also interesting data that was presented a few months ago by Evangelos Terpos from Greece, there was a Phase I study that he was conducting called the TERPOS trial, as we call it, looking at the triplet of BLENREP in combination with RD. And the data from that actually was -- or has been presented across ASH, EHA, a few times.

What was interesting is at a recent meeting called EMN which is a European myeloma network meeting. He presented some interesting data. It was actually some modeling work that he did. And the modeling work looks at the data from his study, the first-line study newly diagnosed the triplet regimen, which is in DREAMM-10, head-to-head against the MAIA regimen, daratumumab.

And it looks at across different dose levels, 2.5, 1.9, 1.4, all 3 - just all 3 regimens. It projects what the median PFS could look like based on the extent to follow-up he has right now. And the modeling projects that across all 3 doses, the median PFS would be about 115 months across the 1.9 milligram dose specifically, which is the dose that is being used in DREAMM-10. It's about 100 months.

So imagine, we know that quadruplet CD38-based quadruplets are delivering about maybe 90 months PFS. Well, imagine if you could deliver 100 months with a triplet with a better tolerability profile in these newly diagnosed transplant ineligible patient segments.

So I'll leave you with that and say that we're going to continue, of course, as I alluded to earlier, to think about business development opportunities. We've done a lot on the research, the discovery side. And I think at the end of the day, for us, as we think about things that complement the portfolio, they have to fit into this framework of: one, address a key unmet need just based on the pharmacology and the mechanism of action. Two, align to key prioritized tumor types where we have strong capabilities. Three, there's preliminary clinical data that's indicative of a high probability of technical success. And then four, of course, bring the right value proposition for the organization and complementarity with existing assets.

Fantastic. And then final question, and maybe the answer to this is, hey, I'm the R&D guy. But if I look at guidance or ambition for the company, 2031 in revenues is GBP 40 billion. The GAAP to consensus is GBP 5 billion. And so far, the answer has been the biggest gap between GSK's expectations and the market is like 50%, that's BLENREP. If I look at what you've got with 7-H4 with IDRx, Jemperli data, these data coming through that there's a lot going on. It's -- I don't need that much out of BLENREP to get to a more ambitious outlook.

Yes. I mean, Michael, I love your view like that. So I think what we need is for everyone to embrace that, that's really the key. And you're right. We just talked about all this data across velzatinib, H3, H4, dostarlimab and let alone, of course, momelotinib, which is growing quite well. Yes, I think there's a lot of potential. I mean, there's a slide that Emma presented probably sometime in early 2025, that looks at, for example, the contributions that specialty medicines would be making to the long-term growth of the organization. And I think when you look at, for example, oncology, it's expected to be significantly contributing by 2031 as well, too, and 2034. So you're right, I think there is a reason to believe, I guess, maybe is the best way to put it.

Fantastic. Hesham Abdullah, thank you very much.

Thank you very much.

Dear ladies and gentlemen, welcome to this GSK EASL presentation on Bepirovirsen B-Well 1 & 2 pivotal phase III studies. My name is Constantin from IR. I'm also joined by Nick from IR, and I'm delighted to introduce the following speakers for today's call: Nina Mojas, President, Global Product Strategy; Professor Seng Gee Lim, Director of Hepatology, National University Health System, Singapore; Kaivan Khavandi, SVP, R&D, Head of Respiratory, Immunology and Inflammation, Head of Translational Development and Sciences; Melanie Paff, Vice President, Medicine Development Lead Hepatitis B Programme; and Pedro Zarazaga, SVP, Global Product Strategy, Specialty.

Please note on the next slide, our cautionary statements. Also note that during this presentation, we will also make the slides available.

With this, I'd like to hand over to Nina to kick us off. Over to you, Nina.

Great. Thank you, Constantin, and greetings from Barcelona. Thank you. So chronic hepatitis B remains a large lifelong infection largely untreated at the moment. Majority of the infections happen vertically, so from mother to child at birth or in early childhood. And as you can see, about 95% of these infections lead to chronic hepatitis B. At the moment, the standard of care in hepatitis C varies globally, but nucleoside analogues are the backbone and the benefit of nucleoside analogues is the suppression of hepatitis B virus DNA. These treatments do very rarely achieve -- functional cure. They are also lifelong therapies with no defined endpoint.

The unmet need in hepatitis B is durable loss of hepatitis B surface antigen. And with the full suppression of hepatitis B DNA, this is referred to as functional cure. Receiving functional cure will transform hepatitis B treatment into finite treatment, which is highly desirable and at this point, not available. Next slide, please. Nucleoside analogues and the impact and current standard of care. As you can see on the slide, nucleoside analogues do lead to complete suppression of DNA and the benefit of that is significant 41% reduction in hepatocellular carcinoma. For those patients who are treated with nucleoside analogue in this study, if they achieve so-called functional cure, the reduction of the risk of hepatocellular carcinoma goes further down by 76%.

Next slide, please. When we look at the opportunity, as I mentioned, this is highly undertreated disease. You can see the global gap between number of infected individuals, number of diagnosed individuals and those who are currently on treatment. U.S. and China, we are looking at about 120,000 in the U.S. and about 6 million treated patients at the moment, of which in both regions, about 70% are hepatitis B surface antigen below 3,000. In the U.S., standard of care are nucleoside analogues. Patients who are treated are largely patients who originate from immigrant backgrounds, so originating in Africa and Asia. In China, hepatitis B is very high national health priority. In China specifically, nucleoside analogues are used in addition to interferon.

Next slide. Looking at 3 key markets for us, thinking about bepi, about 80% of the opportunity are between United States, China and Japan. All these geographies have accelerated regulatory processes, breakthrough designation in the U.S. We are expecting approval in October, PDUFA 26th of October. The market in the U.S. is highly concentrated in 5 states where -- that are marked by high immigration. So we are looking at states like California, New York, Texas, Florida and New Jersey. Patients who are treated are highly motivated. They have access to treatment and are very much willing to look for finite treatment. In China, you have seen our announcement that we have signed a collaboration with Sino Pharma.

Sino is market leader in hepatology in China with very broad commercial footprint with access to more than 5,000 medical centers. Japan, SENKU designation as well. We are looking at accelerated review period. Again, Japan is second market in terms of number of treated patients with very high government incentives for treatment.

And with this, I will pass on to Professor Lim to walk us through B-Well 1 & 2.

Thank you very much, Nina.

So I'm going to go through the presentation that I did this morning for the EASL conference and excuse my voice, I've got a bit of laryngitis. So the title of the talk was -- can we go back one slide, clinically meaningful rates of functional cure in virologically suppressed patients with chronic hepatitis B infection, treated with bepirovirsen in Phase -- B-Well Phase III clinical trials. Next slide, please. I think Nina has already covered that chronic hepatitis B infects more than 240 million people and causes more than 1 million deaths annually.

It actually is the most common cause of hepatocellular carcinoma globally. Functional cure is now the new treatment goal of chronic hepatitis B, and that's defined as shown in the slide, more than 24 weeks of sustained HBV DNA below the lower limit of quantification and HBsAg loss after finite therapy with or without anti-HBs. Bepirovirsen is an antisense oligonucleotide that targets all the HBV transcripts, reducing HBV DNA and HBsAg levels. And this is the first therapy in global Phase III trials with functional cure as a primary outcome. So here, I'm going to show you the primary efficacy and safety results of the trials.

Next slide, please. The objectives of the B-Well 1 and B-Well 2 studies are shown here. The primary objective was evaluated at week 72, which is the functional cure rate in those with a baseline HBsAg level below 3,000. And the key secondary outcome was also evaluated at week 72. This is a functional cure rate in those with a baseline HBsAg level below 1,000. In addition, also was assessed the sustained HBV DNA below LLOQ off all HBV treatments in those with HBsAg levels below 3,000 and below 1,000.

Next slide. So B-Well 1 and B-Well 2 were replicate studies, which are identical in study design. So patients could be enrolled in -- the studies they had chronic hepatitis B or on stable nucleoside analogues had HBsAg levels between 100 and 3,000 had DNA suppressed below 90 IU/mL, had ALT levels below 2x upper limit of normal, did not have cirrhosis or did not have interferon therapy more than 12 months. Upon enrollment, patients were stratified by HBsAg levels above or below 1,000 and were randomized 2:1 to receive bepirovirsen or placebo as 2 loading doses followed by weekly injections for 24 weeks on the background of nucleoside analogue therapy.

Upon completion of treatment, they were followed up for an additional 24 weeks on nucleoside analogue therapy after which they were assessed at week 48 for eligibility to discontinue nucleoside analogues. The eligibility criteria is shown in this slide. They had to have DNA less than LLOQ and HBsAg not detected between week 24 and week 46. ALT had a bit below 2x upper limit normal and had to be HBeAg negative. Those who were eligible to discontinue nucleosides then stopped therapy and were monitored for 24 weeks, after which they were evaluated for functional cure at week 72, which is the primary outcome of the study.

Next slide, please. The baseline characteristics were similar across groups. Average age was around 50 years. They were predominantly male, mainly Asian. The mean HBsAg level was between 900 and 950. Patients with HBsAg below 1,000 comprise 60% to 65% of patients. And most of these patients were HBeAg negative, only 8% were e-antigen positive. Next slide, please. This is the primary outcome. Functional cure was achieved in 19% of bepirovirsen recipients and no placebo recipients shown in the pooled study results on the right-hand side.

Next slide, please. For the key secondary outcome for HBsAg levels below 1,000, slight differences in B-Well 1 and 2, the pooled results showed a 26% functional cure rate in bepirovirsen-treated patients and none in the placebo. Next slide, please. This treatment effect was seen across all regions, this regardless of HBsAg level. There were minor differences in efficacy rates between different regions, largely due to differences in baseline characteristics between study populations in those countries.

Next slide, please. The key secondary outcome of HBV DNA below LLOQ off all HBV treatments was seen in 23% of bepirovirsen treated recipients and none in the placebo. This 23% constituted 19% of patients had functional cure and 4% additional patients who had DNA below LLOQ but did not achieve functional cure and none in the placebo group. Next slide, please. Sustained HBV DNA below LLOQ off all HBV treatments was seen in patients with HBsAg levels below 1,000 IU/mL. There were slight differences in B-Well 1 and B-Well 2. The pooled results showed a 31% DNA below LLOQ comprising 26% of patients with functional cure and 5% of patients who had DNA below LLOQ who did not have functional cure and none in the placebo group.

Next slide, please. This is the patient disposition of all patients in the B-Well 1 and B-Well 2 studies. I would point you to the pie chart on the right-hand side. I've already shown you 19% of patients achieved functional cure, but an additional 30% of patients achieved HBsAg levels below 100 IU/mL without functional cure. And these comprise 12% of patients with HBsAg levels below between 100 -- between 10 and 100 IU/mL and 18% of patients with HBsAg levels below 10 IU/mL.

HBsAg levels below 100 IU/mL are thought to be clinically significant because these patients may have a future possibility of HBsAg loss. Next slide, please. This is the on-treatment safety profile, which is consistent across B-Well 1 and B-Well 2, and I will point you to the pooled results on the right-hand columns in blue are the bepirovirsen results show that AEs, meaning the permanent discontinuation study treatment constituted only 3% of patients and SAEs related to study treatment only constituted 2% of patients. There were no fatalities and no fatal SAEs related to study treatment. Next slide, please. treatment AEs reported in more than 10% of patients is shown here. Most of these were injection site reactions comprising injection site erythema, pain, pruritus, or bruising.

There were also safety signals in ALT [indiscernible] increase and platelet count decrease. Participants had permanent discontinuation or liver-related events. However, 2 of these 4 patients actually achieved functional cure as well. Transient ALT increases after bepirovirsen initiation were associated with HBsAg reduction. There were platelet and eGFR declines, but these resolved once treatment was completed or paused and there were no clinically significant bleeding events attributed to bepirovirsen. Clinically significant changes in eGFR were not associated with markers of renal injury.

Next slide, please. So to conclude, functional cure rates of 19% treated with bepirovirsen among those with a baseline level of 3,000 IU/mL and 26% in bepirovirsen-treated patients among those with baseline HBsAg levels of 1,000 IU/mL was achieved and none was placebo. In addition, sustained HBV DNA below LLOQ off all HBV treatment seen 23% of bepirovirsen-treated patients in those with a baseline level of HBsAg below 3,000 IU/mL and 31% of patients with a baseline level below 1,000 IU/mL and none with placebo.

So bepirovirsen is a first-in-class 24-week finite therapy achieving functional cure in virologically suppressed patients with chronic hepatitis B infection with an acceptable safety profile. And this will definitely change the landscape of chronic hepatitis B treatment for the future. So you can access the full paper in the New England Journal of Medicine from today. Thank you...

Thank you, Professor Lim. My name is Kaivan Khavandi. I lead Specialty R&D at GSK, and I'm joined by Dr. Melanie Paff from R&D, who's the Medicine Development Leader for bepirovirsen. Next slide, please. The key point that's important to consider for a moment is the clinical impact these data show bepi could have. When we think about clinical importance, we typically consider the target value for an effect size and how this translates to improvements that matter for patients.

This is sometimes conflated with the proportion of patients who respond to therapy when exposed. And so I wanted to cover both. It's now accepted that functional cure is the very highest bar of efficacy to aim for in this disease. It's the single greatest predictor for prevention of hard endpoints, hepatocellular carcinoma and mortality. As the term suggests, this allows patients to come off all treatments with a finite management, and you'll appreciate that curative intent is a rare goal for a medicine in any portfolio.

So there's clearly no question of the clinical importance of functional cure, and this is reflected in management guidelines and regulatory processes. It also comes with a high burden of proof to demonstrate this in an [ RCT, ] as shown in this slide, requires undetectable DNA and loss of surface antigen once off all treatments for 6 months within a study. Bpi met this high bar in the B-Well studies. The comparative arm emphasizes this high bar, which we labeled in the presentation as placebo, but which actually represents the standard of care, nucleoside -- tide animal treatments for 48 weeks before coming off treatment compared to a similar group who received bepi for the first 24 weeks.

So it's 48 weeks of active treatments with NAs that we refer to as the placebo group. And in that comparator group, you see 0% achieved the primary endpoint of functional cure in the ITT population, those with surface antigen of 3,000 or less. Further, 0% achieved functional cure in those with baseline surface antigen of less than 1,000. And finally, 0% achieved response to HBV DNA at the lower limit of quantification at 72 weeks. So 0 is all around for the comparator arm, which is the standard of care. In comparison, in the ITT group, bepi achieved 19% cure. In the prespecified population with surface antigen less than 1,000, bepi achieved 26% functional cure. If we relate this to real-world numbers, the majority of the treated population with chronic hepatitis B have surface antigen less than 3,000 and over 40% have surface antigen less than 1,000.

And then when we consider the pie chart that Professor Lim presented, an additional 30% of patients achieved surface antigen levels below 100 bepi, a threshold reduction now accepted in guidelines as partial cure on the basis of the strong longitudinal data that shows protection from hard endpoints and which standard of care is poor at achieving. That allows us to appreciate the breadth of benefit across patient groups. So 1 in 5 and 1 in 4 patients achieved the highest bar of efficacy cure depending on baseline surface antigen levels in the most commonly treated patient groups and 1 in 2 patients received a response expected to predict protection from long-term outcomes by achieving surface antigen less than 100 IU/mL.

These data are clearly recognized and reflected in the impressive regulatory breakthrough and priority review designations achieved in filings across multiple authorities. Now if we go to the next slide, I'd like to take a moment to consider that this is a monotherapy. And so it's quite remarkable that a single product can confer such protection. How can it do that? Well, it's a single therapy, but it unlocks a 3-pronged efficacy benefit. And it does this in a large part because bepi targets a highly conserved region across all HBV genotypes and present across all HBV RNAs. As such, it targets protein-coding RNAs pcRNAs that stop translation of HBe antigen. It targets pre-genomic RNA, pgRNA, which prevents the translation of HBV polymerase and correlated proteins, knocking down HBV DNA.

And of course, the RNAs that translate HBV surface proteins or antigens, which really stops this latent substrate that's responsible for reactivation and relapse when, for example, the immune system is tested. And last but not least, it directly acts as an innate immune stimulator, which when combined with the strain that residual HBV antigen burden places on T cells, prevents the immune exhaustion that's problematic in hepatitis B. This gives the system a chance to recover and therefore, sustain the durable clearances that we observe. From a portfolio and competitive perspective, the efficacy of bepi truly resets the bar when we consider what could add meaningful benefit beyond bepi. And you'll appreciate it's not typical to have a first-in-class programme for a major public health challenge with a finite and curative solution.

For this reason, we see the hep B portfolio positioned with bepi as the anchor. And to this end, Mel will later cover one such programme that does offer real promise alongside bepirovirsen in those with surface antigen levels not studied in B-Well. But first, Mel will help put these data in the context of standard of care and clinical management of these patients.

Thank you, Kaivan.

So I want to talk a little bit about the established standard of care that we have in hepatitis B now. And you'll note that both nucleoside analogues, which are used around the world and pegylated interferon, which is primarily used in China, neither of these drugs were designed for functional cure. So nucleoside analogues were specifically designed to stop viral replication. So it's not surprising that the functional cure rate is extremely low. And as Kaivan stated, in our trial after 6 months of therapy, you can see that the functional cure rate in the placebo or the nucleoside analogue comparator was 0% in our trial. pegylated interferon on the other hand, is primarily used in China, and it's a treatment for 144 weeks for HBsAg loss.

Now it has a fairly low functional cure rate, around 2% to 8%. The issue that you have with pegylated interferon is the unfavorable safety profile and the limited tolerability. So patients have a problem staying on this drug because it basically makes you feel like you have flu-like symptoms. So there's quite high dropout rate and compliance is a problem. And we contrast that to what is the expectation of a standard for tomorrow. So clearly, we're looking for functional cure as the gold standard. We're looking for a finite duration of therapy. Patients don't want to be on nucleoside analogue for the rest of their lives. We're looking to lower that risk of cirrhosis and liver cancer and all of the associated reduction in morbidity and mortality.

We're looking for a larger eligible patient population. And I think it's really important for us to point out the burden that these patients walk around with the psychosocial burden of having this chronic infection and the lifelong medication. So if we could go to the next slide, please. In addition to the information that Nina shared earlier, I want to point you to an analysis that was recently reported this past year that looked at the clinical outcomes of surface antigen loss. So this was a retrospective cohort study using an electronic medical record database over a 7-year period, and it showed significant association between HBsAg loss and the reduction in the risk of liver cancer and even all-cause mortality. So 89% reduced risk for liver cancer and 62% reduced risk for all-cause mortality.

Next slide, please. One of the questions that we get a lot is what about the ongoing development? What is GSK interested in from hep B from a portfolio perspective? And we'd like to draw your attention today to another study that we have going on right now in Phase IIb with an siRNA that was in-licensed from Janssen. In this particular study, you can see from the graph, we're looking to expand the patient population to all treated patients, 100% of treated patients, not just the 70% of patients that are below 3,000. Dap, tom or siRNAs are classically shown a very strong and robust response to lower even very high levels of HBsAg to a low level.

Unfortunately, by themselves, they don't seem to be able to achieve functional cure. However, what these siRNAs can do is bring the HBsAg down to a sweet spot where we know bepi works best. So our intention with the B-United study is to test 6 months of Dap/tom therapy, allowing the HBsAg to come down to this low level, then following that with 6 months of bepi, again, to achieve functional cure on the backbone of nucleoside analogue treatment. After week 48, those patients will continue on their nucleoside analogue for another 6 months. And those that are available to cessate, their nucleoside analogue will then stop and functional cure rate will be called at week 96.

So we're very excited about the study. It has the potential to show both the increase in functional cure rate overall as well as opening up a treatment for functional cure to patients that now have no ability to get functional cure. So we're very excited about this. Can we go to the next slide? So I think in summary, what we've shown today is that bepi is clearly a clinically significant functional cure medicine. It's achievable, it's durable, and we additionally have almost half of the patients who receive a clear medical benefit after one year of treatment. What we want to do is to think about the things that we have heard today around the EASL conference. Physicians that we've talked to and that you've seen in print have said things like transformational, generational change in treatment, historic. The editorial from the New England Journal said remarkable results.

I think this also reflects the innovation that we've seen by regulators and their recognition of that innovation. And you can see both in the U.S., China, Japan, we have things like Fast Track priority review, breakthrough, SENKU designation. It's not a regular occurrence that you get this across so many regulators. And I think it's a recognition of the innovation that we bring. So we'll stop here and then move to question and answers.

Thank you very much, Mel. With this, we are ready to take your questions. [Operator Instructions] First question comes from Peter Verdult.

We also checked in with Professor [ Wong ] at Stanford earlier today, who's also at EASL. He definitely thinks the data is exciting, but he did say it's not groundbreaking. So a couple of follow-on questions. He -- on the presentation talked about an applicable population as defined by B-Well is about 70%. He was saying that in that -- the B-Well study probably only represents 30% to max 50% of treated patients. So I just want to square the circle there. That's a clarification.

My real question is the interesting stuff. I mean the sequencing in the combination study with siRNA is definitely interesting. But what about some of the other questions from B-Well? So the one I'm really interested in, in the trial design, patients were allowed to stop their nucleoside therapy. And I think that finite treatment is a real sort of selling point. So within B-Well, can you tell us how the patients that stopped their [ Nucleoside analogues ] after 48 weeks, how did they do to those that continued? So that would be my one question.

So patients were eligible to stop treatment. They had HBV DNA negative and HBsAg was undetectable, ALT was below 2x upper limit of normal, and they were HBeAg negative. So they had to fill all those criteria for them to stop Nucleoside analogues therapy. So in other words, they already had HBsAg loss. Does that answer your question?

Peter, I assume this has answered your question. If not, raise your hand again, and we can have a follow-up. With this, we...

Sorry, I was muted.

Yes. And I'm happy to address also the treated population. So the average that we have shown you today, meaning 68% of the treated population is less than 3,000 and 45% is less than 1,000 is the average across the 5 major markets, meaning U.S., China, Japan, EU5 and Germany. But there is variability from market to market. So for instance, in the less than 3,000 population, the average across those markets is 68%; however, Germany is a little bit lower at 54% and Japan is a little higher at 86%. So what we're providing is the average.

Can I just follow up on that issue about whether this is breakthrough or not breakthrough, which I think is a matter of opinion. But I think the breakthrough part is the fact that 90% of patients achieved functional cure. That's never been achieved in any treatment programme before. Nucleos(t)ide analogue for interferon. So if you don't call that breakthrough, I'm not sure what else you call it.

Next question comes from Sachin Jain.

I've got a question around testing and monitoring. The editorial calls out need for stringent safety monitoring referencing every 1 to 2 weeks. So I just wanted to clarify the safety monitoring requirements in the study, what do you expect from the label and how onerous that will be? And then around HB surface antigen testing, obviously, approvals in October, minority of patients are currently tested in the U.S. is our feedback. How quickly do you think that can mobilize post approval?

So let me take the question on safety monitoring. So patients were injected weekly. So they were obviously monitored weekly for safety features. I think the 2 safety features that were important, the ALT rise. And I showed you in the -- I didn't show you in the presentation, but ALT abnormality was seen in about 45% of patients. ALT more than 10x was seen in 6% of patients and 20x was seen in, I think, 1% of patients. However, if you had an ALT rise more than 3x baseline, you had an 85% chance of getting a cure or HBsAg loss. If you had ALT less than 3x baseline, then your chance of getting HBsAg loss was only 35%.

So it seems that the ALT rise is associated with efficacy. There were no drug-related liver injury problems that were called. So from the ALT viewpoint, it seems to be an efficacy feature. As far as the other safety issues is concerned, they comprise 3 issues: thrombocytopenia, renal function abnormalities and complement abnormalities. These 3 features are actually features of class effect of antisense. They're not related specifically to bepirovirsen. Thankfully, all these features resolved once bepirovirsen was stopped and including the renal function and the thrombocytopenia and the complement activation process, none of them were clinically significant.

There were no bleeding effects and renal abnormalities resolved once the bepirovirsen treatment was discontinued or paused. And also, there was no markers of renal injury that were related, particularly things like proteinuria. So I think safety monitoring needs to continue. But as far as the long-term safety is concerned, it seems to be a transient effect related to study treatment.

And maybe I can address the difference between a clinical trial in real world setting. When you go into especially a Phase III clinical trial, you don't know the outcome. So of course, we're going to measure and we're going to monitor more than you would in a normal setting once you know the outcome. So I wouldn't be concerned about the clinical trial monitoring that takes place right now. Now as we submit this data to regulators around the world, the regulators will decide what monitoring should or should not be in place. And in my experience as a drug developer, that may be a little different from region to region, but they will approve what is appropriate for the safety and efficacy for patients.

As far as HBsAg antigen testing goes, you are correct that quantitative HBsAg antigen is used primarily outside of the United States. However, quantitative HBsAg antigen is readily available inside the United States as a laboratory developed test. We use laboratory drive tests all the time. That's not a problem. It's available on Epic. You can order it, you can get it. And I think one of the things that we are going to see much like you do in many diseases, the patient wants to know whether the medication is working.

And this quantitative test is going to be able to give them that immediate feedback of how they're doing on therapy, which is going to provide extra motivation and compliance for them to finish the full 6 months of therapy. So I think what's going to happen in the future in the U.S., now that we have a reason to use quantitative HBsAg, you're going to see a significant uptick in that.

Yes. Sachin, I would just add on the testing. Testing in the U.S. is available. This is not some kind of novel test that is not available. And just from the execution perspective going into the launch, it's clearly our priority to make sure that physicians, whenever they want to use it, will be able to use it. It's just that the testing so far did not -- was not needed for diagnosis, treatment or anything like that. And therefore, it's used less or less available. But going forward, this is something that from the commercial execution perspective, it's a priority, and this is going to be changed.

Next question comes from Graham Parry.

I was just going to follow up on the testing question. So can you just confirm the frequency of testing -- of liver testing during the trial and why you think the regulator wouldn't require you to have the same level of testing because that may have masked additional ALT elevation. And then on commercial strategy, can you just talk us through how you're thinking about pricing commercial strategy just given the very large number of untreated patients, both across the U.S. and China. But just given the large numbers of untreated patients and even undiagnosed patients, can you just talk us through how to access that and how you think about pricing?

So I'm happy to take the testing question. I think what will happen, again, discussing the ALT, the platelet, the EGFR, I suspect what will happen around the world is that we will want to monitor those patients on a weekly basis for the first 12 weeks, and then it will loosen from there on out. But again, as I said, we can't really comment on exactly what the monitoring profile will be because the regulators will decide that on a country-by-country basis.

I'm going to make a quick point to put the safety data in context. Isolated ALT increases within the range of the fold increases in question without associated increases in bilirubin or evidence of liver injury. And in this setting, it tracks with efficacy and it's all mechanism. So you've got a boost in immune competence. It clears infected hepatocytes and you have an associated increase in ALT, which for those of you who are familiar, will remind you perhaps of the eGFR dip you get with SGLT2s, which is a marker of benefit and efficacy. But finally, I think the adverse events should be put in the context of a finite treatment, where if any effects are resolvable or reversible, that's a very favorable setting for benefit versus risk.

I will touch base on pricing. So our approach here is to access patients who are on treatment, who are being treated, who have desired to be treated, who are willing to go through it for whom physicians will recommend treatment. At the moment, our initial commercial approach is not focusing on going after all pool of diagnosed and let alone those who are infected but not diagnosed. So from that perspective, I think we mentioned before in terms of pricing for the U.S., we are looking at a price range that is similar to hep C space that we have seen. And so far, we have a very clear understanding that this is very acceptable price level from the payers in the U.S.

Next question comes from Ben Jackson.

I guess, can I ask for some further color on this 30% of patients that are achieving the antigen levels below 100 without the functional cure. You've made reference to the current antigen testing frequency in different regions. Does this mean that this kind of supportive data is more impactful in different regions, particularly ex U.S.? And how meaningfully could this mean that uptake is diverges between different regions as a result of that data?

Just to get some clarification, you're asking about HBsAg levels below 3,000?

Below 100 to be clear. And how meaningful is that data? And is there a disparity by region about how important that data is?

I see in terms of the effect of bepirovirsen, I think we don't know whether bepirovirsen treated patients with HBsAg levels below 100 are the same as nucleoside analogues treated below 100. So we'll need some long-term follow-up to determine whether that's the case. However, these patients are all of nucleoside analogue therapy. And after 6 months of nucleoside analogue therapy, they seem to have HBsAg levels below 100. So that's definitely a good sign. Some of these patients will continue to have HBsAg loss. So I think there's definitely a beneficial effect of patients below 100 IU/mL. Whether there's any regional specific differences, not as far as I know.

I think across the regions and across clinical studies, the 100 IU/mL cutoff seems to be holding on quite well.

I'd like to also point out from an R&D perspective, when we were designing this clinical trial, you'll note that the inclusion criteria only allowed patients to come in that were greater than 100. There was a reason for that. Patients who have less than 100 more naturally have a chance over several years to achieve functional cure, and we were concerned that, that would overly bias the outcome. So I think that in itself is evidence of this effect.

Just one final point that both the EASL and the AASLD guidelines were updated in the last 18 months, acknowledge that surface antigen less than 100 represents partial cure and is clinically important as a treatment goal.

Our next question comes from Zain Ebrahim.

So my question is on the efficacy and the potential breadth of label that you might receive given that -- so the ITT population efficacy looks really good at 19% functional cure rate and then in the less than 1,000 is 26%. But in that intermediate sort of patient subgroup, so 1,000 to 3,000 international units per milliliter, the functional cure rate was about 5%, 10% or 7% pooled. So just your thoughts on whether the data set you have, you think is sufficient to get a broad label covering the ITT population or whether that might be more focused on that less than 1,000 unit subgroup or and whether -- and even if you have a sort of broader label, how uptake could look?

Yes. Thank you for the question. I believe that what we'll see in this population, and this is the biology of the virus and the biology of the disease. As you go from 3,000 down to 100, it is a continuum of efficacy. So the lower the HBsAg has been seen as probably the strongest predictor of response. So what we want to be able to say about this is that when we designed the clinical trial, we specifically stratified on 1,000. But that 1,000 to 3,000 group will contain people who are 1,050, and it will contain people that are 2,998.

So it will be up to the physician to have a discussion with their individual patient as to whether the risk benefit of this drug is available. And I suspect from the feedback that we have heard from patients, a 7% functional cure is about what you see with pegylated interferon. And if you had a finite therapy that gave 7%, patients would be highly motivated to take that.

I see we have one more question in the queue. Zach, please go ahead.

This is Zach Dunn on for Seamus Fernandez from Guggenheim. Appreciate the question. So I guess I want to follow up on the 1,000 to 3,000 group because then at least based on the China functional cure rates, you're kind of falling in that peg interferon level.

So I guess when you compare then the side effects, can you provide any maybe qualitative color on those Grade 3 adverse events? Are they evenly split between the 2 groups? And then yes, if we can just kind of hear a little bit more on the risk benefit in this 1,000 to 3,000 population? Or does it really seem that this drug will most likely be used in 1,000 and below?

Thank you for your question. I don't have any visibility on the data comparing below 1,000 and between the 1,000 and 3,000. So I can't really give you an answer. But I cannot be sure that these AEs are related to efficacy. The primary AEs we're talking about, particularly the complement platelet reduction and the renal function were class effects of the antisense. So this might be a random effect on patients. As far as the ALT increase, maybe we can speculate that, that's more likely to occur in the 1,000 and below population, mainly because HBsAg loss rates are related to the level of ALT increase.

If your ALT increases more than 3x baseline, you have an 85% chance of HBsAg loss. But if your ALT is below 3x baseline, your chance of HBsAg loss is actually only 35%. So most of the patients who achieved HBsAg loss were below 1,000 IU/mL. So I suspect the ALT rises will be seen in that population. As for the other AEs, they're probably going to be more random.

Next question comes from Christopher LoBianco.

This is Chris on for Stephen Scala. Can you provide any comments on time lines for gaining payer reimbursement in the U.S.? And what sort of prior authorization criteria do you expect for bepi in the U.S.

The time lines for the U.S., we are expecting approval probably by the end of this year and then the traditional negotiation with payers that will be ramping up during 2027. And regarding the prior authorization question, we are expecting, of course, antigen levels as per label as part of it and also NA treated restrictions. So those are the main 2 that we are expecting right now.