AstraZeneca Aktie

Good morning to those joining from the U.K. and the U.S. Good afternoon to those in Central Europe, and good evening to those listening in Asia. Welcome to AstraZeneca's Q1 2026 Webinar for Investors and Analysts. Before I hand over to AstraZeneca, I'd like to read the safe harbor statement.

The company intends to utilize the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Participants on this call may make forward-looking statements with respect to the operations and financial performance of AstraZeneca. Although we believe our expectations are based on reasonable assumptions, by their very nature, forward-looking statements involve risks and uncertainties and may be influenced by factors that could cause actual results to differ materially from those expressed or implied by these forward-looking statements.

Any forward-looking statements made on this call reflect the knowledge and information available at the time of this call. The company undertakes no obligation to update forward-looking statements. Please carefully review the forward-looking statements disclaimer in the slide deck that accompanies this presentation and webcast. [Operator Instructions]

And with that, I'll now hand you over to the company.

A warm welcome to AstraZeneca's First Quarter 2026 Presentation Conference Call and Webcast for Investors and Analysts. I'm Joris Silon, Head of Investor Relations. And before I hand over to Pascal and the members of our executive team, I would like to cover some housekeeping items. All of the materials presented today are available on our AstraZeneca Investor Relations website.

Next slide. This slide contains our forward-looking statements, including the safe harbor provisions, which I would encourage you to take the time to read. We will be making comments on our performance using constant exchange rates, or CER, core financial numbers and other non-GAAP measures. A non-GAAP to GAAP reconciliation is contained within the results announcement. All numbers quoted are in millions of U.S. dollars unless stated otherwise.

Next slide, please. This slide shows our agenda for today's call. Following our prepared remarks, we will open the line for questions. As usual, we will try to address as many questions as we can during the allocated time. Please limit the number of questions you ask to allow others a fair chance to participate in the Q&A.

And with that, please advance to the next slide, and Pascal, over to you.

Thank you, Joris, and welcome, everyone. Next slide, please. We delivered a strong first quarter, building on the momentum we generated in 2025. Total revenue grew 8% in the quarter, supported by robust demand for our innovative medicines. We saw strong growth in operating profit, which increased 12%, reflecting our ongoing focus on operating leverage.

Core EPS grew 5%. Our EPS growth was held back by the low tax rate in the prior period. Since our Q4 2025 results, we have secured 14 approvals in major regions across our diverse portfolio, a clear illustration of the value our medicines bring to patients globally. Additionally, we continue to see strong delivery from our pipeline.

In the past weeks, we announced results from 4 positive Phase III programs, including 2 NMEs, tozorakimab and efzimfotase alfa. We continue to invest in our commercial capabilities, both to support ongoing launches and multiple future launches such as baxdrostat, camizestrant and tozorakimab. In R&D, we continue to invest in our pipeline, including our transformative technologies.

Please move to the next slide. The breadth of our business remains a competitive strength with a solid growth outlook across therapy areas and key markets. Oncology and Rare Disease saw strong double-digit growth, while high demand in R&I was offset by loss of exclusivity in CVRM.

We saw strong performances across our key regions. Our largest market, the United States, grew at a double-digit percentage, benefiting from our investment behind recent launches with Europe and emerging markets growing at high single digits. Importantly, we continue to deliver impressive growth in the emerging markets with ex-China revenues up 9%, reflecting the benefit of our sustained presence in this market.

Revenues in China increased by 2% with VBP implementation impacting Farxiga, Lynparza and roxadustat growth. We are confident in our growth outlook in China based on the positive 2026 NRDL outcomes.

Next slide, please. In the first quarter, we saw a continuation of the successful clinical trial delivery seen in 2025. We announced 4 positive high-value programs, reinforcing the continued progress we are making towards our 2030 ambition and beyond. We look forward to discussing the significant potential of these readouts during this call.

And with that, I will hand over to Aradhana to take you through our financials. Please advance to the next slide.

Thank you, Pascal, and good morning and good afternoon, everyone. As usual, I will start with our reported P&L. Next slide, please. As Pascal has already highlighted, we saw very good top line momentum in the first quarter with total revenue increasing by 8%. Product revenue consisting of product sales and alliance revenue also increased 8% with continued growth seen across all key regions.

Alliance revenue increased by 26%, reflecting our increased profit shares for our partnered products, Enhertu and Tezspire in regions where our partners book product sales. Next slide, please. This is our core P&L. The core gross margin in Q1 was 83%. For the full year, we continue to anticipate a stable to slightly higher core gross margin versus 2025. Core R&D expenses increased by 8%, driven by continued acceleration and investment in our pipeline.

The number of active clinical trials increased by 10%, and the number of patients enrolled in our studies increased by 30% compared to Q1 last year as we continue to bring new innovative medicines to patients while creating value for our shareholders. As previously highlighted, we continue to invest in transformative technologies, including cell therapies and T cell engagers to drive growth also beyond 2030.

As a percentage of total revenue, core R&D costs accounted for 23% in the first quarter. For the full year, we continue to expect core R&D costs to be at the upper end of the low 20s percentage range. Core SG&A costs increased by 7% in the first quarter. This was partly driven by prelaunch investments behind baxdrostat, which has a U.S. PDUFA date in the second quarter of 2026.

As you've seen, we have had a great start to 2026 in terms of R&D with success in 4 high-value programs, including tozorakimab, which will require SG&A investment to maximize their potential. In addition, we have several other upcoming launches for products with high-value potential, including baxdrostat, camizestrant and tozorakimab, all of which will help drive growth through 2030 and beyond.

Other operating income increased to $189 million with some nonrecurring milestones booked in the quarter. Core operating profit grew by 12%, reflecting a strong underlying performance. Core EPS grew by 5% to $2.58 with growth rate impacted by a low tax rate in Q1 2025.

Next slide, please. Cash flow from operating activities of $3.4 billion was a slight decline versus the same period last year due to large milestone received in Q1 2025, but partly offset by strong underlying performance. CapEx of $600 million includes previously announced multiyear investments such as our new ADC manufacturing facility in Singapore and our new manufacturing plant in Qingdao, China, for an inhaled respiratory portfolio.

We continue to anticipate CapEx to increase by around 1/3 in 2026. Deal payments of $1.1 billion include milestone payments to partner and an upfront payment for the Jacobio license agreement announced last year.

We have now paid the last royalty payment for Farxiga. For the full year, we continue to anticipate milestone payments of around $2.5 billion relating to past transactions. The recent CSPC deal closed in April, so will be booked in the second quarter. Our capital allocation priorities remain unchanged. Net debt increased by around $2.5 billion in the quarter, driven by a payment of the second FY 2025 interim dividend in March.

We are comfortable with our current level of gross debt. And as previously indicated, we anticipate core finance expenses to increase this year, driven by higher lease expense and lower interest income. Today, we are reiterating our full year guidance. Total revenue is anticipated to increase by mid- to high single-digit percentage and core EPS is anticipated to increase by low double-digit percentage at constant exchange rates.

Based on average March exchange rates, we anticipate a low single-digit positive FX impact on total revenue and a neutral impact on core EPS. In summary, a very strong financial performance in the quarter. And with the investments we are undertaking both in R&D and behind new launches, we are well placed to grow through 2030 and beyond.

With that, I will hand over to Dave, who will take you through the business performance of our oncology business.

Total revenues grew 16% in the first quarter to $6.8 billion with double-digit growth across all reported geographic segments. Performance in the U.S. and Europe was particularly strong with growth of 18% and 19% over the prior year respectively, continuing the momentum demonstrated through 2025. Turning now to quarterly performance of key medicines. Tagrisso grew 5% in the quarter to revenues of $1.8 billion. Performance was driven by demand across all stages of EGFR mutated lung cancer in the U.S. and Europe, partially offset by higher than historic destocking in the U.S.

In the frontline setting, Tagrisso remains the treatment of choice with an increasing proportion of physicians opting FLAURA2 combination. We anticipate continued growth over the balance of the year across all indications. Our foundational immuno-oncology assets, Imfinzi and Imjudo, delivered growth of 28% in aggregate. Imfinzi growth of 30% was, as in previous quarters, underpinned by robust demand growth across all regions. We are seeing an increasing contribution from more recent launches such as MATTERHORN in gastric, NIAGARA in bladder and ADRIATIC in lung cancer, alongside continued growth in more established indications such as HIMALAYA and TOPAZ.

With continued strong demand for Imfinzi and Imjudo across indications, we are well positioned to sustain growth throughout the remainder of 2026. Calquence revenues grew 17% in the quarter to more than $900 million with double-digit growth in all major regions. Focusing in on the U.S., Calquence continues to maintain its share leadership position in the frontline CLL setting despite intense competition.

Our finite regimen for frontline CLL based on AMPLIFY is gaining momentum in reimbursed European markets and driving incremental new patient starts. While too early to comment on the trajectory in the U.S., excitement is building among prescribers, and we believe AMPLIFY will be a key contributor to growth this year. Turning to Enhertu, which is now annualizing as a $5 billion brand on an alliance view, we delivered growth of 34% in the quarter, which was balanced across regions.

This growth reflects ongoing demand in both the HER2-positive and HER2-low breast indications. In China, the exceptional performance we saw through 2025 post-NRDL enlistment continues into 2026 with share gains in both HER2-positive and low breast cancers. We're also seeing encouraging early signs of adoption of Enhertu in first-line HER2-positive breast cancer in the U.S. following the DESTINY-Breast09 approval in December last year.

We look forward to broadening our reach further with additional launches into early HER2-positive breast cancer later this year. Truqap revenues of $198 million in the quarter represents 47% growth over the prior year. We expect some further growth to be delivered in ex-U.S. markets, and we see U.S. market share at peak. Datroway revenues of $43 million in the first quarter reflect ongoing demand in the U.S. in later-line EGFR-mutated lung cancer with more than 1 in 3 third-line patients now treated with this medicine.

Following its acceptance for priority review, we look forward to the U.S. approval of TROPION-Breast02 later this quarter. This has the potential to drive significant further growth for Datroway given the differentiated profile demonstrated in patients with metastatic triple-negative breast cancer that are not candidates for immunotherapy, an area of high unmet need.

After a robust first quarter performance, we are excited about the outlook for the remainder of the year as we continue to deliver transformative regimens to more patients across the globe.

With that, please advance to the next slide, and I'll hand over to Susan to cover key R&D highlights from the quarter.

Thank you, Dave. Earlier this month, we announced the positive results of the Phase III EMERALD-3 trial. Building on the success of HIMALAYA in advanced liver cancer, EMERALD-3 now moves Imfinzi in combination with Imjudo into the earlier local regional setting with the goal of transforming outcomes for more patients with hepatocellular carcinoma.

EMERALD-3 is a 3-arm trial, investigating whether the STRIDE regimen made up of a single priming dose of Imjudo together with regular interval dosing of Imfinzi with or without lenvatinib can improve outcomes when given before and then alongside standard of care transarterial chemoembolization or TACE.

Data from the primary analysis are very encouraging, demonstrating a statistically significant and clinically meaningful improvement in progression-free survival for the STRIDE plus lenva arm with a positive trend to overall survival. The STRIDE-only arm also demonstrated a strong trend to both PFS and OS benefit, although this arm was not formally tested at this time. We await further follow-up and are excited by the potential EMERALD-3 offers for more than 200,000 patients with local regional HCC currently eligible for embolization.

We look forward to presenting the data at ASCO. EMERALD-3 marks the beginning of a series of high-value Imfinzi readouts over the course of 2026. In the coming months, we expect results from VOLGA, which will complement our NIAGARA indication in muscle invasive bladder cancer and further reinforce our position in genitourinary cancers.

Then in the second half of this year, we have 2 data sets that present opportunities to further broaden use of Imfinzi in lung cancer with AVANZAR aiming to improve outcomes and significantly expand Imfinzi's reach in the first-line metastatic setting and PACIFIC-9, which looks to consolidate and deepen our leadership in Stage III unresectable disease.

Imfinzi is the current backbone of our immuno-oncology franchise, and we're excited by its potential to become standard of care across an even broader range of tumor types and settings. We're also excited to highlight several new developments from our oncology pipeline that will be presented at ASCO this year. Our in-house ADC program continues to progress at pace. We look forward to sharing more data on puxi-sam, our B7-H4 directed ADC in endometrial and ovarian cancers.

And we're also excited to be moving forward with our plans to open 2 further Phase III trials for our folate receptor alpha-targeted ADC, [indiscernible] in ovarian cancer later this year. We will also share further data for sone-ve in Claudin18.2 positive gastric cancer from a broad global population, which supports the ongoing Phase III CLARITY-Gastric01 trial now expected to read out in the second half of this year.

Also at ASCO, additional evidence supports the use of our PD-1/TIGIT bispecific rilvegostomig, in combination with Enhertu in gastric cancer. Early phase data for volrustomig in head and neck cancer will also demonstrate safety and efficacy in this indication. And finally, I want to highlight that we will present impressive first-in-human data for our PRMT5 inhibitor, AZD3470 in a heavily pretreated classical Hodgkin lymphoma population, strengthening our expanding hematology pipeline. ASCO 2026 looks set to be another significant congress for AstraZeneca.

And with that, please advance to the next slide, and I'll pass over to Ruud to cover biopharmaceuticals performance.

Thanks, Susan. Next slide, please. Our Biopharmaceuticals total revenue was broadly stable in the quarter with growth in key brands mostly offsetting the anticipated headwinds from Brilinta, Farxiga and roxadustat. Overall, biopharmaceuticals total revenue declined by 2% to $5.8 billion.

Our Respiratory & Immunology portfolio was up 7% to $2.3 billion. This performance was driven by our key brands, which grew 18%. Within the portfolio, Fasenra delivered another strong quarter, growing 11% to reach $483 million. This was supported by strong uptake in China following its NRDL listing with revenues in emerging markets up 63%. Breztri generated $353 million in revenue, growing by 13%. Earlier this month, Breztri achieved its first label expansion beyond COPD with U.S. approval for asthma.

Breztri is now the first and only triple therapy in asthma approved for patients aged 12 and older. Regulatory reviews continue in other countries. Tezspire continues to perform well and delivered $303 million in revenue, representing a growth rate of 34%. Tezspire is now approved for chronic rhinosinusitis with nasal polyps in all major markets following approval in Japan and China this quarter.

Saphnelo grew 24% to achieve $171 million in revenue. The new subcutaneous formulation is now approved in Europe, the United States and Japan, which extends its reach to the large segment of patients who favor self-administration. 2026 marks a transition year for CVRM as we navigate loss of exclusivity headwinds ahead of the launch of several key pipeline medicines and new indications.

CVRM total revenue for the first quarter stood at $3.3 billion, representing a decline of 6%. Farxiga total revenue fell 3% to $2.2 billion. Farxiga has a phased LOE profile. And in quarter 1, that LOE effect was seen in established rest of the world and also with the implementation of VBP in China. As expected, generic manufacturers entered the U.S. market in April. U.S. markets continue to perform well, fueled by Farxiga's market share leadership within the fast-growing SGLT2 inhibitor class.

Lokelma achieved global market leadership in the potassium binder class and $199 million in the quarter, reflecting growth of 26%. Our commercial teams are preparing for the launch of baxdrostat later this year with the PDUFA date for FDA regulatory decision set for quarter 2. If approved, baxdrostat will be the first aldosterone synthase inhibitor to serve patients with uncontrolled and resistant hypertension.

In 2026, we anticipate gaining commercial access. And over time, we expect to see broader use across patients eligible for Part D reimbursement in line with the typical negotiation cycle. With the new approval for Breztri in asthma, the anticipated baxdrostat launch, the recent success of tozorakimab Phase III COPD program and the upcoming results from Wainua-ATTR-CM trial, we have much to look forward to across biopharmaceuticals this year.

I will now hand over to Sharon to take us through the exciting tozorakimab readouts in more detail.

Thank you, Ruud. Next slide, please. I am delighted to share the significant progress from our respiratory pipeline this quarter with compelling new data that underscore our commitment to pioneering science and addressing the most urgent challenges in respiratory disease today and for the future. We recently reported high-level results from our 3 pivotal Phase III studies and long-term extension study in our LUNA program, studying tozorakimab in COPD, OBERON, TITANIA, MIRANDA and PROSPERO.

This represents the most comprehensive Phase III program ever conducted for COPD biologic, and the results reinforce our confidence in tozarakimab's potential to be a first and best-in-class treatment option for patients living with this devastating disease. COPD remains a critical area of unmet medical need. It is the third leading cause of death globally, claiming over 3 million lives each year. Even when patients are on an inhaled standard of care, approximately half still experience exacerbations, which amplifies their risk of cardiovascular events, including heart attack, stroke or even death.

Importantly, only 50% of patients live more than 3.5 years after their first severe COPD exacerbation. These statistics underscore why innovation in COPD is so urgently needed. What sets tozarakimab apart is its dual-acting mechanism and the breadth of our clinical program. This is a true AstraZeneca science success story. Over a decade ago, our scientists uncovered IL-33's two distinct forms and their role in COPD.

Our research confirmed the reduced form of IL-33 activates immune cells through the ST2 pathway. They also discovered that IL-33 released from cells undergoes oxidation and converts to a different form, which activates the RAGE/EGFR pathway and the cycle of mucus production in COPD. These discoveries informed the development of tozorakimab, a differentiated molecule, which uniquely inhibits the signaling of both reducing the inflammation and breaking the mucus dysfunction cycle, which drive disease worsening.

In OBERON and TITANIA, tozorakimab achieved statistically significant and highly clinically meaningful reductions in the annualized rate of moderate to severe exacerbations. This efficacy was seen in former smokers and in the overall population, which included former and current smokers and had patients independent of eosinophil levels and lung function severity.

MIRANDA, testing an every 2-week regimen showed clinically meaningful benefits in exacerbation reduction as well. These results are truly exciting, marking the first time a biologic has demonstrated efficacy in COPD in 3 pivotal trials that enrolled broad populations. These results are further supported by PROSPERO, the long-term extension study of OBERON and TITANIA.

While the narrower primary endpoint of severe exacerbations, those leading to hospitalization or death, did not reach statistical significance in former smokers, we observed a numerical reduction in this population and a nominally significant reduction in the overall population. Tozorakimab was well tolerated with a favorable safety profile across the entire program. We are working at pace to share these data with the regulatory authorities and the scientific community. With approximately 6 billion biologic eligible patients globally, tozorakimab has the potential to address the broadest population of COPD patients.

And with that, please proceed to the next slide, and I'll pass over to Marc to cover rare disease.

Thank you, Sharon. Can I get the next slide, please? Rare Disease delivered total revenue of $2.4 billion in quarter 1, up 15% year-over-year. This is driven by growth in neurology and metabolic diseases, increased patient demand and continued global expansion. If you recall, first quarter 2025 performance included transitory headwinds, most notably tender market order timing for both Soliris and Strensiq.

In the quarter, Ultomiris grew 18%, driven by patient demand across indications, including the competitive myasthenia gravis and PNH markets. Soliris revenues continued to decline due to successful conversion to Ultomiris as well as biosimilar pressure. This was partially offset by favorable order timing in certain tender markets.

Strensiq grew 43% year-on-year, reflecting strong underlying demand and a favorable comparison versus the prior year. We saw demand growth for Koselugo, including the newly launched adult indication for NF1-PN patients. We continue to see great momentum across the rare disease portfolio. Please advance to the next slide.

I'm delighted to announce the positive high-level results for our Phase III programs in rare metabolic and renal diseases. Efzimfotase alfa, our next-generation enzyme replacement therapy demonstrated positive results from the global Phase III clinical program for patients with HPP. The MULBERRY trial in treatment-naive pediatric HPP patients met its primary endpoint, showing meaningful improvements in bone health as well as other objective endpoints, including physical function and quality of life.

In parallel, the CHESTNUT Phase III trial showed that efzimfotase alfa was well tolerated in children switching from Strensiq while maintaining benefit on bone health. In the HICKORY Phase III trial in adolescents and adult with HPP, efzimfotase alfa demonstrated numerical improvement but did not achieve statistical significance in the primary endpoint of 6-minute walk test in patients who have been -- who have not been previously treated with Strensiq compared to placebo.

The results show clinically meaningful impact on mobility, physical function, pain and fatigue that are key aspects of this heterogeneous disease that are beyond one single endpoint such as the 6-minute walk test, the only approved adult endpoint. Efzimfotase alfa represents patient-centered innovation, improving upon Strensiq profile through a longer half-life more patient-friendly dosing and an improved manufacturing process.

The Phase III trials were designed to reflect the broad symptomatology or HPP, and efzimfotase alfa is well positioned for broader global adoption by removing key barriers to access. There are approximately 14,000 addressable HPP patients across the top 8 countries. Approximately 20% of these are pediatric cases, 60% adult with pediatric onset disease and 20% adult with adult onset disease.

We will share data across the program with regulators and present at an upcoming medical meeting. We believe efzimfotase alfa represents a peak year sales opportunity of $3 billion to $5 billion. In addition, we recently announced positive high-level results from a prespecified interim analysis of the I CAN Phase III trial, which showed that Ultomiris met its primary endpoint, demonstrating a statistically significant and clinically meaningful reduction in proteinuria based on 24 hours urine protein creatinine ratio at week 34 in adults with IgAN who are at risk of disease progression.

The primary endpoint of change from baseline in estimated glomerular filtration rate will be measured at week 106. Ultomiris demonstrated complete and sustained terminal complement inhibition with proteinuria reduction seen as early as week 10. Benefits are consistent across patients, including those at higher risk of progression and with more inflammatory disease. Importantly, updated 2025 KDIGO guidelines recommend using disease-modifying agents such as Ultomiris in combination with supportive medicine that manage a disease symptom such as RAS or SGLT inhibitors.

Across U.S., Japan and the EU5, there are over 560,000 patients diagnosed with IgAN and 60% of patients would be eligible for IgAN treatment based on proteinuria. We are confident this indication could reach blockbuster potential given our established nephrology presence across AstraZeneca and Alexion, and we are seeking accelerated approval in key markets.

In addition, today, we disclosed the discontinuation of Ultomiris in CSA-AKI high-risk patients with kidney ischemia due to lack of consistent efficacy across CKD severities. And finally, I'm pleased to report that CALYPSO, our Phase III trial investigating the safety and efficacy of eneboparatide in adults with chronic hypoparathyroidism will be presented at ECE in May, and CARES, our Phase III program anselamimab in light amyloidosis patients will be presented at ASCO in June. These presentations mark important milestone in bringing new therapeutic option to people living with rare diseases.

And with that, please advance to the next slide, and I will hand back to Pascal.

Thank you, Marc. Next slide, please. We are off to a strong start with 4 meaningful programs readouts already delivered in 2026 and a rich catalyst path across the rest of the year. As shown here, the volume of high-value readouts through the year is notable, collectively pointing to a risk-adjusted peak year revenue potential exceeding $10 billion, supporting growth of the company to 2030 and well beyond.

Next slide, please. As you can see, our recent R&D success is resulting in an extremely eventful year in 2026. We're excited to showcase our positive data from several programs at upcoming congresses, including ASCO and EDA. We're also expecting a significant wave of approvals, including the potential first approval of 4 NMEs and 4 life cycle management indication. We also look forward to additional regulatory decisions in major markets to continue to bring our medicines to more patients across the globe.

Next slide, please. In closing, Q1 delivered strong commercial momentum and excellent pipeline execution, reinforcing our growing confidence in achieving our 2030 ambition. With a broad portfolio, a deep pipeline and meaningful advances across multiple transformative technologies, we are well positioned to extend growth beyond 2030. And with that, please advance to the next slide, and we will move to the Q&A. As Joris mentioned at the start of the call, and we will see if he's more successful than his predecessor Andy, please limit the number of questions you ask to allow others a fair chance to participate. Please use the raise hand function on Zoom. And now let's move to the first question. which is from Richard Vosser at JPM. Over to you.

Two questions, please. First question on tozorakimab. Could you characterize how you see the product profile relative to Dupixent and Nucala? And do you think the breadth of activity sufficiently differentiates the product so physicians wouldn't need to test for eosinophils anymore? And then a second question, just on the ramp of Enhertu. Could you just give us a bit of color around the DB09 rollout and how we should think about the pace of uptake for the adjuvant setting and neoadjuvant setting in DB11, DB05?

Thanks, Richard. Joris didn't go very far, right? You failed on the first step. Who is going to take the tozo. Sharon, do you want to take this? Ruud, if you have anything you want to add later?

Sure. I'm happy to. So as you know, we announced the positive high-level for tozorakimab in OBERON AND TITANIA and MIRANDA. And in these Phase III studies, we were able to demonstrate that we had a statistically significant, and in the case of OBERON and TITANIA, highly clinically meaningful result, both in the primary and in the overall population. So our primary population was former smokers. Our overall population included former and current smokers, patients across all blood eosinophil counts and all stages of lung function severity.

Now we can't slice and dice those data until we present them at an upcoming medical meeting. But we are encouraged by the data that we have seen, and we've characterized it as highly clinically meaningful in the case of OBERON and TITANIA, and we are moving at pace to submit that to regulators.

Yes. And the only thing, Richard, I would like to add regarding the potential is that the current biologics in COPD are primarily for high eosinophils. The studies were done above 300 I think the uniqueness, as Sharon has shared is that this is across the eosinophil count of patients. So whether in the end of the day, physicians want to test in COPD, the eosinophil count is up to them. But we are hoping for a very broad label on the basis of the OBERON AND TITANIA data.

Yes. And I think really, of course, it's left up to physicians, but we think we have a true all-comers product from that viewpoint of EOS levels. Dave, do you want to take the Enhertu question?

Yes, absolutely. Thank you very much. So at the highest level, Enhertu with DB09 clearly is bringing transformative benefit with PFS now exceeding 40 months. That has been very well received in our promotional efforts that we've been engaging in. We're seeing encouraging early adoption across a broad frontline population.

So utilization both in hormone receptor negative and hormone receptor positive patients. We do, as you would expect, see academic HCPs are driving early adoption more so than you would see within the community within this first quarter post launch, but we will look forward to continuing to see our efforts in the community. And I think importantly, we are seeing increased recognition of the importance of continuing in HER2 treatment for a prolonged duration.

With less consideration of this sort of maintenance notion, which I know was something that we had gotten some questions about coming out of ASCO. In terms of the early breast cancer studies with 05 and 11, I think they build really nicely on the existing confidence that exists within the HER2-positive space with 03, 09 and now these studies. We've got upcoming PDUFA dates here shortly, and I think that there's a lot of energy around both of those studies and incorporating them into practice.

Thanks, Dave. So next question is from James Gordon at Barclays. Over to you, James. You may be on mute, James. We can't hear you.

Hopefully, you can hear me now. James Gordon from Barclays. The question was on camizestrant for hormonal breast cancer and the route to this being a $5 billion-plus product. So I know you've got a couple of angles, but one is the SERENA-4 readout in the second half. But on that one, to what extent does failure of Roche's persevERA first-line metastatic ESR1 all-comers trial mean you're more cautious on that readout?

A other important differences like maybe patient enrichment or the potency of your drug or other factors that mean you still think you've got a good shot at this? Or is this quite a long shot based on persevERA? And I know the other angle, probably the bigger angle would be adjuvant hormonal breast cancer, which that could be a $20 billion-plus category. But I think your CAMBRIA-2 trial, which is like the analogous trial to lidERA that's already up for approval in Q4 for Roche, that's only going to have final data in 2013 still recruiting. So is there a way you can still be a big winner here? Or is it looking tougher?

Okay. Thanks for the question. So in terms of the first-line metastatic hormone receptor positive patient population, obviously, we'll have to wait and see the persevERA data at ASCO. But remember that we've said that we do have a differentiated asset in camizestrant. The effect size that we saw in the second-line setting was robust in both the ESR mutant and wild-type.

And we also have enriched the first-line patient population to hopefully enrich for a greater endocrine sensitive population. One key differentiation as well from the persevERA study for SERENA-4 is it's a much larger patient population. So we sized for an effect size that will still be clinically meaningful in that population. So that's why I think we need to look out for both what the safety and the efficacy data are for persevERA at ASCO.

Moving on to the adjuvant population. Just as a reminder, we have 2 adjuvant studies, CAMBRIA-1 and CAMBRIA-2. So CAMBRIA-1 study takes the patient population that's already had 2 to 5 years of CDK4/6 inhibition. So that's the, if you like, the prevalent patient population of ER-positive. And then CAMBRIA-2 is in a setting that's more similar to lidERA, but is differentiated from lidERA because it does allow for combination with CDK4/6 in the adjuvant setting.

And given the benefit that's been seen with CDK4/6 inhibitors in the adjuvant setting, there's an increasing demand from patients and treating physicians to treat with CDK4/6 in that setting. So if you think about the combination of CAMBRIA-1 and 2 together, I think we have the opportunity to get the largest share of the adjuvant patient population given that. And the success of lidERA, I think, does show that, first of all, there's positive proof of concept for the effect of these drugs in that setting. And given that we've got a very good profile with camizestrant, I think that builds confidence on our likelihood of success in those settings.

Thank you, Susan. Next question is from Sachin Jain at Bank of America. Over to you, Sachin.

One topic, Wainua in CARDIO-TTRansform, a question for both Sharon and Ruud. But for Sharon, as we head into the Phase III, could you just remind us of a few factors. So could you remind us of TAF and SGLT usage at baseline and whether you think that will complicate a cross-trial comparison versus the 30% benefit AMVUTTRA in HELIOS-B?

And then on the secondary TAF subgroup, are you powered to be statistically significant if you repeat the AMVUTTRA benefit? And then just a quick one for Ruud. If you could just talk to the commercial relevance of both of those points, cross-trial benefit comparison and the secondary endpoint.

Thanks, Sachin. Sharon, do you want to start?

Sure. So Sachin, let me just clarify the question because there was a little bit of a skip. I think you were asking about the number or the rate of SGLT2 background therapy.

So 2 bits. So TAF, tafamidis, and SGLT2 usage at baseline and whether that complicates cross-trial versus AMVUTTRA, 30% benefit and then the secondary TAF subgroup powering.

All right. So now we haven't disclosed the exact numbers there, but let me speak broadly about this. We always anticipated that the treatment landscape would evolve during the time that we're running the CARDIO-TTRansform study, and we designed a large study to account for that. The baseline standard of care treatments, and here, you've included SGLT2 and tafamidis, so stabilizer and SGLT2 are expected to have an impact on the event rate, but we previously extended our trial duration to account for that.

If we look at the HELIOS-B study, the treatment effect with vutrisiran versus placebo looked very similar in trial participants who were on background tafamidis versus those who were not. So while we think background therapy should have an effect on event rates, we don't expect the differences in background therapy to have an effect on the overall treatment benefit. You also asked about secondary endpoints.

As you know, we designed the secondary endpoints to evaluate different patient subsets. And one of those is patients on tafamidis versus those who are not. And if we are able to demonstrate statistical significance, and it depends on how far we go through the statistical analysis plan, we view this as the icing on the cake. Ruud, would you like to comment further?

Yes. Thank you so much. And regarding, let's say, the peak year sales, Sachin, we have indicated in 2024 during the Investor Day that we see this asset as a $5 billion-plus asset. I think, of course, as always, it's incredibly important to hit the primary endpoint and the primary endpoint is different from the endpoint of in the Alnylam trials with AMVUTTRA, because here, we are talking about the change from baseline to a composite endpoint of cardiovascular death plus CV recurrent events up to 140 weeks.

So that in itself, I think, is a very important part of the differentiation of Wainua versus the competition. Now equally, as Sharon mentioned, every secondary we can hit will further differentiate our product from the competition. So let's wait and see, but we remain highly excited about the prospects of this asset.

Steve Scala, TD Cowen. Steve, over to you. You might be on mute, Steve. Okay. We can't hear Steve, so we'll come back to Steve in a minute. Maybe we move to Graham Parry at Citi.

It's one on tozorakimab again. Just wondering if we -- you can confirm that we should interpret the way the headline press release was worded and your comments today to mean that the effect size across the different eosinophil groups is consistent across those groups. I think you talked just now about potentially having a broad label. So that would be the interpretation. And then secondly, could you just give some sort of clarity as to what you think the implication of PROSPERO missing is and perhaps some rationale as to how you could have such highly clinically meaningful data in the MIRANDA and OBERON trials without missing on the endpoint on PROSPERO.

So I hope, Sharon, you got the second question because the line broke up a bit. On the first one, I can quickly answer. We expect -- we hope and our expectation is we will get a broad level, including all EOS level, but we can't today disclose the results in each group. You will see this when we present the data. And the second question, PROSPERO, Sharon, hopefully, you got it in full.

Yes, I did hear the question. So I'll just repeat that PROSPERO was the long-term extension study and that PROSPERO was unique from OBERON, TITANIA and MIRANDA in that it had a different primary endpoint. It looks specifically at severe COPD exacerbations, those that cause hospitalization and death over the duration of 104 weeks.

We really look forward to sharing the data. This will be a component of our regulatory package. We are really delighted with the overall data that we've seen across the LUNA program. PROSPERO supports the clinical profile of tozorakimab, and we look forward to submitting our data in totality to the regulators as quickly as possible.

Thank you, Sharon. Next question is with Sarita Kapila at Morgan Stanley.

So you've had a number of successes for Datroway across lung and breast cancer, as you've outlined. So how should we now think about the totality of the commercial opportunity? And are you confident in reaching multibillion peak sales for Datroway excluding AVANZAR? And then just a quick one on efo alfa. How has the initial dialogue with the FDA been? And is there scope for approval in the subgroup of adolescents and adults with pediatric onset? And perhaps you could quantify what percentage or how large this population is?

Thank you. I think, Dave, you can take the second one. The first one, second one is for you, Marc. But if you -- Sarita, if you go back to the script, I mean, maybe Marc can repeat it. Marc gave the split of the various groups, pediatric, pediatric onset, adult and adult onset. For the first question, Dave, do you want to go?

Yes, Sarita, I think that the best way to address this is that when we laid out a $5 billion-plus ambition on Datroway. We continue to see the opportunity being just that. And we've got a series of really important readouts that are going to be happening over the course of the next several quarters.

Obviously, we've got AVANZAR TL07, TL08, but also we've got TROPION-Lung15, and then that will be followed afterwards by TROPION-Lung14 and a series of Dato studies incorporating with Next-wave IO. So we've got quite a few programs underway. Lung cancer is obviously an important element of this. The work that we've done on QCS, we think, has positioned us well to be able to have multiple shots on goal within the AVANZAR study, and we're confident in the forecasts that we've got at this time.

It's important to really keep in mind, our view hasn't changed about the potential of this agent since the time when Dave talked about it back a little while ago. Of course, all these studies have to work, in particular, AVANZAR, but our view hasn't changed. Marc, do you want to cover the second?

Yes. So maybe I'll take the second question first. In my prepared remarks, I had indicated that the pediatric cases are about 20%. The adults with pediatric onset would be 60%. And then the remaining 20% are covered by adult with adult onset. So these are -- this is basically the breakdown of the population suffering from HPP.

In terms of data, as I've explained, we have 3 clinical trials, which we are going to submit to authorities. The first 2 are on the pediatric population. And the third one is on adolescent and adults with as a primary endpoint, 6-minute walk test, but there are many other endpoints which are measured in this trial, and we have concluded that this study is clinically meaningful, and therefore, we are going to submit this data to the regulators.

Thank you, Marc. Rajan Sharma, Goldman Sachs. Over to you, Rajan.

So just a couple more on Datroway. Just wanted to understand the rationale for adding the QCS biomarker primary endpoint to TL07 and then also including it in TL08. Does this increase the probability of success of the trials in your view? Or is it more about building a moat around the potential patient opportunity given that you have the biomarker? And then related to that, is there any reason why control arms across these Datroway lung trials, including AVANZAR, may perform better or worse than you expected in a QCS-positive population specifically?

Thanks for the question. So in terms of the rationale for including the biomarker in TL07, it's similar to the rationale for including it in AVANZAR based on the totality of data that we've seen so far across multiple data sets, we've seen consistent improvement in performance for both PFS and OS in the biomarker-positive patient population, both as monotherapy and in combination with IO in a first-line setting.

So that's the logic that says that it makes sense to include in TL07 as well. As we did with AVANZAR, our colleagues at Daiichi Sankyo went and approached the regulatory authorities and had discussion about this approach. So similar for TL07, similarly to AVANZAR, there's an opportunity in the ITT and in the biomarker-positive patient population in TL07, which, as a reminder, is in the PD-L1 less than 50% of the patient population.

I think I've mentioned previously that for TL08, which is in the greater than 50% patient population, given that that's a smaller segment already, the numbers that are accrued in that trial means that it makes sense to only include that as a secondary endpoint and not part of the primary analysis.

But of course, assuming that AVANZAR does show an improvement in the biomarker positive, of course, everybody, including regulators will want to know what the performance is in the biomarker-positive patient population. So I hope that addresses your question about why we're doing it in TL07 and TL08 and why it's different in the statistical analysis in TL07 versus OA.

In terms of your question about event rate, the event rates for these trials are determined by the event rate in the overall ITT patient population. So whilst it's possible that the patient population that is biomarker positive has a different event rate, that isn't what determines the cut point. So it's really the event rate in the overall population that's determining when we can do the data cutoff and therefore, report the results.

And we have no way to predict how the control arm will behave, right? So they have to wait for the end of the study. The next question is Michael Leuchten, Jefferies. Over to you.

One question maybe too on the delay. So you've got a TL07 delay, just linking back to the last question because of the implementation of QCS. Just wondering if you could talk to how complicated it is to run the test over existing tissue samples and whether that could slip any further or whether that's a firm view on a readout? And then a question on cliramitug, the depleter. There's also the delay here. What's driving that, please?

So the timing of the results for TL07, I'll just -- based on the requirements for implementation of the biomarker within the clinical trial, that obviously requires an amendment and there's other aspects of that. We have to actually sort of run the analysis on the samples that are available. There's no further delay to the event rate on TL07.

Maybe, Michael, also just one of the maybe questions that's embedded within your question gets to the commercial readiness and how we think about testing in a post-approval world. We've been working really diligently to set up and be ready for QCS across the globe through a combination of central labs, but also decentralized testing work that we're doing.

There's a lot of enthusiasm across regions to incorporate computational pathology into the way in which care is being delivered. And it also gets to the previous question that Rajan asked. I mean, in many respects, you incorporate QCS into these programs because if it works and truly helps select patients, it's very differentiated for the program.

Yes. It's a really important point. And we've made that point before, but maybe just to remind you, if you assume that the ITT population will be positive, it's possible to assume that the QCS population might be even more positive in the positive scenario overall, of course. So in the U.S., we would expect ITT use everywhere. In some countries where payers are more difficult and QCS gives us another chance to get reimbursement if we cannot achieve it in the ITT population. So it's really -- we have 2 shots on goal in terms of reimbursement. So next question is ...

So first of all, the -- just remind you that cliramitug is not an event-based trial, but a time-bound trial. And as the trial recruited faster than we expected, in order to reach the target medium exposure of the trial, we decided to extend the study by 6 months. It's not an event-based, but we wanted to return to the targeted medium exposure.

Thank you, Marc. Matt Western, UBS...

Two questions, please, if I can, on eplontersen. The first is now that tafamidis generics are delayed to 2031, if the combo is superior in CARDIO-TTRansform, is it realistic to expect reimbursement of a double-branded regimen in that setting?

And then the second question is around Wainua in ATTR-PN. One of your other differentiations potentially is going to be the home administration claim in the U.S. So can you update us on the commercial performance in the U.S. market in the PN setting so we can understand how advantageous home administration really is?

Yes. Thank you, Matthew, for both questions. First of all, regarding the combination, of course, it fully depends in my view and our view on the size of the effect if the effect size is very, very substantial. I truly believe that payers certainly in the United States will be open to reimburse both branded products for this debilitating disease. So let's not forget that the mortality rate of patients with ATTR-CM is very high. So once again, if the trial is going to show a very substantial benefit for the combination, I believe that the payers, the reimbursement authorities will certainly consider this for -- in order to reimburse it.

Regarding the PN indication, I think overall, we are quite happy how it goes. It's very encouraging. There are a lot of patients with a so-called mixed phenotype certainly in the United States. Of course, with the registration of the competitor also in the CN trial, there's not always to capture all those patients. But if you look at pure PN patients. We are clearly, clearly leading the pack here.

You are mentioning the home administration for many patients, that's an ideal way in order to get the medicine because there's no need to go at least 4 times a year to a hospital in order to get the drug administered by the physician. So I think the combination of a higher quality of life or a better quality of life, home administration and a very strong efficacy in general, I think, is one of the reasons we see a very strong uptake in the United States and other countries for the PN indication.

Thank you, Ruud. Peter Verdult at Exane.

Can you hear me?

Yes, go ahead.

Peter here from BNP. Just Sharon and Ruud, could we come back to tozo quickly. Sorry to labor the point, but just coming at a different angle, I just wanted to explore maybe potential upside scenarios to your $3 billion to $5 billion peak sales assumption. So are you assuming that you will see IL-33 competition or competitors eventually making it to the market when you provide that peak sales target?

And do you have any plans to explore tozo beyond COPD or lower tract respiratory disease? I'm thinking maybe nasal polyps or bronchiectasis. And then just a quick clarification, Sharon, just on the PROSPERO question earlier. Am I right in thinking that the endpoint there was a bit different to OBERON [indiscernible]?

Thank you, Peter. So Sharon, do you want to start with the second one and then Ruud, you can cover the first one?

Sure. Yes. So you're spot on. The endpoint for PROSPERO was different than for OBERON and TITANIA. In PROSPERO, we specifically looked at selectively severe exacerbations, which is different than TITANIA that looked at moderate to severe exacerbations. The overall trial population that we enrolled in our comprehensive LUNA program is different from what competitor molecules did, and it really provides us with a point of differentiation for tozorakimab. We have a differentiated molecule in terms of its bifunctional inhibition, and we also have a differentiated clinical trial program. Ruud, would you like to take the rest?

Yes, of course. So first of all, Peter, we have indicated once again that this product in our view, is a $3 billion to $5 billion opportunity in COPD alone. Of course, the competitive environment has changed somewhat, and we don't know exactly what they are going to do moving forward.

Now having said that, based on the results, of course, we are also thinking about potential other indications. You are mentioning bronchiectasis, potentially asthma. We haven't taken any decision yet on that. But if everything moves well, of course, we will have a look whether it makes sense also to move tozorakimab in other indications where there's still a high unmet medical need.

On top of that, overall, the bio penetration of the current biologics in COPD is still relatively limited. It is below the 10%. So it also shows the potential in COPD, which is a very heterogeneous disease in order to use a completely new biologic specifically designed for COPD in order to capture the full potential in COPD.

Christopher -- sorry, Peter, did you want to say something? All right. Christopher Uhde at SEB.

So my first is on MFN, if you wouldn't mind commenting. So how are you forecasting the future impact, let's say, across the 7 major markets? Or how would you recommend we do it perhaps is the question you'll answer? And then is this for -- should we be thinking about it applying to only future launches as some of the competitors have said?

And then on IL-5, we've got a competing long-acting IL-5 that's launched and tracking rapid growth. So Ruud, what are you seeing on the competition? What are your thoughts then on the long-term future? I guess that part is for Sharon of the role of IL-5 in the R&I therapeutic area? And how are you working to adapt to play a key part in that going forward?

Yes. Let me take the first one or the second one, sorry, the IL-5. Yes, first of all, we are very pleased with the performance now for quite some time of Fasenra. It's clearly the leading anti-IL-5 in the class. I think the EGPA launch in countries like Japan, United States have been very successful. Equally, of course, the class is changing somewhat. It's now a long-acting anti-IL-5.

Now having said that, the NIMBLE study was not specifically successful regarding the switch from Fasenra IL-5 to the long-acting one. It was even getting worse. So I think what we need to do is to cement our position as the leading IL-5. I think the molecule is doing extremely well. I think the mode of action, we sometimes forget that is fundamentally different from the other anti-IL-5. We are depleting eosinophils -- and we have seen very, very strong traction across the world.

And there's no reason to believe that, that will not continue. And last but not least, what I said in my prepared remarks, we have just launched Fasenra in China. China, there's a high unmet medical need and the potential of Fasenra in China is very, very substantial as well.

Sure. So building on that, Ruud, I'll just restate that we have a lot of faith in Fasenra. It's a fantastic molecule. It provides targeted complete and fast sustained eosinophil removal, effectively treating EOS inflammation and reducing the risk for patients. We've got a winner in Fasenra. And we have an 8-week dosing regimen that delivers that sustained control and really stands out for its high adherence.

We've got about 80% to 90% of patients remaining on Fasenra through our pivotal studies, which is really remarkable as well as in our real-world studies. And it remains the only biologic with clinical evidence proven to reduce for both oral and inhaled background therapy. So we've got a strong molecule there.

As we think about future growth in the portfolio, building on our success in Fasenra is part of our early strategy. I won't comment further on molecules that sit in our discovery pipeline, but we think about how to continue to leverage the success that we've seen in this program.

So the first question, I mean, you can take a very conservative approach and remove the 7 plus -- G7 -- I mean G7 being 6 countries and 2 from the forecast, if you want a very, very conservative approach. knowing that the last 2 are smaller markets. But we are working very hard, not only we, but the whole industry to improve the access and pricing environment in all of those countries.

I should remind you all that it's only for new products, future new products. And it will also be different product by product, country by country in terms of what is the gap between the GDP per capita adjusted price in that country versus the U.S. But ultimately, our goal is to launch those products in every single market and improve the access environment.

We have time to do this because new products will not be launched immediately. You've seen some movements in the U.K. already, discussions based on the 301 investigation will start with other countries, I think, in the next few weeks or months. We are ourselves in the whole industry talking to countries and explaining the importance of improved access, not only for patients, but also for investments in R&D and in particular, in R&D in their respective countries.

And we are getting positive response in some countries and more wait and see in other countries. But we have it -- this is going to play out over the next 18 months, 2 years. So we have time to hopefully reshape the environment. So I've given you the most conservative approach in terms of forecasting, but I don't think it's going to be like this.

And as it is today, you have to remember, the whole of Europe represents 20% of our global sales. So take a fragment out of this. This is not huge. And so we truly hope we are going to get better pricing and better access and be able to launch our products everywhere, which is, of course, the ultimate goal. Seamus Fernandez, Guggenheim.

Thanks, Pascal. So our question is actually on the positioning of the GLP-1 and how you're thinking about that. So can you maybe just walk us through how the upcoming ADA is really going to help us fully derisk your strategy in this space? Maybe help us understand the safety supporting the aggressive advancement into Phase III.

And maybe if you could just specifically comment on whether these data are likely to convince investors that product half-life is key to differentiation on tolerability over and above planned titration scheme. So just trying to get an understanding of how these data coming at ADA are really going to wrap around the very broad Phase III program that you've initiated.

Thank you, Seamus. This one is for Sharon. And maybe Ruud, you can also jump in. I just want to be clear, fully derisk is a bit ambitious. We will fully derisk when we are at the end of the Phase III program, where we are moving as fast as we can into Phase III. So over to you, Sharon.

Yes. Thank you for the question, Seamus. As you know, those data are upcoming at ADA in June. So I cannot tell you what the data say, the conference organizers would frown on that. But we did announce that we completed the Phase IIb trials for elecoglipron and that the data that we saw in those Phase IIb trials, one for obesity and one for patients with type 2 diabetes, gave us the confidence that we need to move into a very comprehensive Phase III development program.

We have dual goals there. We're looking at both weight loss efficacy, and we're also looking at outcome benefits, which are key drivers for us because we are focused not solely on weight loss, but on being able to address complex interrelated comorbidities. And AstraZeneca is in a unique position with our broad portfolio.

We are ideally suited to creating both monotherapies and fixed-dose combinations with elecoglipron that allow us to address comorbid disease. So at ADA, we look forward to sharing the data and continuing this conversation. But what we saw in those data gave us the confidence that we needed to fully invest in our comprehensive program.

No, there's not a lot to add what Sharon has said. I think the focus on outcomes, I think our strength with fixed-dose combinations, and we have articulated a few of those potential combinations. And one of them is clearly with our SGLT2 Farxiga. And last but not least, I think also AstraZeneca is quite uniquely positioned regarding our global footprint. We have a very strong presence, as we all know, in the international markets and there's still an incredible high unmet medical need in those markets regarding obesity treatment, but clearly also diabetes.

We have a very ambitious Phase III program that is excellent really. The team has done an amazing job. And so we have a very, very strong data set, assuming, of course, the studies are positive, which we believe we have a good chance for that, of course, but we will have a very strong set of data across a very broad Phase III program to launch this product. So next question is from Luisa Hector at Berenberg. Over to you, Luisa.

Thank you, Pascal. A couple, please. So on camizestrant, are there interim analyses still pending for the CAMBRIA's or even SERENA-4? And then given that we've had some discussion on Phase III trials, which are in flight, but you've been making some changes such as TL07, 08.

I wonder whether you could give us some more color around your work with the FDA on real-time clinical trials because I see Astra mentioned as 1 of 2 companies working with the FDA there. So what kind of benefits could this ultimately bring in terms of timing and savings?

I think, Susan this for you. The question is really a real-time collaboration -- study collaboration with FDA.

Yes, sure. Thanks for the question, Luisa. So for interim analysis, you know we don't comment on those. So I can't really address that question anymore. For the real-time clinical trials, I think this is an exciting first step towards this future. So the trial that we are collaborating with the FDA on is the TrAVeRse trial, which is with a well-established medicine, acalabrutinib in a mantle cell lymphoma setting.

So what this enables us to do is literally to -- as the adverse events and the things come in, we'll get notified simultaneously with the FDA. So I think this will enable us to have learnings. I think the opportunity, though, is in a future world where you're not submitting based on documents, but you are submitting based on access to data. This could save time in terms of preparation for submissions and also time from the regulatory side in review of those submissions because the various analyses can be done.

And then you can spend more time on the discussions with the agency about the context and the relevance of the data and the impact that that's going to have on treatment outcomes. So the hope is that this will lay the groundwork for that collaboration, and we're very happy to be partnering with the FDA in that regard and at the forefront of learning here.

Thank you, Susan. Maybe we could try again Steve Scala. If Steve is back, can you hear me, Steve? Okay. He's given up or he has technical difficulties. Let's move to Mattias Häggblom at Handelsbanken. Mattias, over to you.

Can you talk about CAR-T and specifically how you feel about the Gracell BCMA CAR-T program, but also Gracell's FasTCAR as a platform in light of industry's rapidly growing interest...

So the line was not very good, Mattias, but hopefully, Susan, you got it. It's about AZD0120, but I'm not sure that...

I just want to clarify the question a little bit. I think you were asking about how the FasTCAR process helps the differentiation of AZD0120, the lead product. Did I get that right? I can't hear the answer. So I'll answer what I thought the question was. So one of the differentiations of AZD0120 is that it's developed with this FasTCAR process, which enables the ex vivo growth of the cells in a 3-day process, which means that you can get a turnaround time reliably in around a 16-day time frame, because after the cells have been produced, there's still some quality testing that needs to be done before the cells are shipped to the patient.

That reliable and shorter delivery time is really important for sites and for the operationalization. But there are other factors that are involved in here as well. You end up giving a lower dose and you give a lower dose of fitter T cells, then it can then expand in the patient's body, in vivo more rapidly. What that also delivers is a predictable time of onset of any cytokine release syndrome and enable it to be positioned as a potentially outpatient treatment because people know what the timing of the cytokine release syndrome is can be prepared for that and then the patient can go back after that period of time.

So it's not just the FasTCAR process in itself. It also is the dose that you end up with and the timing of the CRS that also make it differentiated. I think the other factor, of course, is that it's a dual CAR. It's got CD19 and BCMA targeting. We think that's important for avoidance of the escape mechanisms from downregulation of one target or the other.

So overall, we're delighted with the profile that we've got with 012. It was presented in detail at the ASH meeting, and we now have ongoing DURGA-4 study, Phase III study in later line multiple myeloma, and you'll see further studies in the coming months as we open up this program more broadly.

Thank you, Susan. The next question is from Simon Baker of Redburn.

Just one for me, if I may, please, for Dave. I was wondering if you could give us an idea of the underlying demand growth for Tagrisso. As you said, it was distorted by wholesaler destocking. And related to that, is that wholesaler destocking specific to Tagrisso? Or are you seeing that anywhere else in the portfolio?

Thanks, Simon, for the question. Just within the U.S., we have really seen Tagrisso with strong frontline leadership, just to build and quantify some of the comments that I made in the prepared remarks. The demand growth for the quarter for Tagrisso was mid-teens. And so you can see that the really truly and higher than historical destocking levels is what brought the net results down to where they were.

Now specific to your question, we have seen some suggestion of this on other orals, but it didn't include Calquence that could be because of a buildup for AMPLIFY. So not entirely sure. But we are seeing some destocking across the oral agents that's taking place, but it was particularly noteworthy on Tagrisso. I think the most important piece, though, is that I don't see that going any further down.

The demand growth is very strong. We're seeing a clear preference for FLAURA-2. Very importantly, on MARIPOSA, we have not seen any impact from the subcutaneous launch on U.S. Tagrisso shares. So the subcutaneous launch is cannibalizing IV, but it is not having impact on Tagrisso shares. And by the way, that same is true in Germany and in Japan.

Thank you, Dave. And the last question is Justin Smith at Bernstein.

I've got one for Ruud. Ruud, if I remember correctly, during the August call last year post ESC baxdrostat, you said it could be above $5 billion, it could be above $10 billion, time would tell. Just wondered over 6 months on for that, if those remarks are the same or if you would qualify those remarks at all.

Yes. No, I think they are still the same. So once again, what we have indicated during the Investor Day that this is potentially a $5 billion asset. Let's not forget that we're investigating and the $5 billion is built roughly half of that is in the fixed-dose combination. That study will read out beyond 2027. And the other one is the mono component, but we are also looking into CKD for baxdrostat. So there are 4 other indications, which potentially, if successful, can move that number up to potentially 10 billion, and that view hasn't changed at all.

Very good. Let's hand on that, Justin. You're making Ruud nervous. We're moving into budget timing. Baxdrostat is definitely a big product, and we're all excited to see it launch in many countries very soon. So thank you, everybody. Thank you for your great questions and for your interest in our company, and we wish you a good rest of the day.

Good morning to those joining from the U.K. and the U.S. Good afternoon to those in Central Europe, and good evening to those listening in Asia. Welcome, ladies and gentlemen, to AstraZeneca's Full Year and Q4 2025 Results Conference Call for investors and analysts.

Before I hand over to AstraZeneca, I'd like to read the safe harbor statement. The company intends to utilize the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Participants on this call may make forward-looking statements with respect to the operations and financial performance of AstraZeneca. Although we believe our expectations are based on reasonable assumptions, by their very nature, forward-looking statements involve risks and uncertainties and may be influenced by factors that could cause actual results to differ materially from those expressed or implied by these forward-looking statements.

Any forward-looking statements made on this call reflect the knowledge and information available at the time of this call. The company undertakes no obligation to update forward-looking statements. Please also carefully review the forward-looking statements disclaimer in the slide deck that accompanies this meeting.

For those joining remotely, there will be an opportunity to ask questions after today's presentations. [Operator Instructions] I must advise you that this presentation is being recorded today. And with that, I will now hand you over to the company.

All right. A warm welcome, everybody, to AstraZeneca's Full Year Fourth Quarter 2025 Presentation Conference Call and webcast for investors and analysts. I'm Andy Barnett, Head of Investor Relations. And before I hand over to Pascal and the rest of the executive team, I'd like to cover some housekeeping items.

Firstly, all the materials presented today are already available on the AstraZeneca Investor Relations website. Next slide, please. This slide contains our forward-looking statements, including the safe harbor provisions, which I'd encourage you to take the time to read. We would be making comments on our performance using constant exchange rates, or CER, core financial numbers and other non-GAAP measures. A non-GAAP to GAAP reconciliation is contained within the results announcement and all numbers quoted today are in millions of U.S. dollars unless stated otherwise.

Next slide, please. Here's the agenda for today's call. Following our prepared remarks, as usual, we'll open the line for questions. We will try and address as many questions as we can during the allocated time or to please limit the number of questions you ask set to allow others a fair chance to participate. We do have a hard stop today at quarter past the hour as many of us have to catch flights in order to participate in the full year roadshow. So we will need to cut it short. We'll try and get to as many people as we can. Hopefully, everybody gets a clear chance to ask a question.

And with that, Pascal, great year. Over to you.

Thank you, Andy. Welcome, everyone. It's really a great pleasure to see you all again and to present our full year results. It's been a great year. A company -- if we can move to the next slide. The company delivered very strong performance, both on the financial and most importantly, the pipeline front. On the financial side, revenue grew 8% and product revenue importantly grew 10% driven by continued global demand for our innovative medicines.

Our core EPS, as you can see here, grew by 11%. We had 16 blockbuster medicines in 2025, with 17 of those growing at double digits -- with 17 medicines, sorry, growing at double digit. And we have the potential to get to 25 blockbusters by 2030. Remember, when we announced our $80 billion target back in May 2024, we had 12 blockbusters at the time. We now have 16 and we hope to get 25. And many of those new ones actually are either approved or soon approved or in Phase III. So good hopes that we will indeed get to 25.

At our full year results last year, we signaled that we are entering an unprecedented catalyst switch period for our company. Our R&D teams continue to deliver. We had 16 positive Phase III trial readouts in 2025. Together, they have a combined pick-year sales potential of $10 billion, as you see on this slide. In the last 12 months, we have secured 43 approvals for our medicines across major regions, helping us to sustain growth into 2026.

And it's important also for me to recognize the work everybody has done in the company as far as the company to do this, in particular, our global operations colleagues, because each time we launch one product, for them it's probably 50, 60 launches, so many different SKUs around the world. So everybody has done a tremendous job across the organization.

So if we move to the next slide. The strength of our portfolio is really -- was clear in 2025. And we are not taking significant steps to continue to strengthen our manufacturing and R&D footprint in both the U.S. and China. Together, our global reach and our diverse revenue streams really support our low concentration risk and ensure resilience to regional disruptions. But one to keep in mind, I know a couple of years ago, many questions we were getting where your pipeline is complicated, it's diversified. I struggled to get my head around it. I hope today, people realize better the value of this diversification.

We're now talking about concentration risk. It's great to have 1 or 2 big, big products, makes you very, very profitable and make you look good. But one of those, if you lose one of those as we've seen happen to some actors in the industry lately, it really becomes very painful very quickly. So this diversification, both product-wise but also geographically, is certainly becoming more apparent as we drive growth through therapy areas, but also through regions.

So if you look at this chart, we saw growth across oncology and R&I in particular, growing each 17% and 12%, respectively. CVRM, of course, was impacted by the patent expiry of Brilinta and Farxiga in the U.K. and there will be more of this, unfortunately, in 2026. Despite this, we still grew 2%. And overall, biopharmaceuticals still grow 6% and represents about 40% of our global sales.

Rare disease grew 5% despite the impact of biosimilars on Soliris. I would say the transition from Soliris to Ultomiris is not totally finished, but close to being completed and Ultomiris is now growing very nicely. We continue to see increasing demand for our medicines across all our regions. Of course, growth -- strong growth in the U.S., 10%. We continue to grow in Europe.

But importantly, I think I would like to highlight, attract your attention to the emerging markets outside of China. China still grew 4% despite losing Pulmicort to generics. We still grew 4%, which is quite nice, and we remain the largest pharma company in China. But outside of China, 22%. This part of the world is starting to really play an important role. As I said, Europe, we still grow 7%.

Next slide, please. Importantly, our momentum through the pipeline continues. We now have more than 100 Phase III trials that are ongoing. Think about that, 100 Phase III trials. It's an enormous momentum going through the pipeline. And this year, we should have 20 Phase III readouts. And those readouts, fingers crossed, of course, if they are positive, they will collectively drive another more than $10 billion of peak revenue. And the pipeline '27 should also, again, deliver a similar number, actually slightly higher in 2027. Of course, not all, but at least the great majority of these Phase III readouts need to be positive.

Importantly, you can see that there's the growing number of late-stage assets, but importantly, an increasing value per indication. As our pipeline grows, we continue to focus and prioritize. And of course, we prioritize the most valuable projects. And you can see in light pink, the average peak-year revenue per indication. That reflects the increasing individual value of projects and continuous effort we make to prioritize even though we have a lot of projects.

Next slide, please. So the question is often asked of us beyond 2030. And we said back in May 2024 and we continue saying the same. We want to be a growth company until 2030, reached this $80 billion ambition, but also be a growth company post 2030. And that is why we need to continue investing in R&D. That is why we need to continue focusing on technologies, new medicines that will actually change the future of medicines and drive our growth post 2030.

So you can see here the list of the 5 technologies that we prioritize and decided to invest in. And if you look at weight management, cardiovascular risk factors, we now have 2 products in Phase III, of course, are all PCSK9, for which we will get data in 2027. But we also announced that we have moved our oGLP-1 into Phase III, and we have a broad set of studies covering diabetes, weight loss in monotherapy, combination products, cardiovascular outcome studies. So we have a very ambitious plan for our oGLP-1.

But beyond this, we're also investing in new products that will actually shape the future of this weight management sector, which is in the initial steps really. And the future will be made of better convenience, longer duration of action for injectables moving to weekly to monthly. And -- some of this will come from the partnership we announced with CSPC recently, but also new mechanisms. So we are waiting for data on our GLP-1/glucagon and amylin product. The GLP-1/glucagon in itself has independent value, but we also will combine it with amylin. So we should get data this year. So oral agents, long-acting injectables, new mechanisms, helping patients lose more fat and less muscle are the directions we are heading into.

Now if you look at ADC and Radioconjugates, we now have 8 ADCs that are ADCs that came out of our own pipeline, our own efforts. 3 of those are in Phase III. We will get data in the first half of this year for one of those, as you can see here, sone-ve. And importantly, we have new ones, both as ADCs, but also radioconjugates that are moving through early development. We have novel linker combinations, payload combinations. We have dual payload ADC. We have radioligands. So we continue to build this, that will drive our growth post 2030.

We, of course, invest in our next-generation IO bispecifics, in particular, rilvegostomig. And we combine those with our ADCs, as we've said in the past. Cell therapy, T-cell engagers, we're making good progress with AZD0120 that has good encouraging data in Phase I, but is entering Phase III this year. And we are moving as fast as we can to move it into hematology indications, but also immunology indications. And we also have very exciting data, early data for surovatamig, and it's also moving into Phase III.

And on top of this, we have multiple approaches to CAR-T, not only CAR-T, but also allogeneic projects that some of them will be in the clinic this year. And we're working on the in vivo approach, as you know. And then we also have new platforms, TCE platforms. And finally, we're making progress also in our gene therapy programs.

So if we move to the next one, I'll hand out to Aradhana, who will take you through the financials. Thank you.

Thank you, Pascal, and good afternoon, everyone, and good morning to our colleagues in the U.S. who woke up very early to join us. So as usual, I'll start with our reported P&L.

Next slide, please. Total revenue increased 8% in 2025. Product revenue, which consists of product sales and alliance revenue increased 10% with continued growth across all key regions. Alliance revenue increased by 38%, reflecting increased contribution from our share of profits with partnered products such as Enhertu, Tezspire and Beyfortus in regions where our partners book product sales.

Next slide, please. This is our core P&L. The core gross margin landed at 82% in 2025, in line with expectations set out at the start of the year. Fourth quarter gross margin reflected the normal seasonal pattern as well as $235 million of royalty buyouts for Saphnelo and rilvegostomig, which were recorded in the cost of sales. Core R&D expenses increased by 12%, reflecting the growing number of investment opportunities in our broad and deep pipeline. At the end of 2025, we had more than 300 active trials, and as Pascal mentioned, more than 100 of these in Phase III.

SG&A expenses increased by only 3% in 2025, reflecting continued cost discipline and focus on operating leverage. We continue to streamline our business, and as a proportion of total revenue, SG&A expenses decreased from 28% in 2024 to 26% in 2025. Operating profit increased by 9% with operating leverage continuing to be a key focus for the company. We manage our P&L in totality, enabling flexibility and investment decisions throughout the year. The lower tax rate seen in the fourth quarter reflected a release of certain tax provisions taken in prior years. Core EPS increased by 11%, in line with our full year guidance.

Next slide, please. We continue to see strong cash flow from operating activities, which increased by 23% to $14.6 billion in 2025. We saw CapEx increasing by $1.1 billion to $3.3 billion, in line with the expectations set out at the beginning of the year. For 2026, we anticipate CapEx investment to increase by approximately 1/3 versus 2025 as we expand capacity to support future growth. This includes our recently announced U.S. and China investments and previously announced investments in our ADC facility in Singapore, all of which are multiyear projects.

Total deal payments in 2025 amounted to $4.2 billion, of which around $3 billion were payments relating to past deals and the remaining were payments for deals announced in 2025 such as EsoBiotec.

In 2026, we anticipate success-based milestones and sales payments relating to past deals to total around $2.5 billion. Our capital allocation priorities remain unchanged. We currently have interest-bearing debt of close to $30 billion, which is a level we're comfortable with as we continue making investments to drive future growth, expand our supply chain globally and further strengthen our R&D pipeline. Our net debt-to-EBITDA ratio currently sits at 1.2x.

Today, we are pleased to confirm a second interim dividend of $2.17 per share, resulting in a full year 2025 declared dividend of $3.20 per share. In 2026, we intend to increase the annual declared dividend to $3.30 per share, in line with our progressive dividend policy. Today, we also issue our 2026 guidance. As usual, our full year guidance is at constant exchange rates. We anticipate total revenue to grow by a mid- to high single-digit percentage, driven by strong underlying momentum in the business.

The growth will be delivered despite known headwinds in 2026, including VBP in China this quarter for Farxiga, Lynparza and roxadustat. Farxiga will also face loss of exclusivity in the U.S. in April. In 2025, U.S. Farxiga generated $1.7 billion or 21% of global revenues, while China represented just under half of emerging markets revenue. In Europe, which accounts for 35% of Farxiga total revenue, patent protections across EU markets extend to 2028. While the MFN deal presents a headwind in 2026, the effect is already factored in our guidance and can be absorbed given our large and growing revenue base.

Despite these headwinds, we anticipate a broadly flat to slightly higher core gross margin in 2026 driven by backing out the royalty buyout and product sales mix. We expect a core tax rate between 18% and 22% in 2026 and core EPS growth of low double-digit percentage at constant exchange rates. Based on January average exchange rates, we anticipate a low single-digit positive FX impact on total revenue and neutral impact on core EPS.

Next slide, please. As I mentioned earlier, we continue to make significant R&D investments in emerging areas such as ADCs, cell therapy, bispecific and late-state CVRM portfolio which have the potential to drive growth beyond 2030. As a result, we anticipate R&D expenses to be at the upper end of the low 20s percentage range of total revenue in 2026.

SG&A as a percentage of total revenue has continued to decline over recent years, reflecting our disciplined approach to efficiency and operating leverage. At the same time, we're making targeted investment to support the next wave of growth with several important NME launches ahead of us, including baxdrostat, camizestrant and gefurulimab, all of which are medicines with blockbuster potential.

While we continue to target a mid-30s operating margin in 2026, our priority remains to drive absolute profit growth and long-term value for our shareholders. As highlighted earlier, we remain comfortable with our current level of gross debt, we anticipate a step-up in core net finance expense for 2026 driven by higher lease expenses and lower interest income. In summary, we saw a very strong financial performance in 2025 which we anticipate to continue in 2026.

Next slide, please. With that, I will hand over to Dave, who will take you through the commercial performance of our oncology business.

Thank you, Aradhana. Next slide, please. In 2025, Oncology delivered total revenues of $25.6 billion, an increase of 14% on the prior year or 17% excluding the 2024 Lynparza sales milestone. Many of our key medicines have surpassed notable multi-blockbuster milestones with Tagrisso achieving over $7 billion in full year revenues, Imfinzi over $6 billion, Calquence over $3.5 billion and Enhertu over $2.5 billion in AZ revenues.

This performance is a tangible demonstration of our commitment to bringing medicines with transformative potential to patients globally and is particularly notable given the headwinds from the introduction of the 20% manufacturers liability under Medicare Part D reform from last year.

Turning now to our fourth quarter performance. Total revenues exceeded $7 billion for the first time, up 20% on the year, excluding the Lynparza milestone with all our key medicines in regions demonstrating double-digit growth. Tagrisso global revenues were up 10%, reflecting continued demand growth across all indications. In the first-line setting, we are now seeing a significant proportion of patients receiving a combination regimen. With FLAURA-2 being the clear preference across key markets. In earlier lines, increased adoption of ADAURA and LAURA has been another meaningful source of growth.

Imfinzi and Imjudo delivered 37% and 26% growth, respectively, reflecting continued demand across tumor types. This growth is broad-based from both continued expansion of newer indications such as ADRIATIC in small cell lung cancer and NIAGARA in bladder cancer as well as increased uptake of more established indications such as HIMALAYA in liver cancer.

Calquence total revenues increased 17% in the fourth quarter, driven by additional demand in frontline CLL as we maintain our class leadership position across major markets. Specifically, in the United States, we've seen our market share leadership grow over the course of the year, demonstrating our competitive positioning and differentiation.

Enhertu delivered total revenue growth of 46% in the fourth quarter. Across all regions, Enhertu is seeing share gains both in HER2-positive and HER2 low metastatic breast cancer. And in China, demand continues to increase following NRDL enlistment in January of last year.

Truqap revenues grew 41% in the fourth quarter with year-over-year comparisons benefiting from both inventory build in the U.S. and the reversal of pricing accruals in Europe. In the U.S., we now believe Truqap is at peak with further incremental growth to be driven by other markets. Finally, Datroway revenues of $40 million in the fourth quarter reflect our early launch momentum in late line EGFR mutated lung cancer, including an emerging leadership position in the third line.

Next slide, please. The strong momentum in 2025 continues into 2026. For Imfinzi, we were pleased to see the U.S. approval for MATTERHORN in early gastric cancer at the end of November and are already seeing encouraging uptake. POTOMAC in bladder cancer will add another growth opportunity this year with the first approval expected in the first half. We expect data in 2026 for several Imfinzi combinations, including Imjudo in bladder cancer, and HCC and with Datroway in lung, with commercial launches planned in 2027, pending, of course, positive results and regulatory approvals.

2026 is set to be another landmark year for Enhertu as we further expand our position as the standard of care in HER2-positive breast cancer by bringing this transformational medicine to 3 new settings. This includes the first-line metastatic setting following the recent approval of DESTINY-Breast09, with approvals in early breast cancer for DESTINY-Breast11 and DB05 also expected this year. Looking to 2027 and beyond, we remain focused on bringing Enhertu to more patients globally, including in settings beyond breast cancer, such as lung cancer.

For Calquence, we expect the imminent U.S. launch of the AMPLIFY finite therapy regimen to be an important driver of growth for the year. This complements the sustained demand in the treat to progression segment within first-line CLL, where Calquence remains the leading BTKi inhibitor. Looking ahead, we aim to leverage our broader hematology portfolio to improve outcomes through combination approaches in CLL as well as in other hematologic malignancies.

Building on double-digit growth for Tagrisso in 2025, we anticipate strong performance in 2026 driven by further adoption and geographic expansion of LAURA and ADAURA in early disease and sustained leadership in first-line metastatic disease, particularly within the growing combination market. Longer term, we look forward to the results of multiple combination trials that have the potential to reinforce Tagrisso as the backbone TKI, both in later lines with SAFFRON and TROPION-Lung15 and in the front line with TROPION-Lung14.

As we reflect on another strong year of growth, we continue to see sustained momentum in our oncology business heading into 2026. With a clear focus on expanding the reach of our medicines into new markets and with additional indications. With that, please advance to the next slide. I'll hand over to Susan, who will discuss our key readouts that we anticipate this year.

Thank you, Dave. So momentum continues to build across our oncology portfolio. And as we enter 2026 with a robust pipeline, we have an important opportunity to advance therapies for patients with high unmet needs. Today, I want to spotlight several key catalysts supporting our continued growth, starting with our TROP2 ADC Datroway. Last year, we saw Datroway demonstrate its profile as best-in-class TROP2 ADC with launches in HR-positive breast cancer and later line EGFR mutated lung cancer and with compelling data presented at ESMO in triple-negative breast cancer, demonstrating a 5-month improvement in overall survival versus standard of care chemotherapy. TROPION-Breast02 has now been accepted by the FDA for priority review.

This year, we expect the readout for AVANZAR, a pivotal trial evaluating Datroway as the first-line lung cancer setting. AVANZAR investigates the combination of Datroway with Imfinzi and carboplatin, aiming to deepen and extend responses for this large high unmet need population. Crucially, AVANZAR will be the first trial to validate our QCS TROP2-NMR biomarker designed to identify patients most likely to respond to Datroway in this first-line lung cancer setting. Success here could enable broader application of this technology in other tumor types and across our ADC portfolio.

Building on Datroway's current approval and later line EGFR mutated lung cancer, we also anticipate the readout from TROPION-Lung15, which evaluates Datroway alone or in combination with Tagrisso for patients who have progressed on a TKI. This trial aims to set new standards for second-line treatment, further reinforcing Tagrisso's role as the backbone of care in EGFR mutant lung cancer and paving the way for TROPION-Lung14 in first-line setting which can build on the success of FLAURA and FLAURA-2.

Imfinzi continues to deliver transformative benefits across cancer types. And this year's key readouts in GI, lung and bladder cancer signal a third wave of Imfinzi growth highlighting the potential of combination regimens. I want to highlight 2 today. Firstly, the EMERALD-3 trial aims to bring the combination of Imfinzi and Imjudo into the local regional setting for hepatocellular carcinoma. Building on the transformative results we've already demonstrated in the later line HIMALAYA trial.

Secondly, VOLGA looks to build on our existing presence in muscle invasive bladder cancer. The NIAGARA regimen established a role for Imfinzi as the first perioperative immunotherapy regimen in cisplatin eligible patients. VOLGA explores whether the combination of enfortumab vedotin and Imfinzi plus or minus Imjudo can improve outcomes for the 50% of patients that are not candidates for cisplatin.

This regimen is differentiated in 2 important ways. First, enfortumab vedotin is limited to the neoadjuvant setting, aiming to optimize outcomes while balancing the overall benefit risk profile. And secondly, acknowledge in bladder cancer sensitivity to CTLA-4 blockade, VOLGA's includes an arm delivering 3 cycles of Imjudo, 2 preoperatively and 1 postoperatively with the goal of further deepening responses in this patient population. In 2026, we will also see the second pivotal readout for camizestrant, next-generation oral SERD.

Last year, we shared the first Phase III data for camizestrant in patients with first-line hormone receptor positive disease with emerging ESR1 mutations. The transformational SERENA-6 results demonstrated that intervening at the earliest opportunity and switching to a more effective endocrine option ahead of progression with camizestrant ahead of progression and the switching with camizestrant offers the chance to retain control of a patient's disease for longer and thereby realizes the full potential of first-line treatment.

In the second half of this year, SERENA-4 will read out, targeting a broader upfront first-line population eligible for the combination of a CDK4/6 inhibitor and an aromatase inhibitor and assessing whether camizestrant can replace the aromatase inhibitor to improve outcomes. Our confidence is driven not only by our data from the Phase II SERENA-2 and the Phase III SERENA-6 results, but also from recent readouts in the competitive space that demonstrate the value of this class in ESR1 wild type endocrine-sensitive disease.

Finally, progress is accelerating across our ADC portfolio with sone-ve Claudin18.2 targeted ADC on track to deliver its first Phase III data in second-line gastric cancer in the first half of the year. These 6 trials represent only a fraction of the opportunities of our oncology portfolio, which is poised to drive continued growth. And throughout the year, we'll continue to share updates from our early pipeline, reinforcing confidence in our -- in progress on our transformative technologies and therefore, long-term growth prospects through 2030 and beyond.

And with that, please advance to the next slide, and I'll pass over to Ruud to cover BioPharmaceuticals performance.

Thank you very much, Susan. Next slide, please. Our BioPharmaceuticals medicines delivered strong performance in 2025 with total revenue up 5% to $23 billion with our gross medicines substantially outpacing the impact of generic entry on a limited number of brands such as Brilinta in the United States and Europe and Farxiga in the United Kingdom.

In the fourth quarter, R&I revenues were up by 10% with revenue from growth medicines having increased by 27%. CVRM revenues were 6% down on the prior year with generic competition slowing Farxiga's growth to 2% and Brilinta continuing to decline. V&I total revenue was down 33% year-on-year, largely due to the Beyfortus sales milestone booked in the fourth quarter of 2024.

Next slide, please. Biologic medicines continue to gain share among severe asthma patients. Our medicines now make up more than half of the new-to-brand prescriptions for the severe asthma biologics segment in several markets. Fasenra is the leading IL-5 medicine for severe eosinophilic asthma and its product profile was recently strengthened with the launch of the EGPA indication. Overall, we expect Fasenra's positive momentum to continue in 2026, with growth in the emerging markets set to accelerate following inclusion in the national reimbursement drug list in China.

Tezspire has made rapid market share gains in severe asthma since its launch and its growth potential has been enhanced by recent approvals for use in chronic rhinosinusitis with nasal polyps, where Tezspire has demonstrated that it can nearly eliminate the need for surgery. Nasal polyps are common comorbidity for asthma patients. So this approval further enhances its clinical profile.

Breztri is the fastest growing medicine within the expanding COPD. We are the clear market leader in China and have been gaining share in most other major markets. Additionally, regulatory reviews are underway for asthma based on the KALOS and LOGOS trials, and we anticipate first approvals in the first half of 2026.

Saphnelo, biological medicine for the treatment of SLE is continuing to grow strongly with the IV formulation having gained market leadership in several major markets. Saphnelo subcutaneous formulation was recently approved in Europe and will extend its reach to the large segment of patients who favor self-administration. We are expecting further approvals of subcutaneous Saphnelo in other regions this year including in the United States and Japan in the first half.

2026 marks a transition year for our CVRM franchise. We anticipate Lokelma's strong growth to continue into 2026 driven by market leadership within the growing potassium binder class. We have also increased additional manufacturing capacity to support our growth ambitions.

In 2026, as mentioned, we anticipate Farxiga VBP implementation in China during the first quarter and the first generic competition in the United States in April. While Farxiga revenues in the United States, Japan and China are expected to decline this year. We anticipate strong demand growth to continue in Europe and the emerging markets.

Looking beyond 2026, dapagliflozin fixed dose combinations have the potential to unlock new waves of medicines for patients, and we already have 3 fixed dose combinations of dapagliflozin in Phase III development with the first 2 Phase III trials due to readout in 2027.

We are currently preparing for the launch of baxdrostat in uncontrolled and treatment-resistant hypertension. The U.S. approval is anticipated to broadly coincide with the entry of generic dapagliflozin in this market, allowing us to leverage our existing commercial infrastructure. While baxdrostat will not be a major contributor to revenues in 2026, the clinical data supporting its use is compelling, and the long-term potential of this medicine is substantial with peak revenues from the products -- from this product franchise expected to exceed $5 billion.

I will now hand over to Sharon, who will provide further details on the upcoming developments in our pipeline, including ATTR cardiomyopathy which represents a major potential growth driver for the BioPharmaceuticals business.

Thanks, Ruud. Next slide, please. We saw strong progress across our biopharma clinical pipeline in 2025 and are entering 2026 with a broad and deep pipeline across CVRM and R&I. Today, I want to highlight 2 high-value Phase III catalysts anticipated this year positioned to deliver meaningful impact for patients and AstraZeneca's growth ambition.

Starting with Wainua. We expect the cardio transform readout in ATTR cardiomyopathy in the second half of this year. Wainua is an anti-sense oligonucleotide designed selectively to suppress hepatic production of transthyretin addressing the upstream driver of amyloid fibril formation. ATTR cardiomyopathy is often underdiagnosed as symptoms overlap with common cardiac issues. Leading to delayed diagnosis, poor prognosis and high morbidity. This highlights the need for better diagnostics and innovative new treatment options.

CARDIO-TTRansform is the largest study ever conducted in this disease, enrolling more than 1,400 patients to receive Wainua or placebo on top of standard of care for 140 weeks. The trial's primary endpoint is a robust composite of cardiovascular mortality and recurrent cardiovascular clinical events designed to capture clinically meaningful outcomes.

Importantly, Wainua can be administered once monthly as a single dose via a subcutaneous auto-injector, enabling convenient at-home dosing. That's an advantage for this largely aging population. Wainua represents just one component of our leading amyloidosis portfolio, we believe that multiple mechanisms of action will be needed to address the full spectrum of ATTR cardiomyopathy, and we look forward to initiating clinical development of Wainua in combination with our DepleTTR, cliramitug in the near future.

Turning now to the Phase III program for our differentiated IL-33 biologic, tozorakimab in COPD, which we anticipate will read out in the first half of this year. We have 3 trials ongoing. OBERON, TITANIA and MIRANDA, which have the potential to redefine the management of this complex heterogeneous and progressive disease. The trials all have the same primary end point, the reduction in annualized rate of moderate-to-severe COPD exacerbations in former smokers.

The program will also evaluate efficacy in a broader COPD population, irrespective of eosinophil count or smoking status and explores a range of dosing regimens to maximize the potential population that could benefit from tozorakimab. Should the results be positive, tozorakimab could be the first-in-class IL-33 biologic for COPD.

I also wanted to take the opportunity to highlight advances in our weight management portfolio. We are delighted to announce today that our once-daily oral GLP-1 receptor agonist, elecoglipron formerly known as AZD5004 met its primary endpoints in both the VISTA and SOLSTICE Phase IIb trials conducted in people with obesity or type 2 diabetes, respectively. We look forward to sharing these data at the American Diabetes Association meeting in June. Based on the strength of these data, we are progressing elecoglipron into Phase III development this year. We look forward to sharing more details once these trials initiate.

Our overarching goal is to create a weight management portfolio that addresses obesity and its interconnected conditions. Our diversified pipeline uniquely positions us to explore innovative novel combinations. And alongside elecoglipron, we continue to advance our broader portfolio of different mechanisms, including a selective amylin receptor agonist AZD6234 as a monotherapy and in combination with our dual GLP-1/glucagon receptor agonist, AZD9550, both of which are expected to deliver first Phase II data this year. We also continued to invest in our earlier programs, augmented by recent external innovation to further strengthen our pipeline in this space.

And with that, please proceed to the next slide, and I'll pass over to Marc to cover rare disease.

Thank you, Sharon. And can I get to the next slide, please? Rare disease delivered total revenue of $9.1 billion in 2025, up 4% over the next -- last year, driven by growth in neurology indications, increased patient demand and continued global expansion. In the quarter, Ultomiris grew 15%, driven by patient demand across indications, including the competitive gMG and PNH markets. Soliris revenues continued to decline due to the successful conversion to Ultomiris as well as biosimilar pressure.

Strensiq grew 15% due to strong demand with a quarter benefiting from tender or the timing. We also saw strong underlying demand for Koselugo offset in the fourth quarter by all the timing in certain tender markets. We continue to see great momentum across the rare disease portfolio with further approvals for Koselugo and Ultomiris, expanding our geographic reach for these medicines.

Five years after announcing the acquisition, I'm pleased to report that Alexion has delivered low double-digit compounded annual growth from 2020 to 2025 at constant exchange rates. We have also significantly expanded our global reach. At the time of the acquisition, Alexion medicines were available in 20 countries by leveraging AstraZeneca footprint and the outstanding efforts of our teams, our life-changing rare disease therapies are now available in more than 75 countries worldwide.

Finally, we have made meaningful progress in deepening scientific collaborations between AstraZeneca and Alexion researchers, further accelerating innovation. Our work across similar disease areas, such as transthyretin cardiac amyloidosis of the development of our dual CD19/BCMA CAR-T across multiple therapeutic areas are 2 evidences of this. This integrated approach enables the seamless exchange of technologies and advancements across medicinal and process chemistry, molecular editing and library platform. We have now more than 120 collaborative initiative across AstraZeneca and Alexion which are advancing our ambition to pioneer new treatments and lead in our core therapeutic area.

Please advance to the next slide. In 2026, we expect Ultomiris to grow -- to continue to grow, driven primarily by neurology indication including new-to-brand patients and those switching from Soliris as well as further market expansions. We indicated peak-year sales for Ultomiris to be above $5 billion with contribution from both existing and new indications, such as HSCT-TMA, IgAN and CSA-AKI.

In the first half of the year, we anticipate high-level results in IgAN where we have guided for the first endpoint at 34 weeks assessing proteinuria. If positive, we will explore the potential for an accelerated approval in certain major markets. We also anticipate results from adult patients with HSCT-TMA. This data built on a positive finding from the single-arm pediatric study completed in 2025.

For Strensiq, we expect continued adoption supported by hypophosphatasia guidelines, which have led to increased disease awareness, diagnosis rates and accelerated new patient starts. As global market expansion progresses, our priority remains advancing disease education to strengthen market readiness ahead of the readout for efzimfotase alfa which we anticipate in the first half of 2026.

Patient demand and geographic expansion in pediatric patients, in addition to the recent approval in adult patients will continue to drive Koselugo's growth. We are well placed to deliver another year of strong performance, supported by global demand for rare disease medicine as well as meaningful indication expansion opportunities.

Please advance to the next slide. Our antibody-based depletion portfolio for cardiac and systemic amyloidosis continue to advance with a focus on the 2 most prevalent form of amyloidosis, transthyretin and light chain. We announced the first Phase III results last year for our most advanced pipeline candidate, anselamimab. In the CARES Phase III program, anselamimab demonstrated a highly clinically meaningful improvement in both all-cause mortality and cardiovascular hospitalization in the subgroup of patients with kappa light chain amyloidosis. Global regulatory reviews and submissions are underway.

We have also expanded our collaboration with Neurimmune in December '25 to include NI009, a fibril depleting antibody for the lambda light chain amyloidosis which represents 80% of the light chain population and complement anselamimab to address the broad patient population. We have accelerated development plan to move this molecule as quickly as possible into the clinic.

Cliramitug, our first collaboration is Neurimmune is now in Phase III for ATTR cardiomyopathy. The DepleTTR trial completed enrollment, a full year ahead of plan with more than 1,000 patients recruited. As Sharon mentioned, we also plan to initiate a Phase IIb of our silence Wainua with our DepleTTR cliramitug and we believe the combination of these 2 medicines has the potential to deliver a new standard of care for patients with ATTR cardiomyopathy. The data generation to date reinforce our belief that targeted amyloid fibril depletion with specific antibodies can significantly reduce mortality and hospitalization transforming the course of the disease for these patients.

And with that, please advance to the next slide, and I will hand back to Pascal.

Thank you, Marc. Please, next slide. As you can see here, the momentum of our pipeline continues, not just in 2026, but also through to 2027. We have a significant number of high-value Phase III trials that can read out and support our growth to 2030 and beyond. And in 2026 alone, the risk-adjusted combined figure revenue opportunities in excess of $10 billion, as I said before, and again, the same in 2027.

So if we move to the next slide. In closing, we saw strong commercial momentum and great delivery across the pipeline in 2025. And our confidence in delivering the $80 billion ambition by 2030 is definitely increasing. With our broad portfolio and our deep pipeline, the meaningful progress we're making with our multiple transformation technologies, we can definitely reach this $80 billion ambition we have, but also continue to grow post 2030.

So if we move to the next slide. Before we move to the Q&A, I want to thank Andy Barnett for his amazing contribution as Head of Investor Relations over the last few years. I know he has enjoyed very much interacting with you, and I'm sure you have enjoyed interacting with him. He's very knowledgeable. He's a great guy and he has a great sense of humor. So definitely a pleasure working with Andy, certainly for me and for the team, and I'm sure it was the case for you. I want to wish Andy a great success in his new role as Country President for Japan. I'm sure he will make a great contribution to our company in Japan, just like you did to the IR function.

I also want to welcome Joris, who must be somewhere in the room, okay. I welcome Joris. So Joris was until recently the Country President for the U.S., Biopharma and overall President, Representative of AZ in the United States. And Joris has driven tremendous growth throughout our company in the United States, in particular, built Farxiga to what it is, Fasenra, Tezspire and really done a great job. Joris before being in the U.S. worked in Asia. And so he has really great experience across Asia, the U.S. and Europe. And since he joined the company in 2000. So I'm sure Joris will also do a great job in IR, and I'm sure you'll enjoy working with him.

So if we move to the next slide, as Andy mentioned at the start of the call, please limit the number of questions you ask to allow everybody a fair chance to participate. [Operator Instructions] And with that, let's move to the first question. There are so many first questions. Over to you.

Thank you, Pascal. So I've got 2 questions, please. I wanted to think a little bit about the growth beyond 2030, but it does connect to the readouts in 2026. You talked about the $10 billion risk-adjusted peak sales potential. Can you give us any more color on that, the mix of the $10 billion, the risk adjustments you've assumed any assets, in particular, dominating the $10 billion? And should we assume higher success rates now for AstraZeneca after last year's strong performance? So that's the readouts this year and the link to the growth beyond 2030.

And then I'd love to hear an update from Iskra on China, 2026, a lot of moving parts but some good new launches and reimbursement going on as well. So just an update there on how we should think about '26 and perhaps some color on profitability of China versus history versus the rest of the group?

Thank you. Iskra, do you want to cover the second one? And maybe for the first one, we'll have to get input from a number of people there. But go ahead, Iskra to start.

Thanks, Luisa, for the question. So let me start by saying that we are very happy to see the strong performance in China in '25 and it definitely gives us a confidence...

Can you speak in the microphone?

So let me try. Is it better now? It definitely gives the confidence in the outlook of '26. Now when you think about '26 in China, I think there are 2 main components. One is obviously the headwind of the VBP for Farxiga, roxadustat and Lynparza. And as we have always seen, there is expectations from the decline post VBP that is driven by both price decrease as well as volume reduction. But when it comes specifically to Farxiga, I do believe that we can also expect the brand recovery in the midterm, and we saw the similar trend with the Betaloc and CRESTOR in the past. And it is really driven by the strong brand perception, strong brand loyalty and recovery, specifically in the retail channel.

When it comes to the tailwinds in China, we feel very confident that we will continue to see the growth of the new launches, specifically driven by our success of including Fasenra, Truqap and Calquence tablets in the NRDL starting 1st of January this year. When you think about the Enhertu performance post-NRDL, they've mentioned that in his presentation, we saw very strong uptake and our ability to include Enhertu in the more than 1,000 hospital listings in the less than a quarter gives us the confidence that we will be able to see the successful launches going forward.

When it comes to the profitability, profitability in China is still lower than the group. But I think you always need to think about a huge volume and huge unmet need and opportunity there and put that in the perspective of the -- a bit lower prices than in the rest of the world.

In your first question, I had like 2 sub-questions really. And then the second sub-question was about success rate. And I wish that we continue experiencing the same success rate, but I don't think we can promise this because, as you know, the risk is part of our industry, really. And we have to brace and accept the fact -- brace for the fact that we actually will experience failures.

Now having said that, I'd like to ask maybe Susan to do 2 things. One is to talk about the joint venture, the project, we are working together with Tempus and using AI and multi-model model to actually help improve the probability of success in our studies and better shape them. So you can sort of give a little bit of highlights on this and then comment on what are the 2 or 3 big projects, not too many, 2 or 3 big projects you think will drive growth in oncology hematology?

Yes. Thanks, Pascal. So my reflection, if you like, of the last decade in oncology about the success rates we've had has been predicated on being able to identify the right patient population to treat. You've seen that there's been important with Lynparza, it's been important with Tagrisso. I think that continues to be something that's important.

The foundation model work that we go with Tempus and Pathos as the ambition is that we'll have the largest multimodal foundation model that will take the unstructured data that's in patient records, the lab data, the genomics data, [ transit ] data were available imaging and pathology and integrate all of that into the largest foundation model for oncology because of the large data set that we have with Tempus and Pathos.

The hope is, I mean what we've already been doing is using those kinds of real-world evidence data sets to both help design our Phase III trials and predict what the control arm performance is going to be, particularly when you're going in with a new biomarker, you don't necessarily have the historical literature data, but if you can benchmark that using these data, it's helpful. So the idea is that you would reduce the uncertainty in both the design and the production of outcome of Phase III trials by using these foundation models.

The hope is also that you could better identify the patient populations where the biology is a little more complicated. So we're still relying, for example, on PD-L1 in the IO space as the only biomarker that has really broadly been uptaken. And everybody is aware that, that is imperfect. So I think this technology can really help in those spaces. Still to be proven, but I'm optimistic that, that can make a difference.

Dave, do you want to cover the second part of the -- and then Ruud if you could also talk about a couple of products in biopharma with [ drive growth ]?

So Luisa, very specifically on the readouts that Pascal went through. EMERALD-3 is a blockbuster plus opportunity in HCC. And I think builds off of a program that has currently success with Imfinzi. Certainly, when you take a look at data across AVANZAR07, that is for just the AZ share alone, multi-blockbuster opportunity if those studies are positive, and we've got an opportunity to move forward with that.

SERENA-4 is multi-blockbuster in terms of the opportunity that it represents. And then lastly, PAC-9, we don't talk a lot about PAC-9, but I think PAC-9, if that study were to come through, gives an opportunity to actually build off of our Pacific leadership where we've been able to enjoy a space without having much competition coming into the area. So those are the highlights I'd hit.

Yes. And a few highlights from a biopharma perspective, laroprovstat, our oral PCSK9. We're going to expect the first data set in the course of 2027 is, in our view, a very high potential -- potentially a $5 billion-plus potential. Clearly, baxdrostat, I'm sure many more questions about baxdrostat. It's not only the mono component but also the combination, I think, with the SGLT2, dapagliflozin is a very important one.

And then the other 2 combinations, balci and dapa in kidney disease and heart failure, there's a high unmet medical need. And the combination of zibotentan and dapagliflozin has sales potential of between $3 billion and $5 billion. So there are a couple of big products. And then, of course, the bonus will be potentially those, as mentioned by Sharon, is a high unmet medical need still in the COPD space. If the product is hitting the TPP, I firmly believe that this will be a multibillion-dollar opportunity as well.

I got to stay on this table, but please, 1 question. I'll pick 1 question and give the second one. If you have a second one follow-up.

Richard Vosser from JPMorgan. Maybe thoughts on the implications of the lidERA result over to the SERENA-4 trial in terms of design. Susan, you mentioned choosing the right patient population. Just thoughts on what you've done in SERENA-4 on the back of the lidERA result. And maybe if I can sneak it, thoughts on CAMBRIA-1 as well, given what lidERA just does that impact the commerciality. Pascal, ignore that if that is 2.

I will grant you the second one because it's still related to CAMBRIA anyway. So over to you, Susan.

So I mean, I think what we've now seen is proof, as we've been saying consistently that is -- because of the mechanism of action of both full antagonism and inhibition of estrogen receptor, but also degradation can have activity not just in the ESR1, but in the endocrine-sensitive is so wild type. And I think you've seen that. We've been saying it for a while. But when you look at the second-line setting, that is less endocrine sensitive and so the effect size has been smaller there.

So the basis of SERENA-4's confidence is that we have try to design the study to enrich for the endocrine-sensitive components of the first-line setting. That's based on recruiting patients with recurrence of early-stage disease after at least 2 years of its standard adjuvant therapy because those that are less adequate sensitive will progress rapider than that. At least 12 months must have elapsed since the patient's last dose of the adjuvant AI. And then there's this some patients with de novo stage IV disease. So these are clinical features that are enriched -- to enrich for the endocrine-sensitive patient population.

Of course, what you've also got is potentially the prevention of emergence of ESR1 mutations because you are essentially blocking that clonal selection drive because of the mechanism of action. So that's what underpins our confidence in SERENA-4. And I think having seen the fact that you've got activity in an adjuvant setting in an endocrine-sensitive population increases the confidence in that. But obviously, there still those trial design features. And of course, it's in combination with the CDK4/6 inhibitor.

To your second question about CAMBRIA-1. Again, I would just point out that we're the only company that has 2 adjuvant studies with our SERD, 1 designed for the patient population after 2 to 5 years of [ CDK4/6 ], which is CAMBRIA-1 and the other from the patient population newly diagnosed, which is CAMBRIA-2. That gives us the opportunity to be able to -- if we're successful to access the largest group of patients in the adjuvant setting from those 2 different patient populations.

And of course, the other difference is that we are allowing a combination with abemaciclib, which is going to be very relevant as the data continue to mature for CDK4/6 in the adjuvant setting. So I think that was the basis of the trial design that we had, and we're optimistic that those trials will read out positive given proof of principle, if you like, that this class can have a difference there.

Next we just finished this table.

I think I've got the mic Pascal, if I can. It's Matthew Weston from UBS. One question, please, on elecoglipron, if I can. You've made the announcement that you're moving to Phase III, which I assume indicates confidence in the Phase II profile that you've seen. But I could read that 2 ways because you also have a unique target product profile, I think, in Phase III because you're looking about weight management in combination with other parts of your cardiovascular portfolio.

So can you make some comments as to whether or not for you being confident to drive that move to Phase III means that you think you have efficacy at least as good or better than the competition or whether or not you think that it meets your target product profile of at least achieving modest weight loss which you can then use in combination with other agents?

Let me just answer this one because it's easy to answer, actually is, we would never move a product in Phase III and unleash the kind of spend we have. We are committing to if we didn't think we have a product with a competitive profile. So I think the short answer to your question is, we believe we have a very competitive profile and it doesn't rely on combinations. It actually relies on the amount of therapy itself. And of course, combination comes on top. But if monotherapy was not competitive, it would be hard to move it into Phase III and unlock so much investment. Maybe, James.

James from Barclays. One of the Phase III readouts in the first half is efzimfotase alfa which I think had been based is a $3 billion to $5 billion opportunity. But I'm aware there's 3 different trials. So is it all or nothing to get the $3 billion to $5 billion or other scenarios where some trials are more or less successful? And how would that break down?

Yes. So thank you for asking the question there. As you are mentioning, there are 3 trials. There are 2 trials in the pediatric population, where Strensiq was originally approved. One of this trial is a switch from Strensiq to efzimfotase. There is another trial in the pediatric population in the naive -- in Strensiq-naive population against placebo. And the third trial combines both adolescent and adult. You know that the level of Strensiq, depending on the jurisdiction is usually focusing on the pediatric population.

And sometimes, we have adult with pediatric onset in the label, but the intent of the efzimfotase program was to test in the totality of the population from pediatric, adolescent, adult -- and even adult of a certain age, if I may say, So this is what this program of 1850 covers, so that we would know the answer to the question. We have been asking a lot about Strensiq. And we are now expecting the results in the first half of 2026 and we'll put all this together and hopefully, we'll be able to submit for a product that is much easier another enzyme therapy product, but much easier to utilize than Strensiq, which has to be administered every day or every other day, which, of course, is very cumbersome.

So this product would be provided once every other week, it would provide a great benefit. And if we demonstrate efficacy and safety in the total population, this would make efzimfotase alfa a product several times the value of Strensiq.

It's Michael Leuchten from Jefferies. I think this is for Dave and Susan. TROPION-Lung07 now has QCS in the protocol. Is that also the plan for TROPION-Lung08? And can you talk about the relative importance of AVANZAR versus TL07 or TL08?

Do you want to go first? Okay. Thanks for the question. So TROPION-Lung08 is only in the PD-L1 greater than 50% patient population, which is a smaller segment overall. So if you just look at the trial characteristics, it makes sense for the biomarker to be applied within the TL07 population. And that's what the priority has been there. Very similar to what we've seen with the AVANZAR redesign where we put it at the -- in the ITT, but also in the biomarker-positive patient population.

Obviously, between AVANZAR and TL07, we'll be answering the question about the added benefit of platinum in addition as well. And I think these are all important trials that have the opportunity to really position Datroway as a key component of the first-line setting across multiple segments of that patient population.

Graham Parry from Citi. So it's another question follow-up to Richard's question on camizestrant in the adjuvant setting. So CAMBRIA-1 is looking at essentially switch from aromatase inhibitors, but the giredestrant and lidERA study suggest that perhaps that market opportunity might be quite small over time if giredestrant is become standard of care in naive patients in the intermediate risk setting. So is there any plans to run a lidERA-like study or would you be looking predominantly the market opportunity here coming in the high-risk population in combination with [ Verzenio ]?

So just to go over again, the CAMBRIA-2 studies in a setting that's very similar to lidERA, but it does allow for the combination with abemaciclib, which I think is going to become an increasing piece. So of course, what lidERA doesn't answer is relevance of the oral SERD in that context. And given that we think that CDK4/6 prevalence in the adjuvant setting is going to grow. I think it's very important to have the data with and without that combination and after a period of CDK4/6. That's why I'm saying, when you look at the 2 trials in totality, I think it gives us the opportunity to have the greatest segment of the patient population in the adjuvant should they both be positive.

I don't know, Dave, if you want to comment?

Yes. I'd simply amplify and echo some of the things that you had said previously, Susan on this, which is, if you think about CAMBRIA-1, which is in this 2- to 5-year population, that's the prevalent population. And so while it's true that over time, the upfront CAMBRIA-2 population, we would expect to grow. There is a large population of patients that are prevalent on AI and AI CDK4/6. And the program allows for looking at both AI and CDK4/6 combinations. It's the broadest program that also allows both that prevalent and incident pool, and it allows us to be in a competitive set of time lines by putting it together in the way that we have.

Thanks, Dave. Can we go here and then maybe there.

Simon Baker from Rothschild & Co Redburn. One if I may, please, probably for Sharon. Could you just remind us of the points of differentiation of tozorakimab both in terms of the molecule and trial design and how that underpins your confidence in the program?

Sure. Thanks for the question. So the story about tozorakimab is the same one that we've been telling all along, which is that we think we have a highly differentiated IL-33 biologic. And the reason we think it's differentiated is because our molecule is able to hit both the ST2 pathway as well as the RAGE EGFR pathway and importantly, to impact signaling downstream event. And why does that matter?

Because being able to inhibit signaling through RAGE EGFR is impacting mucus production and epithelial remodeling. And that's incredibly important in COPD where mucus production drives exacerbation, exacerbations drive mucus production, and it gives you a vicious cycle. So we think that's a really important component to our IL-33. Now as you know, we've designed a broad study to allow us to examine the efficacy of tozorakimab in current and former smokers. Our primary readout is in smokers, but we're looking at a broad population across eosinophil levels and across smoking status so that we have the opportunity to bring this to the broadest possible patient population.

Can we tie one more question in the room, and then we'll take Steve Scala's question online. Can we get a microphone over there?

Christopher Uhde from SEB. It's on Calquence and the room for growth. It's done a nice job beating again lately. Consensus has about 10%, give or take, growth for '26 or '25 and then another 10% from then to about 2031, so peaks $4.4 billion. So will AMPLIFY live up to its name? Or is consensus in the right ballpark? That's my question. And are there any other meaningful gating events to unlock?

So thanks, Chris, for the question. AMPLIFY is very much an important part of the growth moving forward for Calquence and the fact that we've got positive study approval within Europe, and we're anticipating the U.S. approval is important. In general, the desire that we're hearing among hematologists across the multiple malignancies that they treat is to move towards more finite based therapies. That trend has already happened within Europe. And we've got, I think, a very differentiated and strong profile to be able to compete against the existing venetoclax-based options that are available there.

In the U.S., remember that there is not a BCL2 and a BTKi combination finite CLL approach that's been approved. So we have an opportunity in the U.S. to really be the first to come into this space and 1 in 2 patients are receiving finite as opposed to treat progression in the U.S. So you can see how getting to growth numbers within the U.S., which is certainly the largest portion of our global Calquence sales really can be very, very meaningful. The other places in terms of opportunities, we have continued opportunity to expand Ecco in the second line MCL. And we also have DLBCL with ESCALADE which is something that will read out a little bit later on.

We need a microphone there.

Justin Smith from Bernstein. Sharon, one for you, if that's okay, cardiac transforms. Could you just remind us on the powering with regards to monotherapy versus combo with TAF. Is the TAF combo arm big enough to prove something clinically meaningful?

Right. So this question comes up a lot with Wainua. I think it really speaks to the interest in novel therapeutics for patients living with ATTR cardiomyopathy, which is a growing patient population as diagnostic rates improve. Now we have designed, as I mentioned earlier today, the largest ever cardiomyopathy study so that we would be powered to do preplanned subgroup analyses. One of those is to be able to differentiate between patients on baseline tafamidis versus those who are not. And our trial will have the largest proportion in number of patients who are on baseline tafamidis.

So should we be able to proceed through the statistical hierarchy? And answer that question, we have designed a trial that allows us specifically to get at that. And we think it's important because that's going to inform treatment guidelines for patients and help to shape the way cardiomyopathy patients are treated in the clinic. So we look forward to the readout of this in the second half of this year, and we'll share the data when they are mature.

Thanks, Sharon. So we'll take Steve Scala's question online and then return to the room. I think Rajan has the microphone.

Pascal, a general question, but a hellaciously competitive market of undifferentiated products, which isn't growing very much despite huge awareness, doesn't strike me as the type of market AstraZeneca pursues aggressively. Obesity could be described as that, and you are not only involved but increased exposure. So what am I missing? Are you assuming that fundamentals improve that pricing stabilizes and increases, that strong growth will resume? I know that you're pursuing combos, but value-added products launched into a tough market would strike me as a high probability path to success. And if I could just tack on, can you shed light on why AstraZeneca continues to pursue an oral relaxant?

I will only take the first one, if I may. It's an easy one, Ruud for you.

No, I think it's a fair question. First of all, I think we truly believe that the market in itself is still quite immature. Yes, injectables have their place. The first oral is moving in, but there's still so much improvement possible in combination therapies and for obesity overweighted people, I think, is very crucial in order to help those patients to reduce their risk of cardiovascular events. So that's one big ticket item.

Second part is that those products are still not very much used in, let's say, the international markets. If you look at the success of Farxiga, a big part of the success of Farxiga across the 3 indications is that we have a very large footprint in the international markets. So there's clearly room to maneuver.

The third piece is that we are doing a lot of research and development work regarding the quality of weight loss. Yes, it's not only about the percentage of weight loss, but also are you able to preserve lean muscle, yes or no? Are you able to attach or attack the bad fat, the visceral fat. So I think there are still an enormous amount of possibilities to move to the next generation of anti-obese medicines.

And I truly believe that AstraZeneca is one of those companies well equipped in order to address those questions. I think we have an excellent development and discovery team. You have seen our excitement of the deal we made last week with CSPC, which gives an opportunity to move in long-acting medicines. So I think there's still so much to win in this marketplace. And we are keen to play an important role in that.

It's Rajan Sharma from Goldman Sachs. I just wanted to focus on the growth drivers in 2026 outside of oncology. Do you think the biopharma business can grow through the Farxiga LOE? And then just thinking about the guidance for '26 at the group level, what has to go right to get to the upper end of that guidance? And when do we get visibility on those factors?

Yes. So let me take that question as a start. First of all, I think the respiratory and immunology portfolio is growing very fast. It was already $9 billion in the course of 2025. There's no reason to believe that products like Breztri potentially also with asthma or I said in my prepared remarks, product like Tezspire, Fasenra are not growing anymore double-digit moving forward. So that is, I think, a very important growth driver, not only in the United States and Europe, but also clearly in the international markets. So that's one big ticket item.

The other one is clearly that hopefully, we will see the approval of baxdrostat in the course of this year as an approval that, of course, will not immediately generate substantial sales in the course of 2026. It's a highly dominated Part D population. But based on all the market research, we truly believe that this product has a multibillion-dollar opportunity as well. So if you see our internal forecast, yes, we will have a blip for sure regarding the Farxiga LOE but there are enough other growth drivers in order to compensate and potentially to exceed the growth moving forward. So we are quite bullish in our internal forecast regarding the forecast for the biopharma business.

Rajesh Kumar from HSBC. Looking at 2026 you are sitting at 1.2x net debt to EBITDA. You got consensus, which is inching by the minute close to your $80 billion target by 2030. You've got a few patent lifts soon after that. When you think of capital allocation, people have factored in a higher R&D in their models now. Would you go the organic route to basically support growth beyond 2030 or what sort of firepower do you intend to deploy for acquisitions?

The question is basically underpinned by what Steve Scala was asking earlier that you've gone to obesity at a time where almost no one is sure whether this market has the same kind of growth. And every player is going in. So if you keep going organically into different segments, you might run out of idea. So how are you thinking about that problem in terms of reallocation of capital, share buyback or future investments?

So let me make a general comment, and then Aradhana can make more specific comments about capital allocation. One thing I would add to what Ruud said about oral GLP-1 and others is cardiometabolism is going to be -- is today the biggest issue mankind is facing. So -- and we are in the early phase of this transformation and the way we can actually tackle this disease, if you want. And beyond GLP-1, you also have SGLT2, and I really believe in the oral segment, combining those 2 is going to make a huge difference to how people are treated.

I think the foundation treatment of many of these people should be GLP-1 and an SGLT2, protect the kidneys, the heart, reduce weight, improve metabolic status. And then beyond that, we have other mechanisms, of course. So I think this is going to remain -- I mean, it is looking very crowded, but it is also a huge issue for medicine. And over time, I think things will settle down because not everybody will succeed in this market.

We have the pipeline. We have the R&D strengths, in particular, development strengths, and we have the commercial network and the manufacturing network to manufacture those products and commercialize them around the world. So I think it will continue to -- it will be an important issue to tackle from a medical viewpoint, and it will be a driving growth for us -- a driver of growth, and we become profitable as soon as we can get to scale. In terms of a general question about capital allocation.

Yes. So a few things to clarify. So the $80 billion ambition was on an organic basis, and that does not assume any M&A of any size and scale. And I think we're on track to achieve that. We do have substantial firepower. I think we're very comfortable at 1.2x leverage, but we have plenty of capacity. That being said, I think we remain very disciplined in terms of what type of assets we bring in because it's not about just buying assets. It's about actually creating value for shareholders from those assets that we acquire. And that requires substantial investments in R&D once we acquire those assets or license those assets, et cetera.

And so again, we are very disciplined in how we do that, and we need to continue to add value. I think on your question of beyond 2030, that's why Pascal highlighted all -- I mean, if you look at our R&D expense, a substantial portion of that, I wouldn't say, the majority, but a substantial portion is going actually in assets, which won't have any substantial revenue in 2030. So that's all the investment for the beyond 2030 to continue the growth rates because we know in that time frame, there are going to be substantial LOEs.

If you look at it, I mean, we are in a good position. We don't have to go after Phase III assets that are proven in cost of fortune and you pay front which you're going to get later. We really try to focus our BD activities on earlier assets where we can add value and create shareholder value because we don't need products immediately. We need to invest for the future.

And so our strategy really has been to build our pipeline, of course, and add to it, but through earlier BD investments and then add value over time. So that's really our strategy. And as you said, we have a good capacity in terms of raising debt if we wanted to. But we also have to absorb all these products in our P&L, right? So it's not only a question of cash, a question of P&L, too, and a question of focus. We have a very broad portfolio. But within this, we need to stay focused on what our key priorities are.

There's one online.

Sorry, online, that's what you mean, I'm sorry. Over to you Peter Verdult.

Peter Verdult here from BNP. Sorry, I can't be with you live. Just 2 quick ones, please, Susan and Sharon. For Susan on Alteogen. Can we have an update here and your confidence in this formulation technology significantly extending your key oncology biologic franchises? Are there any products you can call out that will be leading the charge or entering the clinic in the next 12 months?

Secondly, for Sharon, sorry to do [indiscernible] But can I just try my luck. Can you sketch out in a little more detail what Astra would consider a win given existing silence data in the market? So put simply, do you think you can raise the bar further on outcomes in the silence market?

Can we focus on the first question? And if we have time, we will return to the second one later.

So obviously, I think subcutaneous formulations have the opportunity to offer convenience to patients, which I think is very attractive. And we're obviously investing in this across our immuno-oncology portfolio, the bispecifics and and Imfinzi to look at. But also we have the opportunity to look at subcutaneous formulations also with our ADC portfolio, which is perhaps slightly more surprising to people, but it is possible to do that in certain circumstances.

And then, of course, across our T-cell engagers, the actual doses in the T-cell engager portfolio are often low enough that, that enables a subcutaneous formulation without necessarily requiring something like the hyaluronidase technology as well. So I would just say that this is a trend that you've seen already across multiple different settings and is one that I think will continue to grow across the biologics part of the portfolio.

Sure. So going back to CARDIO-TTRansform for eplontersen. A few things to note about our clinical trial relative to competitors' clinical trial. The first is that the key objective of CARDIO-TTRansform was to have a balance of naive patients and defamitive patients. And given that CARDIO-TTRansform is the largest ever trial run in this setting, we've achieved that. So we'll be able to address that question pending positive results, which we think will be very informative to the clinical community.

And the second is that CARDIO-TTRansform allows for stabilizer drop in, so acoramidis drop-ins, which speaks to the remaining unmet medical need. We know that patients who are currently on stabilizers continue to progress on therapy. If that were not true, we wouldn't be able to enroll our trial. So understanding how those patients are succeeding on a silencer on top of their standard of care, including a stabilizer is incredibly important.

It's also important to note that in this larger trial, we have specific hard cardiac endpoints, including cardiovascular mortality as opposed to all-cause mortality, which really helps us understand how this drug is doing what it's doing and how it ultimately impacts those important readouts for patients who are living with ATTR cardiomyopathy. So overall, we expect to have landmark data for overall benefit and be able to demonstrate the additive benefit of a silencer on top of stabilizers.

So maybe we take the last one. Mattias Haggblom at Handelsbanken.

I'm curious to hear how you think about the AstraZeneca's competitive advantage from an in-license or M&A point of view given you have 2 [ science ] sites in China when committing for assets with a competitor who does not have R&D on site in China.

So the first part of your question was a bit hard to understand, but I think you're asking us about our position in China from a BD viewpoint. If that's the question, let me try and I'm absolutely convinced we need to be in China to collaborate with, partner with Chinese companies but also to compete and learn -- learn to compete with them and how they compete, not only commercially, but mostly from an R&D perspective because the world has changed and they are increasingly becoming a fundamental part of innovation in our industry and some of them at some point will become global companies. So it's fundamental for us to be there.

And I think we have quite a good position to do this. We have 2 R&D centers. We have a strong position, strong profile in China. A few of the deals we've made -- we were able to make because people wanted to work with us. With -- the recent deal we made, I know that someone else wanted to pay more money. But the company wanted to work with us. So I think that relationship we build with local Chinese companies over time and our reputation and our focus and the focus they know that we have on a few limited diseases have really helped us secure a number of deals over the last few years.

Now what happens, though, is the cost, the price -- the price of these BD deals is going up, right? And that's -- I assume that would be the case. And that's why after COVID and when the contrary we opened, we quickly went down. We've done quite a number of deals over the last few years at reasonable prices and it's becoming more difficult because everybody is going there. But yes, I continue to think we have a good position. We can leverage our position in China, but we will have to remain disciplined because there's competition for this and the prices are going up. And of course, we have to stay focused on what we're doing.

So Andy, I think we have to stop here. Some of us have to be on the road show. So thank you so much for all your interest and your great questions. Have a good rest of the day.

Welcome to the second day at the JPMorgan Healthcare Conference. I'm Richard Vosser, European pharma analyst with JPMorgan. It's my great pleasure to introduce AstraZeneca for you today.

From AstraZeneca, we have Aradhana Sarin. Sorry, Aradhana. I'll get there in the end. And who's the CFO of AstraZeneca. And we also have Dave Fredrickson, EVP of Oncology, who's going to be here for the Q&A. Just before I hand over to Aradhana, just a few housekeeping issues. [Operator Instructions]

Aradhana, welcome to the conference.

Thank you so much, Richard, and welcome, everyone. My name is Aradhana Sarin, and I'm proud to represent AstraZeneca this morning to share our remarkable progress in 2025, and expectations that we have of the sustained momentum in 2026.

These are forward-looking statements, which I encourage all of you to review. We saw very strong commercial performance over the first 9 months of 2025. Total revenue was up 11% and core EPS grew 15%.

Our pipeline delivery was unprecedented. We had 16 positive Phase III readouts since our fiscal 2024 results, spanning the breadth of all our key therapy areas. Our strong growth was driven both by our global reach and diverse sources of business, key strengths for AstraZeneca.

Oncology grew 16%, reflecting the ongoing demand for a broad portfolio of medicines. Biopharmaceuticals and rare diseases were up 8% and 6%, respectively. With the growth of our newer medicines more than offsetting the impact from loss of exclusivity of a limited number of mature brands, including Brilinta, Pulmicort and Soliris. We saw impressive performances across all regions, notably in the U.S. with 11% growth in emerging markets outside of China, growing 21%.

The underlying growth momentum in the first 9 months of 2025 allowed us to reiterate our full year guidance with total revenue and core EPS to increase by high single digits and low double-digit percentage, respectively, at constant exchange rates. We do anticipate fourth quarter headwinds related to VBP and year-end hospital order dynamics in China as well as tender offer timings in certain emerging markets as previously communicated.

Also as a reminder, we booked more than $800 million in sales-based milestones under collaboration revenue in the fourth quarter of 2024, which will affect year-over-year comparisons. We will report our full year results on February 10, and welcome all of you to listen in.

The significant progress we've made this year has further strengthened our confidence in reaching our $80 billion ambition in 2030, which we first set out in May of 2024. We have continued to see our commercial portfolio deliver and look forward to launching a number of new medicines in 2026, including Baxdrostat, Camizestrant and Gefurulimab, all of which are under regulatory review.

And looking beyond 2030, we are investing behind transformative technologies that have the potential to change the practice of medicine. 2025 was a catalyst-rich year with readouts collectively representing peak revenue opportunities of over $10 billion. Towards the end of 2025, we were delighted to receive FDA approvals for Imfinzi in perioperative gastric cancer and in HER2 in first-line HER2-positive breast cancer, further strengthening the global outlook for these medicines.

In addition, the FDA accepted Baxdrostat for priority review in hypertension. A deep and rich pipeline reflects years of robust and disciplined governance over R&D investment and portfolio prioritization. We consistently generate more high-quality ideas than we can fund. Each year, our world-class teams of clinical and commercial leaders conduct a comprehensive strategic planning exercise, which assesses the broadest opportunity for sustaining leadership within our core therapy areas.

These opportunities are then optimized during our mid- and long-term budget planning cycles to align with our enterprise aspirations, and ultimately, each project is signed off through project-specific investment decision. Ensuring rigorous scrutiny and challenge so that every investment is commercially viable and designed with the ambition of truly advancing clinical practice.

R&D budget is not pre-allocated by therapy area. Rather, all projects are ranked collectively using a rigorous decision-making model, enabling us to take targeted science-driven smart risks. This disciplined approach supports our late-stage success rate and allows us to optimize investment decisions across therapy areas, balancing near-term launches with platform opportunities and with the potential to compound over time.

As previously communicated, we anticipate full year 2026 R&D cost to land towards the upper end of the low 20s percentage range of total revenue. This level of spend will allow us to invest in emerging opportunities, while at the same time, deliver 104 Phase III studies that we have ongoing.

Our late-stage portfolio continues to grow and broaden and the value associated with these trials is not only increasing as a whole, but also at an individual asset level. As you can see on the left-hand side of the slide, the number of unique assets in our late-stage pipeline has grown over the years. In parallel, the average nonrisk-adjusted peak year revenue potential per indication has also increased, now approaching about $1.3 billion.

The composition of our pipeline is also evolving as we continue to invest behind our transformative technologies, including novel ADCs, radio conjugates and cell-based therapies. At the same time, patient enrollment in our trials is increasing with a large step-up anticipated in 2026, driven by increased investments in our CVRM pipeline, where we are running several large outcome studies.

AI is transforming our ways of working and is already embedded in end-to-end across AstraZeneca, from discovery to development, to commercial, to operations through health care delivery. AI is helping us drive outcomes, boost efficiency and productivity and accelerate innovation with measurable impact.

To highlight a few examples. First, IDA, our agentic system for synthetic drug process development, integrate simulations and internal expertise. In CMC, this approach has the potential to decrease time to commercial scale up for synthetic manufacturing by up to 50%. Secondly, in clinical development, our proprietary AI-enabled solution, QCS, or quantitative continuous scoring applies computational pathology to help identify patients most likely to respond to treatment. We are actively applying this technology across our ADC pipeline.

And just this morning, we announced the acquisition of Modella AI, which has the potential to further our pathology foundation models, enabling further development of targeted therapeutics along with diagnostics in our oncology portfolio. Over the course of 2025, we have made substantial progress over transformative technologies, accelerating multiple programs and to late-stage development to support our growth into the next decade.

Over the next few slides, I will dive deeper into some of the recent advances across these pillars. Cardiometabolic disease remains a major global burden. And to address this need, we are developing multiple pipeline assets. Laroprovstat, our oral PCSK9 inhibitor for dyslipidemia is a true small molecule with no food effect or fasting requirements.

In the Phase IIb trial, we were excited to achieve greater than 50% LDL-C reduction on top of standard of care statins, and we anticipate the first pivotal Phase III readout from the [ Azure LDL ] and the [ Azure AGF ] trials in 2027. In weight management, we're advancing a portfolio of different mechanisms, and oral GLP-1, formerly known as 5004, [indiscernible] a selective amylin receptor agonist is a D6234 and a GLP-1 glucagon is a 950 all of which are expected to report first Phase II data this year.

Our goal is to address weight management and cardiometabolic risk holistically and our broad pipeline uniquely positions us to explore innovative novel combinations. Should Phase II data demonstrate competitive profiles, we plan to rapidly move to broad Phase III trials in 2026. Following the acquisition of CinCor, announced at this conference 2 years ago, we have been excited to see Baxdrostat emerge as a potential best-in-class, aldosterone synthase inhibitor for uncontrolled and resistant hypertension with compelling data from both the BaxHTN and the Bax24 Phase III trials.

The FDA recently accepted Baxdrostat with priority review, and we anticipate it being first to market with a PDUFA date in the second quarter of this year. We look forward to leveraging our strong existing foundation in primary and specialty care in the U.S., as well as our global reach to maximize the value of this medicine. This provides us with a considerable competitive advantage, and we're investing strategically to support the Baxdrostat launch, anticipating initial uptake with specialists followed by broader adoption in primary care as is typical for a cardiovascular launch.

Turning to oncology. We are rapidly advancing a broad high-value portfolio of antibody drug conjugates. We now have 8 wholly owned ADCs in the clinic. Giving us the potential to address around 80% of the patient population in our focused solid tumor areas.

We anticipate the first pivotal data for SONi-B are Claudin 18.2 ADC in the first half of this year for second-line gastric cancer with blends underway to move into the first-line setting.

We've also rapidly progressed both [ Boxitam ], our B7-H4 ADC and [ Torbusam ], our folate receptor alpha ADC into late-stage development with first subjects initiated in Phase III trials in the second half of 2025 in endometrial and ovarian cancers, respectively. These are the first ADCs to move into Phase III using AstraZeneca's proprietary linker payload technology.

Looking forward, we are excited by the potential to integrate our proprietary QCS technology into future trials, enabling us to better identify and target patients most likely to benefit from these innovative therapies. At ESMO last year, we presented encouraging updated Phase I/II data from ARTEMIDE-01 study for rilvegostomig, a PD-1/TIGIT bispecific. We demonstrated promising activity in checkpoint inhibitor-naive non-small cell lung cancer cohorts, highlighting the opportunity rilvegostomig has to replace current generation immune checkpoint inhibitors.

We also shared promising early data for rilvegostomig in combination with our TROP2 ADC, Datroway in lung and breast cancer. And we have a broad program, which includes 14 ongoing Phase III trials across 9 tumor types, including lung and GI cancers. Last month at ASH, we presented early data for our cell therapy asset, AZD0120 and T-cell engager, surovatamig.

Both assets have $5 billion-plus nonrisk-adjusted peak revenue potential. AZD0120 is our dual CD19 BCMA CAR-T therapy that has demonstrated a potential best-in-class profile in multiple myeloma with Phase Ib data demonstrating a 78% complete response rate in late-line patients and 80% complete response rate in those previously treated with a BCMA CAR T.

This remarkable efficacy, combined with the favorable safety profile observed, including no Grade 3 or higher cytokine release syndrome or delayed neurotoxicity highlights the potential of this asset. Phase III trials in multiple myeloma are planned to start this year, and we're also exploring early development outside of oncology in Phase I trials in SLE, myasthenia gravis and light chain amyloidosis.

Surovatamig, our CD19 CD3 bispecific T cell engager has transformative potential across multiple hematological malignancies. Phase I data showed high response rate across DLBCL, follicular lymphoma and ALL with a manageable safety profile across trials. Phase III trials in DLBCL and follicular lymphoma are ongoing, and we look forward to expanding the late-stage program in 2026. Our capital allocation priorities remain unchanged and reimbursement in our business remains our top priority.

Looking ahead, 2026 is set to be another catalyst year for AstraZeneca with multiple high-value Phase III readouts anticipated across therapy areas. Just to highlight a few, in oncology, we anticipate several readouts for Datroway in non-small cell lung cancer.

Further data on Imfinzi in bladder cancer and early HCC, first pivotal readout for applauding 18.2 ADC SONi-B, as well as next-generation oral SERD camizestrant in first-line hormone receptor positive breast cancer. In biopharmaceuticals, we are looking forward to the readout of Wainua in ATTR cardiomyopathy and the COPD program for differentiated IL-33 biologic to tozorakimab.

And finally, in rare diseases, we anticipate readouts for indication expansion opportunities for Ultomiris, as well as efzimfotase alfa program throughout in -- with readouts in hypophosphatasia.

In closing, we delivered strong growth in 2025, while advancing an industry-leading late-stage pipeline. We remain on track for our 2030 ambition, and we're building beyond investing in transformative technologies with innovations that hold the potential to reshape standards of care throughout the next decade.

Our diversified portfolio and global reach provide resilience in an ever-changing external environment, and our disciplined capital allocation ensures that we can fund innovation and generate returns.

And with that, I would like to thank our host, JPMorgan, and I would like to move over to Q&A, along with Dave. So thank you very much.

Thanks, Aradhana. Maybe I'll kick off with one question to start with. You highlighted the 2030 ambition, and you also highlighted the 19 Phase III readouts, the successful readouts. And we've seen Baxdrostat. We've seen in HER2.

We've seen camizestrant amongst others. So what are you thinking about the potential to get there, the achievability of that and your level of confidence there? And of the assets that you've highlighted, what are we underappreciating from our side as consensus?

So we set this $80 billion target last year, not last year, the year before, '24. In May of '24. And at that time, it was obviously a stretch target. It was risk adjusted. And we felt -- obviously, we felt it was within reach. And you fast forward and 1.5 years later, I think we do feel it is very much within reach.

And we have a whole lot of -- if we have the same success rate this year as we had last year of our Phase III, then I think the confidence increases even further, a good data point, I think, to maybe remind folks, when we had put out that target in May of 2030, consensus estimates for us -- for AstraZeneca in 2030 were $67 billion, and we'd put this $80 billion target. Mid next -- last year, mid-2025, those moved up to closer to like 76. And now they're actually at 80. So I think people are getting more confident.

And I think, Richard, on this, just within the oncology portfolio. First, having 10 positive Phase III readouts in oncology turns over a lot of cards that we get to play now, between now and 2030. And when I look at four of our current multi-blockbuster medicines, Imfinzi and HER2, Calquence, Tagrisso, I continue to see with those medicines opportunity to grow to 2030 and beyond.

We've got MATTERHORN in hand, VB09 in hand, DESTINY-Breast05/11 in hand, AMPLIFY. These are all indications that are substantial and that we've got a really nice opportunity to drive great growth on. Then on top of that, Aradhana talked about the hematology portfolio. I think 0120 and surovatamig are underappreciated to be very specific to your question. We remain very enthusiastic about the next-generation SERDs.

And I think actually as a class, we're seeing read-through that give us increasing confidence in camizestrant, and then Aradhana also talked about the ADCs, and we'll see the first, it's up on the slide, right? So you see the first of the AZ, wholly-owned ADCs with SunEV coming through this year. And I think that we've got a really strong platform to be very competitive within the space.

You touched on the SERDs. We've obviously seen data from your competitor in the adjuvant setting. Maybe you could expand a little bit on what that says for your program, both in the adjuvant setting with the CAMBRIA trials and also maybe thinking about building on SERENA-6. This year, we had SERENA-4.

So as we've often said, we do believe that -- not all molecules are the same within a class. And obviously, there's different approaches and strategies to development programs. We do believe, based on the data that we've seen to date that we've got a best-in-class SERD in terms of mechanism of action, but then also the clinical data that we're seeing from that, some of the most compelling clinical data are obviously the early work with SERENA-2, where we look at the combination of Faslodex plus the SERD versus Faslodex.

And within that context, we're really, really encouraged to see that both in patients whose tumors had an ESR1 mutation, but also those who didn't that we saw similar magnitudes of efficacy in terms of hazard ratio. And of course, SERENA-6 gives us a good reason for confidence in the class. And then the adjuvant readouts coming from competition give good positive read-throughs into the hypothesis that we can do better than AIs.

We've got, with our SERENA-4 study, which will read out, as you can see here in the second half of the year. We think that we've got a study that's appropriately sized. We think that we've really included patients in it that are still those patients with endocrine drive and will be endocrine-sensitive. And we think that's been an important part of the design of that study.

And we know that CDK4/6 are playing an increasingly important role in the treatment of both early and metastatic, and that's part of our program. So we've got a really broad program, four studies of SERENA-4, 6, CAMBRIA-1 and 2, and I think that we've been smart in terms of lots of different shots on goal, but also opportunities to make sure that we are on time and bringing data in a timely fashion in the marketplace.

You alluded to on Imfinzi. Lots of clinical data, MATTERHORN. You've been driving indications, ADRIATIC and beating estimates over the last year. How should we think about the peak sales for that opportunity for Imfinzi? Where can we go?

So this year -- or sorry, last year in 2025, the key growth areas have been GI cancers. So not only as you mention. Obviously, the work that's happening and starting to see underway within MATTERHORN, but really, HIMALAYA, being an important part of the growth that we've seen, GU, so bladder cancer with NIAGARA being an important area and then small cell lung cancer with ADRIATIC being an important piece going ahead.

And all the while within that, I think very important to remember, Richard, very strong position in the Stage 3 unresectable PACIFIC setting. This has been an area where despite competition, we remain the IO of choice and the only one that's really approved in this set. I think that GU, GI and small cell continue to grow going forward. I think that we'll continue to see that, how big could we be?

Well, I think that you take a look within this. Certainly, Imfinzi with Avonzar could have the opportunity to come into the Stage 4 setting. We have very little sales of Imfinzi in Stage 4 lung cancer. So this would be a really nice opportunity to grow into that setting, continuing also with EMERALD-3 and VOLGA, those are important and big opportunities to grow ahead.

Imfinzi, I think, will likely be our largest oncology medicine in the midterm period. And that's not because Tagrisso is not going to be doing well. It's just because I think Imfinzi has got more engines to grow off of.

You touched on that way. We've seen TB02. We saw great data at ESMO. But I just wanted to ask about what you're seeing in the launch launched indications, how is the uptake going? And on TB02, how are you thinking about the potential there given the strong data and the good tolerability?

Launch trajectories in our lung and breast indications are well underway and doing nicely. It really does demonstrate that there is a real need and an appetite to replace classic chemotherapy with new, more precision targeted options.

TB02 was so important because this is a population where there's no doubt that chemotherapy is today the standard of care and an opportunity to bring a more precise approach with TB02 into this triple-negative population is highly sought after.

We also got an opportunity to see in a cross-trial comparison way, that Datroway compares very well to the other in-class competition and studies that were pretty similarly set up and designed to one another and in fact, presented at the same congress.

And so I think that was really useful for us to see. If you compare also then and take a look, that TB02 indication, that's a blockbuster opportunity for the brand. And I think if you then look at that, you start to say, well, we've derisked a very important part of the breast cancer opportunity through TB02. And I think that we're starting to get good positive experiences with the medicine, and we're looking forward to really the further readouts that are happening over the year.

Maybe touch on one earlier oncology pipeline, the BCMA CAR-T that's -- Aradhana, you mentioned and you mentioned going into Phase III. Maybe just the details of where could you go and how fast could you go? Obviously, this is late stage, but can you go into the earlier stages of multiple myeloma?

Absolutely. I mean, I think that Aradhana showed the fact that we're seeing really strong efficacy in the way of response without CRS, without delayed neurotox. These are the liabilities that are preventing CAR-T from moving from the later line settings where they've been highly effective into the newly diagnosed setting.

So if we continue to see a profile as we've been seeing so far to date and presented at ASH, our ambitions for 0120 are absolutely to move into the earlier stages. And Aradhana made the point, and I think it's really important and absolutely something that's probably not on the collective radar. The opportunity to move into autoimmune and also into rare disease, I think is substantial as well.

And we'll need to share more data as it comes available on the successes that we're having there, but we are starting to really get increased enthusiasm and ambition to be able to move our car into those spaces.

Makes sense. Maybe we could just pivot for a moment to policy. It's been -- or rather '25 was an eventful year in terms of policy in the U.S. and you have one of the first White House agreements. But there is the ongoing IRA negotiation. So maybe a couple of questions here. Just how should we think about the impact of these -- of your White House deal on 2026? And then I think Calquence might be subject to IRA in '27. So we're going to see that on a list and then the end of the negotiation. So how should we think about that as well?

On your first question, as it relates to the most favored nation definitive agreement, and those -- I think what's really important is a starting point. You've heard Pascal comment on this, and it's a really important first piece, which is the disparity in funding for innovation that has been taking place and growing over the last decade among wealthy nations, we don't see and didn't see as sustainable.

It's very clear that there's a big gap that exists here. And I think that this is an opportunity to address that. The fact that we now have, I think it's 16 now of 17 companies that received a letter from the President have now signed on to agreements, also means that there's an opportunity for there to be some real scale and inertia behind increasing the funding for innovation across the globe in a more balanced way.

And so as you think about the impact specifically to your question in 2026, I think one of the things that we were encouraged by with the administration, and you'll have the administration here later today at lunch. But the administration understood the nuanced aspects of ensuring that life sciences continue to be competitive and robust within the United States.

And that meant a phased approach to the work that we're doing. The phased approach on MFN is going to start first with America's most vulnerable in Medicaid, which for us represents low single-digit global sales over time, they'll grow to represent multiple channels of business and multiple medicines, but it gives us the opportunity to plan to get towards that and offset by increasing funding for innovation across the globe as the U.S. prices come down.

So I think that the '26 impact is going to be within a defined population of the Medicaid population. And I think that, that's something that we've got so many growth drivers that are happening that I think that we manage that well. And it will obviously be incorporated into whatever guidance we provided at the front end of the year.

On IRA, I expect for Calquence to continue to be the leading frontline CLL, both in continuous and as we launch within AMPLIFY opening up into finite, and we'll be the only all-oral fixed duration frontline CLL option in the U.S., and I think we've got great growth opportunity there.

I mean, one of the readouts on the slides is Wainua, which is -- and we've seen a very strong uptake for Amvuttra from Alnylam. So maybe we could talk a little bit about how you see Wainua being differentiated. What's the difference in trial designs and how you see the relative profiles?

Yes. So the study that's ongoing right now is the largest study ever done in the cardiomyopathy population. And we specifically increased the size of the study.

In terms of the design, the way -- I would say, the key differentiation other than the size is the fact that we're also looking at mortality endpoints, not just all-cause mortality, but also cardiovascular mortality.

And then secondly, because of, again, the size of the study, we will also have data in the population, which is on tafamidis, for example. So again, that data is not or doesn't have that, and I think that will be a key differentiator.

Other than that, I think we feel, because of our global and very strong cardiovascular presence, for many decades, obviously, with Farciga, but then now also with Baxdrostat. And our entire portfolio, we're really well positioned to commercialize this assuming, obviously, the trial reads out positive.

The other element, I would say, is diagnosis rates still remain very, very low in this indication. So Alnylam is doing a great job, but there still is a huge opportunity to improve diagnosis, have earlier diagnosis and expand the entire patient population.

On the slide, there's a couple of -- maybe 3 readouts on obesity in the portfolio that you highlighted. Maybe we could drill down on one of them, the glucagon GLP-1. The obesity space is sort of -- it's evolving, shall we say. So where does this fit?

Yes. I mean it's hard to predict really how the obesity space will evolve. We have sort of one world view of what the universe will look like 5 years from now, and I'm sure everybody has their different world view.

But our view is that the market will segment over time. There will be a role for injectable GLP-1s, but there'll also be a big population for oral GLP-1s. Then there will be more elements like the amylin or the injectable GLP-1 glucagon, which may be as a monotherapy, but potentially also in combination.

And patients will segment based on not just sort of weight loss, which has really been the only element people are measuring. But other comorbidities, lean muscle preservation what effect there is on kidney disease or hard disease. So I think there will be further subsegmentation and that's why our strategy also on the oral side is to do combination like the 5004 in combination with [ DAP1 ] and so forth.

So -- our -- again, based on our role view, we have a whole program for many of these assets to fit in different areas and to address different conditions.

Makes sense. We've got one or two questions on the panel. So I'll just ask one of them, which is on Tagrisso, Dave, which is just asking how are you thinking about next-generation EGFR portfolio from your side in terms of life cycle management and longer growth of that portfolio?

So we're continuously looking for opportunities to raise the bar and beat Tagrisso. Right now, the near and midterm opportunities to do that are through Tagrisso combinations. We're building on top of the FLAURA2 experience and one of the things that's been really important coming out of the FLAURA2 overall survival data is a real shift in the lung cancer communities, interest in moving from monotherapy Tagrisso for most and combo is the exception to now really combinations foremost and mono for those who likely aren't going to be able to benefit from combination.

So you see within that context that you've got TROPION-Lung15, which is a second-line study. We also have the frontline studies that we're looking at there, other options to also, ideally, we'd like to be able to bring in other ADC combos with Tagrisso into the space as well.

And we'll continue to share information as we have it becoming available. We're working hard on a next-generation Tagrisso. But right now, I think that for investors to have on their radar, it's really the combinations of Aussie-based combos that I think is where the next opportunity for improving on outcomes resides.

Makes sense. Maybe one last question from me. You talked upfront in the Q&A about the 2030 target, $80 billion. In your presentation, you highlighted the ambition to grow beyond that. Beyond 2030. I suppose the simple question is what's driving the confidence there, what within the portfolio, et cetera, is can we anchor on to give us confidence in that continued growth?

I mean I'd say, actually, a lot of the studies you see here and next year, when we have the same list of 2027 readouts, many of these actually don't reach their peak sales in the 2030 time frame, right?

Actually, they contribute very little of that $80 billion ambition. So if you think of like camizestrant, which Dave talked about and the early CAMBRIA-1, CAMBRIA-2 study. Those will be things that contribute to the post-2030.

Rilvegostomig, we have the bispecific, we have 10 different Phase III studies. That's not going to contribute a whole lot before 2030. That's sort of the post-2030.

Same with the hematology portfolio, whether it's 0120. So there is a lot in sort of the post-2030 time frame. But those investments we're making today and those readouts may happen in '27, '28, '29, but real revenue contribution won't be until post-2030. And that's why we continue to make all these investments and have a high investment in R&D.

Perfect. Aradhana, David, thanks very much. Thanks, everyone.

Good afternoon, and welcome to AstraZeneca's 9 months and Q3 2025 webinar for investors and analysts. Before I hand over to AstraZeneca, I'd like to read the Safe Harbor Statement.

The company intends to utilize the Safe Harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Participants on this call may make forward-looking statements with respect to the operations and financial performance of AstraZeneca.

Although we believe our expectations are based on reasonable assumptions, by their very nature, forward-looking statements involve risks and uncertainties and may be influenced by factors that could cause actual results to differ materially from those expressed or implied by these forward-looking statements. Any forward-looking statements made on this call reflect the knowledge and information available at the time of this call. The company undertakes no obligation to update forward-looking statements.

Please carefully review the forward-looking statements disclaimer in the slide deck that accompanies this presentation and webcast.

There will be an opportunity to ask questions after today's presentation. [Operator Instructions]

And with that, I'd now like to hand the conference over to the Head of Investor Relations at AstraZeneca, Andy Barnett.

A very warm welcome to AstraZeneca's Year-to-Date and Third Quarter 2025 Presentation, Conference Call and Webcast for Investors and Analysts.

I'm Andy Barnett, Head of Investor Relations. And before I hand over to Pascal and other members of our executive team, I'd like to cover some important housekeeping items.

Firstly, all of the materials presented today are already available on our AstraZeneca Investor Relations website.

Next slide, please. This slide contains our cautionary statements regarding forward-looking statements, including the safe harbor provision, which I'd encourage you to take the time to read carefully. We will be making comments on our performance using constant exchange rates, or CER, core financial numbers and other non-GAAP measures.

A non-GAAP to GAAP reconciliation is as usual, contained within our results announcement. All numbers quoted are in millions of U.S. dollars unless otherwise stated.

And next slide, please. This slide shows the agenda for today's call. And following our prepared remarks, we'll open the line for questions. As usual, we will try and cover as many questions as we can during the allotted time, although please limit the number of questions that you asked to allow others a fair chance to participate in the Q&A.

And with that, please advance to the next slide, and I will hand over to Pascal.

Thank you, Andy, and welcome, everyone. I'm pleased to report that our strong growth momentum and pipeline delivery have continued through the first 9 months of 2025.

Total revenue grew by 11%, driven by continued demand for our innovative medicines and core EPS increased by 15%. Since our full year results in February, we've achieved 31 regulatory approvals across key regions and the pace at which we are bringing new medicines to patients continues to accelerate.

Importantly, we've announced positive results from 16 Phase III trials and 6 of our data sets were presented in plenary sessions at major conferences, a clear reflection of the importance of this data to the medical community.

Please advance to the next slide. Combined, our global reach and diverse sources of revenue have a significant strength, ensuring low concentration risk and resilience to regional disruptions.

We have continued to deliver strong growth across therapy areas and geographies. In the first 9 months, our oncology franchise grew by 16%, reflecting the ongoing demand for our medicines across the globe.

Our Biopharmaceuticals and Rare Disease franchises were also up 8% and 6%, respectively, with strong growth from our newer medicines more than offsetting the loss of exclusivity of a limited number of mature brands, including Brilinta, Pulmicort and Soliris.

Importantly, we continue to see robust growth across all key geographies, particularly in the U.S. and the emerging markets outside of China, where revenues were up 11% and 21%, respectively.

Please move to the next slide. We are in a unique catalyst rich period, one that I'm excited to say, look set to continue well beyond 2026.

Shown here are the high-value positive studies we've announced in 2025. And as you can see, we are delivering success across all of our key therapy areas. Since our last quarterly update, we've announced four additional positive Phase III study readouts. DESTINY-Breast05 together with DESTINY-Breast11 that read out earlier this year marks an important advance for patients with early HER2-positive breast cancer that could potentially benefit from a HER2.

TROPION-Breast02 has the potential to establish Datroway as a new standard of care in triple-negative breast cancer. The Bax24 trial results reinforce the best-in-class profile of baxdrostat in treatment-resistant hypertension.

And finally, TULIP-Subcu will enable us to bring a more convenient subcutaneous administration of Saphnelo to SLE patients. All these positive Phase III readouts continue to give us confidence towards our $80 billion 2030 ambition.

Next slide, please. I'd like to address recent developments for AstraZeneca in the United States. The U.S. remains our largest market and is projected to account for around 50% of our total revenue by 2030. We announced a landmark agreement with the U.S. government which provides greater clarity around pricing and a 3-year exemption from tariffs. The agreement will lower the cost of many prescription medicines for American patients, while safeguarding Americas cutting-edge Biophamaceutical innovation.

With the administration support, we are now working with others to deliver price equalization across wealthier markets, an approach that offers a more sustainable future for governments, industry and patients. In addition, we continue to focus on clinical trial diversity and further enhancing our clinical trial footprint in the U.S.

To support our growth ambitions, we've been steadily expanding our global manufacturing capacity including broadening our U.S. footprint over the last several years. Last month, I was pleased to break ground on our new Virginia facility joined by Senator, Lutnick; Governor, Youngkin; and Dr. Ross.

And lastly, I'm grateful for our shareholders to voting through our proposal to harmonize our listing structure in London, Stockholm and New York.

AstraZeneca ordinary shares will be listed on the New York Stock Exchange from February next year. This new listing structure will offer flexibility to access the broadest available pool of capital, including in the U.S. and enable more shareholders to participate in AstraZeneca's exciting future.

And with that, please advance to the next slide, and I will hand over to Aradhana.

Thank you, Pascal, and good morning, good afternoon, everyone. As usual, I will start with the reported P&L.

Next slide, please. Total revenue increased by 11% in the first 9 months. Product sales grew by 9% with strong growth seen across the business in key regions. Alliance revenue increased by 41%, driven by continued growth for both Enhertu and Tezspire in regions where our partners book product sales.

Next slide, please. This is our core P&L. Our core gross margin in the first 9 months was 83%. We continue to anticipate a slight decrease in the core gross margin for the full year versus 2024, due to the Medicare Part D reform, Brilinta LOE, Soliris biosimilars and increased profit sharing from partnered products.

Similar to prior years, we anticipate the core gross margin in the fourth quarter to be lower than in the third quarter, driven by the usual seasonal pattern with more sales from lower-margin products like FluMist and Beyfortus.

R&D expenses increased by 16% in the first 9 months, driven by sustained high activity, including many clinical trials having enrolled ahead of plan. We've also made significant investments in high-value pipeline opportunities, such as our I/O bispecifics, weight management and cell therapy portfolios. As a percentage of total revenue, core R&D costs accounted for 23.3%, and we continue to expect R&D to land at the upper end of the low 20s percentage range for the full year.

We have continued to make progress towards our 2026 margin goal and remain on track, as you can see from our 9-month results with core operating margin at 33.3%. Operating leverage continues to remain a focus internally. And again, as you can see from the first 9 months, product revenue grew at 11% and SG&A grew at 3%. Core EPS of $7.04 represents CER growth of 15%.

Next slide, please. We have seen strong cash flow inflow from operating activities in the year-to-date, up by 37% versus the prior year to $12.2 billion, driven by robust underlying business momentum. In the year-to-date, we saw CapEx of $2.1 billion. And as previously stated, we anticipate an increase of around 50% for the full year versus 2024, which implies a step-up in the fourth quarter which also is normal as in prior years.

Our capital allocation priorities remain unchanged. We currently have interest-bearing debt of close to $33 billion, which is a level we're comfortable with as we plan to continue making investments to support future growth, build our supply chain globally and further strengthen our R&D pipeline. Our net debt-to-EBITDA ratio currently stands at 1.2x.

Turning to guidance. Today, we are reiterating our full year guidance with total revenue and core EPS anticipated to increase by high single-digit and low double-digit percentage, respectively, at constant exchange rates. We expect our strong revenue momentum in growth brands to continue.

I would like to remind you that in the fourth quarter of 2024, we booked more than $800 million in sales-based milestones under collaboration revenue. This year, we do not anticipate any significant milestone revenue in the fourth quarter, which will affect the year-over-year growth rate comparisons for the fourth quarter.

In addition, in China, while growth has been strong throughout the year, fourth quarter revenues are anticipated to be affected by VBP-associated stock compensation costs for Farxiga, Lynparza and Roxadustat and the usual year-end hospital budget capping, in addition to tender order variability in emerging markets.

Similar to prior years, we also anticipate a sequential step-up in both R&D and SG&A expenses in the fourth quarter versus the third quarter.

With that, please advance to the next slide, and I will hand over to Dave, who will take you through the incredible performance of our oncology and hematology business.

Thank you, Aradhana. Next slide, please. Oncology total revenue grew 16% in the first 9 months to $18.6 billion with broad-based double-digit growth across U.S., Europe and emerging markets. The U.S., in particular, continued to report strong year-over-year growth of 19%, highlighting robust demand for our medicines, which substantially outpaced the increased liabilities resulting from Medicare Part D redesign.

Emerging markets also delivered impressive performance with 20% growth during the period. Focusing on third quarter performance, we achieved robust 18% growth for the second quarter in a row.

Tagrisso delivered sales of $1.9 billion in the third quarter, representing 10% growth on the prior year. Widespread demand across all major regions reinforces Tagrisso's role as the backbone of care for EGFR-mutated lung cancer. The first-line lung cancer combination market continues to expand with FLAURA2, the clear leader, in terms of new patient starts and total scripts. The compelling overall survival results presented at the World Congress of Lung Cancer and subsequently published in the New England Journal of Medicine will drive further leadership.

Calquence remains the leading BTK inhibitor in first-line CLL across major markets, with total revenues increasing by 11% to $916 million in the third quarter. In the U.S., we continue to see increased demand more than offset the impact of Part D redesign with improved market share versus the same period last year. We're seeing positive early signs of adoption for AMPLIFY in Europe and expect this trajectory to continue through the remainder of the year with the U.S. launch anticipated in the first half of 2026.

Lynparza, which remains the leading PARP inhibitor globally delivered revenues of $837 million in the third quarter, up 5% year-on-year with consistent growth across key regions.

Truqap total revenues of $193 million in the third quarter represented 54% growth versus Q3 last year. With the AKT/PTEN biomarker altered population almost fully penetrated, growth is now primarily driven by increased uptake of the PIK3CA population and ongoing launches in developed and emerging markets.

This was another outstanding quarter for our I/O franchise with growth of Imfinzi and Imjudo of 31% and 14%, respectively. We see continued enthusiasm for Imfinzi in the new lung indications, ADRIATIC and AEGEAN and in bladder cancer with NIAGARA, alongside further expansion in our more established indications such as HIMALAYA and CASPIAN.

We are also starting to see early signs of adoption of MATTERHORN in the U.S. following its Category 1 NCCN guideline inclusion and eagerly await regulatory decisions.

Enhertu total revenues grew 39% in the third quarter with ongoing launches of the DESTINY-Breast06 indication, further strengthening our leadership position in HER2-low metastatic breast cancer. The strong initial uptake in China following NRDL enlistment has persisted through Q3 as we achieve even broader coverage and continue to drive adoption.

Positive readouts across HER2-positive breast cancer at ASCO and ESMO are anticipated to further drive growth with data now spanning across the spectrum of HER2-positive disease.

And finally, Datroway continues to make inroads in hormone receptor positive breast cancer across the U.S. and Europe. And this quarter, we have started to see encouraging early signals of uptake in the previously treated EGFR-mutated lung cancer space following U.S. approval and NCCN guideline inclusion.

We are confident in carrying our strong performance from the first 9 months through to year-end as we continue to expand the reach of our innovative medicines.

With that, please advance to the next slide, and I'll pass over to Susan to cover key R&D highlights from the quarter.

Thank you, Dave. Just over 2 weeks ago at the European Society of Medical Oncology, AstraZeneca delivered multiple pivotal data sets with the potential to reshape clinical practice, including two featured in presidential sessions. This underscores the quality and breadth of our science and reinforces AstraZeneca's leadership in bringing new advances to patients worldwide.

DESTINY-Breast11 and 05 advanced Enhertu into the early treatment setting for HER2-positive breast cancer, highlighting its potential to become a foundational therapy in early disease and ultimately increasing the likelihood that more patients could be cured of breast cancer.

In DESTINY-Breast11, treatment with Enhertu followed by THP prior to surgery resulted in a pathologic complete response rate of 67% in patients with high-risk HER2-positive early-stage breast cancer, the highest ever reported rate in the Phase III registrational trial in this setting.

We also saw an early trend towards an event-free survival benefit with Enhertu followed by THP. Importantly, this regimen demonstrated a favorable safety profile versus the 5-drug AC-THP regimen with lower rates of Grade 3 or higher adverse events, serious adverse events and treatment interruptions.

This makes DESTINY-Breast11 the first regimen in over a decade to significantly improve outcomes in the earliest treatment setting for HER2-positive breast cancer, and these data are now under FDA review.

In DESTINY-Breast05, Enhertu reduced the risk of disease recurrence or death by 53% compared to T-DM1 in patients with high-risk HER2-positive early breast cancer following neoadjuvant therapy, with over 92% of patients treated with Enhertu free of invasive disease at 3 years. This data set offers a critical second opportunity to reduce recurrence risk in this patient population.

Taken together, DESTINY-Breast11 and 05 have the potential to transform early-stage HER2-positive breast cancer by reducing metastatic recurrence and bringing patients closer to cure. And this represents a blockbuster opportunity across the alliance.

We also shared data from the TROPION-Breast02 trial, which evaluated Datroway versus chemotherapy as a first-line treatment for patients with locally recurrent inoperable or metastatic triple-negative breast cancer for whom immunotherapy is not an option. These patients typically have poor outcomes with the current standard of care and 5-year overall survival rates of just 15%.

TB02 included those with the poorest prognosis often excluded from clinical trials, such as patients with a short disease-free interval and those presenting with brain metastases at baseline. In TB02, Datroway delivered an unprecedented 5-month improvement in median overall survival versus chemotherapy, along with a statistically significant and clinically meaningful 43% reduction in the risk of disease progression or death.

In addition, almost 2/3 of patients experienced a complete or partial response to Datroway, double the rate seen with chemotherapy, alongside a manageable safety profile, low rates of discontinuation and no treatment-related deaths. These data clearly differentiate Datroway and together with its convenient 3-weekly dosing, position it to reshape the TNBC landscape for the 70% of first-line patients who are not suitable for immune checkpoint inhibitors.

Our other key Phase III readout at ESMO was POTOMAC. This trial moves Imfinzi into earlier-stage bladder cancer, demonstrating that adding 1 year of Imfinzi to BCG induction and maintenance therapy delivers both early and sustained disease-free survival benefits with a 32% reduction in risk of recurrence or death compared to BCG alone in high-risk non-muscle invasive bladder cancer.

With this Imfinzi regimen, 87% of patients remained alive and disease-free at 2 years, highlighting its potential to change the trajectory for these patients and further building on Imfinzi's impact in muscle-invasive disease as shown in NIAGARA.

These results reinforce the strength of our bladder program, and we very much look forward to data from the VOLGA trial in cisplatin-ineligible muscle invasive bladder cancer, which is now expected in the first half of next year.

In addition, we presented Phase III data from CAPItello-281 for Truqap in combination with abiraterone and androgen deprivation therapy in PTEN-deficient metastatic hormone-sensitive prostate cancer.

Taken together, these pivotal data sets strongly support our strategy to advance novel therapies into earlier-stage disease, where they have the greatest potential to improve patients' lives.

We also presented significant new data at ESMO across our early programs, including first-in-human results for our folate receptor alpha ADC, AZD5335 or torvusam, in platinum-resistant relapsed ovarian cancer.

New data for our PARP1 selective inhibitor, saruparib, in combination with androgen receptor pathway inhibitors in metastatic prostate cancer, updated findings for rilvegostomig in checkpoint inhibitor naive lung cancer, which compares favorably to current PD-1-based therapies and encouraging new results for the combination of rilvegostomig and Datroway in bladder cancer. All these results build our confidence in the long-term strength of our pipeline, positioning us to deliver innovation well beyond 2030.

Before closing, I want to highlight the upcoming American Society of Hematology Meeting in December, where we will present updates of our CD19/CD3 T-cell engager, surovatamig, and our CD19 BCMA dual CAR-T AZD0120. These pipeline assets both have $5 billion-plus non-risk-adjusted peak year revenue potential, and we will build our position in hematologic malignancies with the opportunity to set new standards across this space.

And with that, please advance to the next slide, and I'll pass over to Ruud to cover Biopharmaceuticals performance.

Thank you so much, Susan. Next slide, please. Our Biopharmaceuticals medicines delivered a strong performance in the year-to-date with total revenue reaching $17.1 billion, reflecting growth of 8%.

Starting with R&I, we saw growth of 40% in the quarter, driven by strong performances across our inhaled and biologic portfolio. The growth medicines now constitute over 60% of the therapy area's revenue and have grown at an impressive rate of 30% year-to-date.

Our products now make up half the new-to-brand prescriptions for the severe asthma biologics segment in several markets. Fasenra continues to lead in eosinophilic asthma. We were pleased to see growth accelerating to 20% in the quarter with Fasenra's product profile being strengthened by uptake in EGPA and our first revenues from China.

Tezspire continued its rapid market share gains in severe asthma with 47% growth in the quarter. Its growth potential has been further enhanced by recent approvals in the United States and the EU for chronic rhinosinusitis with nasal polyps based on the WAYPOINT trial, which demonstrated a significant reduction in nasal polyp size and nearly eliminated the need for surgery.

Breztri grew at 20%, driven by market share gains in the growing triple class. All revenues today come from COPD patients, and we have now filed regulatory submissions for asthma in all major regions following the positive readouts from the KALOS and LOGOS trials.

We are pleased to receive a positive CHMP recommendation for our next-generation propellant, which has 99.9% lower global warming potential, a key milestone towards our company's sustainability goals. Breztri will be the first of our inhaled medicines to transition to the next-generation propellant.

Saphnelo, our biologic medicine for SLE, continues to win share in the intravenous segment of the market and grew at 44% in the quarter. In September, we announced positive high-level results based on the interim analysis from the TULIP subcutaneous study, which paves the way for Saphnelo to reach SLE patients who prefer a subcutaneous option. TULIP-SC recently received a positive CHMP recommendation in the EU.

Total revenue from the CVRM therapy area was flat in the quarter, reflecting the loss of exclusivity for Brilinta, which saw a revenue decline of 56%. Farxiga delivered 8% growth despite a slight decline in Europe due to the earlier-than-expected entry of generic competition in the United Kingdom. Lokelma grew 30%, maintaining its leading share in the potassium binder class for chronic kidney disease and heart failure patients. In anticipation of further growth for Lokelma, we were excited to have recently opened an expanded manufacturing facility in Texas.

In addition to the strong product performances in the year-to-date, I'm also particularly excited to see the number of high-value biopharma trials due to readout in 2026.

And with that, I will now hand over to Sharon to discuss the latest developments for baxdrostat, the next NME we anticipate to launch in biopharma with more than $5 billion peak year revenue potential.

Thank you, Ruud. Next slide, please. At AstraZeneca, our ambition is to transform care across interconnected cardiorenal and metabolic diseases where multiple risk drivers and organ systems overlap. Hypertension is a key part of this challenge. And in the past 20 years, there has been very limited innovation.

For example, around half of patients currently treated in the U.S. remain uncontrolled while on multiple medicines. Baxdrostat is designed precisely for these patients. As a reminder, baxdrostat is a once-daily, highly selective and potent aldosterone synthase inhibitor, targeting the aldosterone pathway at its source. Excess aldosterone is well established as a driver of hypertension and broader cardiorenal disease. By limiting aldosterone production, baxdrostat provides a clean targeted mechanism that has the potential to enable more patients to reach their treatment goals, particularly those with uncontrolled or resistant hypertension.

In the third quarter, we presented the first Phase III data for baxdrostat monotherapy with the BaxHTN trial at the European Society of Cardiology. We were also delighted to report the positive high-level results for the Phase III Bax24 trial. Collectively, these readouts reinforce our confidence in baxdrostat's more than $5 billion potential as a franchise.

In the BaxHTN trial for patients with uncontrolled and treatment-resistant hypertension on maximally tolerated background therapy, baxdrostat delivered the largest systolic blood pressure reduction reported in a primary analysis to date. At 12 weeks, placebo-adjusted reductions were 8.7 and 9.8 millimeters of mercury on the 1 and 2 milligram doses, respectively. Responses were highly consistent across prespecified subgroups, and we saw a powerful target engagement with a 60% to 65% reduction in serum aldosterone at week 12. Importantly, this reduction was sustained over time.

Furthermore, in the randomized withdrawal period, patients continuing baxdrostat saw further reductions in blood pressure out to 32 weeks. Baxdrostat also demonstrated a favorable tolerability profile. Adverse events were mostly mild with no off-target hormonal effects and no clinically relevant drug-drug interactions observed.

Confirmed hyperkalemia above 6 millimole per liter was 1.1% in both dose arms, and we saw low discontinuation rates of 0.8% and 1.5% for the 1- and 2-milligram doses, respectively. 24-hour control of hypertension matters clinically. Early morning blood pressure variability is strongly correlated to the risk of cardiovascular events. So sustained control of blood pressure between doses is important.

Baxdrostat's long half-life is a key differentiator. In an ambulatory sub-study of BaxHTN, we saw substantial reductions in 24-hour average and night-time systolic blood pressure. Building on this, we recently reported positive high-level results from the Phase III Bax24 trial, which was conducted in the most difficult-to-treat patients, those with resistant hypertension.

In Bax24, baxdrostat demonstrated a statistically significant and highly clinically meaningful reduction in ambulatory 24-hour average systolic blood pressure. Efficacy was observed across the entire 24-hour period, including early morning.

We look forward to sharing you exciting data with the medical community at the American Heart Association this coming weekend. These results solidify baxdrostat's potential as a first and best-in-class option for patients with uncontrolled and resistant hypertension, offering convenient once-a-day dosing with sustained blood pressure control around the clock. We are advancing our regulatory filings and rapidly progressing our robust clinical development program for baxdrostat, both as a monotherapy and in combination with dapagliflozin.

And with that, please proceed to the next slide, and I'll pass over to Marc to cover Rare Disease.

Thank you, Sharon. Can I get the next slide, please? Rare Disease medicine grew 6% to $6.8 billion in the first 9 months of the year, driven by growth in neurology indications, increased patient demand and continued global expansion.

In the third quarter, Ultomiris grew 17%, driven by patient demand growth across indication, including the competitive MG and PNH markets.

Soliris revenues continues to decline due to the successful conversion to Ultomiris as well as biosimilar pressure in Europe.

Strensiq grew 28% and Koselugo grew by 79%, respectively, due to strong underlying demand for these medicines. Koselugo's growth also benefited from some tender orders in emerging markets. We continue to see great momentum across the rare disease portfolio with recent approval for Koselugo and Ultomiris that further our geographic reach for this medicine.

Please advance to the next slide. We presented data from our Phase III PREVAIL trial, investigating gefurulimab on our dual branding nanobody targeting C5 in patients with generalised myasthenia gravis.

Gefurulimab demonstrated 1.6 point improvement from baseline, placebo adjusted in myasthenia gravis activities of the living total score at week 26. The MG-ADL total score change from baseline reached 4.2 points at week 26 in the gefurulimab-treated patients.

A clinically meaningful improvement in MG-ADL total score was observed as early as week 1 and was sustained through week 26. Gefurulimab demonstrated rapid, complete and sustained complement inhibition. Gefurulimab also met all secondary endpoints, including quantitative myasthenia gravis total score, where gefurulimab demonstrated a 2.1 point improvement at week 26 compared to placebo.

A pre-specified measurement at week 4 also made statistical significance, again demonstrating the rapid onset of action of gefurulimab in patient with gMG. The PREVAIL trial was conducted in a broader gMG patient population compared with prior trials of C5-targeted therapies.

Gefurulimab is a convenient, self-administered subcutaneous once-a-week treatment with the potential for two delivery option, a pre-filled syringe and auto-injector, which would be the first in gMG. We believe that the strength of this data and convenient administration, gefurulimab has a potential to become a new first-line therapy following immunosuppressive therapies.

I also wanted to update on other important Phase III data we had this year. Analysis of the 52 weeks results on the CALYPSO trial to further characterize eneboparatide are ongoing. We will continue monitoring these patients in the open-label extension.

For anselamimab, we have shared clinical results from the Phase III CARES program with regulatory authorities. Following further discussion, we plan to submit for the pre-specified patient subgroup in which anselamimab demonstrated a highly significant improvement in both time-to-all-cause mortality and frequency of cardiovascular hospitalization compared to placebo.

And finally, efzimfotase alfa, we expect to announce results from all Phase III studies, HICKORY, CHESTNUT and MULBERRY in the first half of next year. Together, these three trials cover patients across pediatric, adolescent and adult hypophosphatasia population.

And with that, please advance to the next slide, and I will hand over to Pascal.

Thank you, Marc. Next slide, please. As I mentioned at the start of this call, we are in the midst of an unprecedented catalyst switch period, one which is anticipated to extend through 2026 and beyond. We look forward to exciting readouts in each of our key therapy areas in 2026, which on a combined basis represent a risk -- sorry, risk-adjusted peak year revenue opportunity of more than $10 billion.

Our exceptional performance for the first 9 months so has delivered a core operating margin of 33.3%. This is a clear demonstration that despite the opportunities to invest in this rich pipeline, we remain committed to driving operating leverage and we remain on track for both our 2026 margin target of mid-30s and our $80 billion 2030 revenue ambition.

Next slide, please. In closing, I'm very pleased to report that we are making exciting progress across our transformative technologies, which have the potential to drive AstraZeneca's growth well beyond 2030.

We are moving at pace with our oral PCSK9 inhibitor, laroprovstat. And now we have three Phase III trials ongoing, and we are looking forward to the results from our Phase II trials across our weight management portfolio next year.

We're driving forward with our ADC and our radioconjugate portfolio with the first Phase III of our wholly owned ADC sone-vedo reading in the first half of next year. Supporting our ambition to replace current immune checkpoint inhibitors with next generation bispecifics, we now have 14 Phase III trials underway for rilvegostomig and volrustomig.

And we are continuing to strengthen our hematology portfolio with our first Phase III trial already underway for our CD19 CD3 T-cell engager surovatamig, and we are planning to advance CD9, BCMA, CAR-T, AZD0120 into Phase III next year.

And lastly, our first gene therapy is now entering the clinic. And with that, please advance to the next slide, and we will move to the Q&A.

As Andy mentioned at the start of the call, please limit the number of questions you ask to allow others a fair chance to participate. For those online, please use the raise hand function on Zoom, and with that, let's move to the first question.

Our first question is from Michael Leuchten at Jefferies. Over to you, Michael.

Two questions for you, please. One, thank you for the comments around the environment in Washington. Just wondering if you could comment on what is the risk of residual activity coming from the administration? How confident are you that the deal that AstraZeneca has managed to secure removes enough of the overhang? So, we don't have to look over our shoulders constantly as we think about R&D productivity and the cost of innovation.

And the second question for you, Pascal, the $10 billion number that you just mentioned in terms of the catalyst potential coming out of the '27/'28 period, is that part of the $80 billion? Or is that incremental potential already on top of that?

So, the first question, what I would say about this is that we have addressed the four points in the President's letter. And the four points, as you know, they covered Medicaid, they cover prospective equalization, direct to consumer and also returning to the U.S. government, some of the potential price increases for existing products. And so, we've covered all of this.

So, now our expectation is that essentially, we have an agreement with the U.S. government, and we don't expect anything more to come. But of course, we are not the government, so we cannot guarantee anything. We can only say that our expectation from the discussions we've had, our expectation is that this agreement is delivering what the President was looking to achieve.

On the $10 billion, this is part of our $80 billion. This is, by the way, not a 2030 number. It's a peak year revenue number. It's a risk adjusted $10 billion. But certainly, it will contribute to achieving our 2030 ambition. There is more to come.

We have a number of readouts next year and we expect from the readouts to expect another $10 billion -- actually $11 billion of risk-adjusted sales to come out of these readouts, assuming, of course, they are positive, we could get even more. So, as I said before, it is quite unprecedented for us as a company to have such a rich series of readout across not only oncology but also hematology, cardiovascular disease, respiratory disease, immunology, rare disease. So really, I would say, the company is firing from all engines in terms of our ability to innovate and come up with new products.

So with this, I'll move to Sarita Kapila at Morgan Stanley.

Sarita, over to you.

Thanks for taking my questions and the comments on 2026 margins. Perhaps you could indicate your level of comfort on where 2026 consensus sits at the low end at 34% and talk about the step-up to get there? And then more broadly, could you speak about the pushes and pulls, please, on 2026 margin?

And then secondly, there's been a lot of investor focus on the Roche persevERA trial coming in Q1 '26, which is looking at duradestrant in all-comer breast cancer. Could you talk about the potential read across to camizestrant? Are there any notable differences between the molecules or any differences in the trial design that could increase chances of SERENA for success versus persevERA and why it may not be a good read?

Thank you, Sarita. So, it's really three great questions. The first two, Aradhana, can you cover, and Susan with -- can you pick up the persevERA question and Ruud to camizestrant?

Sure. Thanks, Sarita. Though as you've seen, we've had very strong momentum in all our growth brands. And with this momentum going into the year-end, we hope it continues and expect it to continue in all markets and all brands.

The key headwind in 2026 will really be the loss of Farxiga in both U.S. as well as China. And that's something that we had anticipated and are obviously planning around. We're right now going through our budget process, and we'll take all these different pushes and pulls as well as the recent agreement with the U.S. government and all those impacts into account. As we set our budget, we will continue to invest behind growth brands and plan for new launches such as baxdrostat, cami and dato.

And given all the portfolio, I think we'll continue to invest in R&D towards the high end of the 20% given all the progress in the ADC and the cardiovascular and weight management portfolio. So, those are some of the pushes and pulls. And you've seen the performance and the continuous margin progression as well as the SG&A, which we have maintained very strong leverage over and R&D, obviously, is where we always find great opportunities. So, while we remain disciplined, we're going to continue investing behind that.

Just before Susan covers the next point. I think, Aradhana covered really very well. Our view of 2026 one, maybe a piece I wanted to add is that, some people may be wondering about the impact of the agreement with the U.S. government. What I would say on this is that, Aradhana covered it, we have a very broad portfolio geographically and also a broad portfolio of new products, new launches, and we think we can absorb the impact of this agreement. We're confident we can absorb it in '26 and beyond and really doesn't affect our 2030 ambition and doesn't affect our midterm ambition.

So, over to you, Susan with persevERA.

Thanks, Pascal. So just as a reminder, camizestrant with the data that we showed in both the SERENA-2 study and then with the recent SERENA-6 study in first-line, has really shown the best profile of all of the oral SERDs that have reported so far. We've had the best hazard ratio versus fulvestrant in both the ESR mutant as well as in the wild type.

But the fundamental point is, as you move from second line to first line, there's an increase in the endocrine sensitive part of the population. So, for those wild-type patients, they can still be expected to benefit because what you're doing is, you're inhibiting both the transcriptional signal downstream of the estrogen receptor regardless of whether it's wild type or mutated.

And you're also reducing the amount of that receptor through degradation to very low levels, and we showed that in the SERENA-3 study. So, both those mechanisms of action are expected to be superior to the aromatase inhibitor component of current first-line backbone therapy.

In terms of cost comparisons, I would point out that the SERENA-4 study is a larger study than persevERA. And we've designed it to enrich for patients that have got endocrine sensitive profile based on the clinical inclusion/exclusion criteria. So, we've designed it taking into account what we've previously learned and including from trials such as persevERA, et cetera, to optimize for the opportunity for success in that first-line setting.

Thank you, Susan. So the next question is Justin Smith at Bernstein. Over to you, Justin.

Just a couple on Wainua for Sharon or Ruud. Just firstly on CARDIO-TTRansform. Just your thoughts on whether that could meaningfully reshape treatment guidelines long term? And then also just your thoughts on whether any new simpler diagnostic tests are coming soon to potentially expand the cardiomyopathy population?

So Sharon, do you want to cover and Ruud if you have anything to add please jump in.

Sure. So, we look forward to the readout of the Phase III CARDIO-TTRansform study in 2026. Do we have the potential to meaningfully transform that treatment algorithm for patients? I think what we're able to demonstrate with the CARDIO-TTRansform study is both the role of silencers in adequately treating disease and in a planned subset, key secondary endpoint readout will be looking at the effect of eplontersen in patients who have tafamidis.

And so that will give us the opportunity to be able to address that key question for patients comparing the effect of silencer plus stabilizer versus silencer, which I think will be very important in guiding patient treatment decisions.

And then finally, AstraZeneca is in a unique position in developing new therapies for patients living with ATTR amyloidosis and that we also have Alexion 2220, the amyloidosis depleter in our portfolio. And we continue to work towards creating a combination approach of a depleter and a silencer, which we think could be truly pivotal for patients living with ATTR amyloidosis.

Now with regards to diagnosis, we know that's a key part of the patient journey. And we know that this is not simply a hereditary disease. The hereditary variants are rare, but the disease is not. This is also a disease of the aging. So, being able to screen for and detect patients earlier in their disease progression will be really fundamental to offering patients improved outcomes.

So to that end, we are exploring a number of different opportunities to be able to more accurately and earlier diagnose ATTR amyloidosis. And those include AI-informed models that allow us to identify patients on screening with echocardiogram or potentially EKG as well as developing new biomarker assays to be able to detect soluble amyloid. So, we continue to work on all fronts to be able to drive both earlier detection and earlier treatment.

Thanks, Sharon. Ruud, anything you wanted to add or?

No. Just like everyone, everyone is eagerly waiting for the results. What hasn't mentioned yet by Sharon is that, this is the largest CM trial so far in ATTR cardiomyopathy. And if successful, hopefully, we will see a CV mortality benefit, which, of course, is extremely important for treating cardiologists. Now on top of that, we are very pleased to see, let's say, the progress we are making in the first indication, the PN indication. So we can only hope for patients and also for the company and other interested that the ATTR-CM trial will be positive, and we will know that in the course of 2026.

Sachin Jain, Bank of America.

I've got one each for Sharon and Susan on Phase III starts you've each referenced. So for Sharon, I wonder if you could just remind us of the obesity portfolio, the oral and amylin as we look for Phase II data next year. How are you thinking about your target competitive profile given the competitive landscape has rapidly changed? Obviously, with oral, we've seen the ortho data since you last presented. And with amylin, we've had the Lilly data out today.

And then for Susan, I think you referenced the Phase III start for the BCMA CAR-T, where we see data at ASH and $5 billion peak. Just looking at the abstract, it looks like you've got 100% MRD negativity in almost fourth-line patients. So just wondering how you're thinking about the fastest route to market for that and beyond efficacy, how you're seeing differentiation on safety and administration.

Thank you. Sharon, do you want to start? And then Susan?

Sure. So Sachin, as you know, we are moving forward with multiple molecules in our weight management portfolio. That is AZD5004 that's currently in Phase II for patients with obesity and type 2 diabetes. AZD6234, that's our long-acting amylin peptide, subcutaneous injectable that is also in Phase II for the same patient populations. And ACD9550, and that's our dual GLP-1 glucagon receptor agonist, also subcutaneous injectable also in Phase II.

As we move all three of these forward at pace, of course, we're looking to have highly competitive molecules that give us reason to believe that these could be valuable treatment options for patients.

As we move forward, we're also thinking about the potential for market segmentation, and we know that there will be room for multiple mechanisms. And the bar is high. We've seen the very interesting data from Eloralintide today. And so that gives us more reason to believe that a selective amylin receptor agonist similar to 6234 has the potential for efficacy in terms of weight loss and better sugar control for patients with type 2 diabetes.

So, we have seen no red flags to date and continue to move forward at pace and expect to enter Phase III pending competitive data and we will be making those decisions in 2026.

So, in terms of the 0120, which is the CD19 BCMA dual CAR, thanks for the question, Sachin. We will be presenting data in the later-line patient population at ASH. This includes patients who are triple-class refractory and a substantial proportion that have had prior BCMA CAR-T therapy. So, what the data show is that, we do have a really impressive response rates and complete response rates in evaluable patients that are also progressing, and they tend to evolve over time. There's a relatively small number of patients that are currently MRD evaluable, but you rightly point out in that small number in the abstract, all of them have achieved MRD negativity.

The overall profile of this cell is as dosed is attractive. We have no Grade 3 CRS and no ICANS in the dataset that we've presented in the abstract. And I think the -- both the efficacy and the safety profile is related in part to the FasTCAR manufacturing, which Gracell had developed, which is helping to deliver this predictable CRS profile and deep and early responses. So, we're very excited about the prospects for this. And we want to reiterate that we're going to start Phase III trials for this next year. And again, we'll be taking this forward in multiple settings, in multiple myeloma.

Thank you, Susan. The next question is from Richard Vosser at JPM.

Two questions, please. Firstly, one, just following up on the TB02 Datroway data at ESMO. Maybe you could talk about the read across. From the better tolerability you showed relative to competing products there, both to your Datroway trials, but also more importantly, across the other ADC programs, what can we learn from that?

And then secondly, maybe a more commercial rollout question. Just the Imfinzi or Imfinzi sales were very, very strong this quarter. I wonder if you could give a little bit more color on the rollouts. You highlighted bladder and lung, but how should we think about the runway of growth from here for Imfinzi?

Susan, do you want to cover the first one? And David, the Imfinzi rollouts question?

Sure. Thanks for the question. So yes, we're delighted with the TROPION-Breast02 data that was presented at ESMO. And I think this does speak to the actual design of this ADC, which similar to the Enhertu design, is based on linker stability. So it's really important to have linker stability so that you're actually delivering a higher proportion of the payload actually to the tumor cells and less exposure in the peripheral circulation. That drives the difference in terms of the bone marrow toxicity profile that you see with Datroway compared to some other TROP2-based ADCs.

And I think that also speaks to the fact that we then delivered a higher response rate, longer progression-free survival and this 5-month improvement in overall survival, which I think is a differentiated profile.

So that -- first of all, within the breast cancer space, it increases the confidence in the early-stage studies, the TROPION-Breast03, which is in the post neoadjuvant setting, a little bit analogous to the DESTINY-Breast05 setting.

And that's in combination, of course, with Imfinzi, the TROPION-Breast04 setting, which is in the neoadjuvant treatment of PD-L1 negative breast cancer and then TROPION-Breast05, which takes that double-up combination of Datroway and Imfinzi also into the first-line setting.

So with those studies, plus, of course, the lung cancer studies, the AVANZAR studies, I think the profile that we've got is one that we're confident about, and we look forward to having the future readouts in the coming months and years.

Thanks, Susan. With respect to the Imfinzi growth drivers in '25 and outlook moving forward, I think it has really been a great example of delivery against multiple new life cycle expansion opportunities. The primary growth drivers have been with Adriatic and small cell, AEGEAN in early lung cancer and then also NIAGARA has also been an important area of growth.

All three of those represent opportunities for us to continue to see full year benefits across the globe as we launch those.

Now, there is competitive pressures that we face on all of those. With that said, our differentiation, I think, is strong and our first-mover advantage is clear. I would also just point out that very importantly, we've got positive studies with MATTERHORN, with strong overall survival that was presented at ESMO. We've got POTOMAC. Those are both studies that we are looking forward to hopefully achieving regulatory approvals across the globe. And there will be further readouts as well that we have coming forward from here. So, the Imfinzi trajectory is one that has been both strong and I anticipate will be sustained.

Thank you, Dave. Next question is from Peter Verdult at Exane.

Peter Verdult here, BNP. Apologies for any background noise. Two questions for you, Pascal. I thought it was noteworthy at the investor event, the ESMO cancer event. You called out baxdrostat in your opening remarks. KOLs that we're speaking to, say, they see sort of placebo-adjusted blood pressure lowering in sort of 11, 12, 13 range. Their excitement around this asset is going to be cranked up. So, I know you can't talk to the data. We're going to have to wait until Sunday. But when you look at consensus expectations down at $2 billion, would you expect that expectations for this asset materially increase post the Bax24 data?

And then secondly, we've talked about the political environment in the U.S. I mean, the industry wants to and has to invest more in the U.S., wants to invest more in China. Where is that leaving Europe? I mean Europe, what's the political environment in Europe? Are the politicians waking up to the direction of travel. Do you think that the innovation debate can be genuinely had in Europe? Or are you more, you say, sanguine about the outlook of -- regarding innovation being paid for in Europe?

Thank you, Peter. So, let me start with baxdrostat and then maybe I'm sure, Ruud, who is very excited about this product, will want to add some more. I'm personally very excited about this product, because not only because hypertension -- uncontrolled hypertension is a big problem. A lot of people are on three drugs and still uncontrolled. That drives kidney disease, heart disease, cardiovascular events. So that's a big unmet need, much, much bigger than people understand really.

The second reason is the effect on aldosterone, the 60%, 65% reduction that Sharon mentioned a bit earlier, I think will prove over time a massive benefit. Because aldosterone has not only effect on blood pressure, but also a deleterious effect on the organ. It still has to be proven, but I think there's good reason to believe it is actually the case because it docks on not only aldosterone receptor, but also the other aldosterone receptors and are not blocked by traditional MRIs.

And if you have too much aldosterone in your body, it drives organ damage over time. So, I think this is going to prove really a big deal. And then you will see the data we have over 24 hours. This is really important because you need to control blood pressure at night in particular, the early morning. Sharon mentioned it. That's when people tend to have cardiovascular events, strokes, MIs. So again, this long-lasting effect over 24 hours is important. And I can tell you, you won't be disappointed with the blood pressure reduction, you would see.

Ruud, anything you want to add in terms of the question about peak sales and the potential for this agent?

Yes. No, of course. And we are very excited, and hopefully, on Sunday, you will see why. I'm not going to speculate whether it is more than the peak $5 billion peak year sales we've articulated. The only thing I can say, Peter, is that we have, in total, seven studies on this program as we speak. And there are a few studies also in the fixed dose combination with dapagliflozin. And Pascal was alluding to that.

Yes, blood pressure in itself is important to control that. But it has a quite devastating effects on the kidney, and we truly believe that the combination of a well-known product like dapagliflozin plus the potential effect -- the positive effect of baxdrostat will be a very substantial driver whether it is $5 billion or perhaps even $10 billion. Time well tell. But there is an enormous amount of excitement, not only in the company, but more importantly, among physicians for these products.

And let's not forget, that's my last remark that if a 10-millimeter mercury increases your risk of a MACE event with 30%. So I think you will see a renaissance of the treatment of hypertension with a product like baxdrostat. So very exciting.

Thank you, Ruud. The the U.S. political environment, I mean, we've talked a lot about it. And this issue has been long coming in my opinion. Because, if you go back 20 years or so, there was limited difference in pricing between the U.S. and Europe. Let's talk about Europe for a second, really. And over time, what has happened is, there's been a growing difference mostly because in Europe, we've been facing price cut, clawbacks, a whole cottage industry of price reductions and control of access.

And if you look at healthcare costs today, well, 20 years ago, I guess, healthcare, 20%, 30%, 15% of healthcare costs were dedicated to pharmaceuticals, innovative pharmaceuticals in particular.

Today, you are at 7%, 8%, 9%. And one of the lowest is the U.K. with 7% of healthcare costs dedicated to innovative pharmaceuticals. And you got to ask yourself, I mean, what can you do with 7%? Not much. It creates limited room for innovation and innovation that can save lives, but also reduce healthcare costs by delaying or delaying things like dialysis, saving patients' lives and in cancer, et cetera, et cetera.

So, I think there has to be a rebalancing. Because the U.S. for the last number of years has been really paying for the cost and the risk associated with innovation. We should never forget the risk. Everybody talks about the cost, but there's a massive risk. I mean, we have a portfolio committee. And very often, we spend several hundred million dollars in one meeting. And if those studies fail, it's a lot of money in the rubbish bin. We've been lucky. This year, we've had almost 90% success rate with our Phase III, but it's -- that's not the norm, right?

So, people have to realize innovation is expensive, but it's also very risky. So, I think there has to be a rebalancing, and Europe has to cover a little bit more of this innovation by increasing budgets allocated to innovative pharmaceuticals.

And finally, I would say that if you look at innovation, it's happening in the U.S., very rapidly now it's happening in China, and there's not so much in Europe. So, it would be great for everybody, starting with patients. If Europe was also innovating a lot in our industry, it will also attract investment from companies and drive economic growth.

Now whether we are able to show the benefit of these investments to governments in Europe is still to be seen, but there's clearly benefits to patients, of course, but it also benefits to healthcare cost as innovation can drive healthcare costs down. And there is also economic benefit as the Life Sciences sector can drive economic growth like we see in the U.S., we see now in China.

So, whether we succeed or not, I don't know, but the danger for Europe is that a lot of these new technologies that we are talking about, they need new capacity, new manufacturing capabilities. And right now, this is going to happen in the U.S.

And so, the risk is in 15, 20 years, Europe realized that they have lost control of their supply chain for some of those most important innovative technologies, because they are manufactured in the U.S. and in China. So more to come, and of course, a lot of convincing to try to achieve, but we'll see whether we are able to do that or not.

So, we see. I'll move to the next question, Mattias Häggblom at Handelsbanken.

Mattias Häggblom, Handelsbanken. Two questions, please. Firstly on Farxiga, following the validation of the pattern in U.K. and subsequent generic launch, remind me why this loss would not encourage generic companies to explore similar challenges elsewhere in Europe prior to pattern exploration in '28. And why the situation in the U.K. was unique?

And then secondly, for Sharon, Marc will present Phase III data for its oral PCSK9 inhibitor this weekend. Once we get the detailed data, what in particular will your team be studying to better understand its clinical profile and how it compares with your own small molecule PCSK9 inhibitor currently in Phase III?

And the first one I can quickly cover for -- in the interest of time, Mattias, it's a very specific U.K. law. We can cover the details separately with you if you want offline. But just for everybody's interest, it's a very specific U.K. law that doesn't apply to other countries.

And the PCSK9 question, Sharon, do you want to cover that?

Sure. I'd love to. So as you know, our own laroprovstat is a true small molecule inhibitor of PCSK9 currently in Phase III. We have shared the Phase II data. They're very encouraging. And we note that because our PCSK9 is a true small molecule, it does not require solubility enhancers, and it doesn't require fasting. And so, it offers a target patient profile that we think is very attractive for both monotherapy and combination approaches. And in fact, we're exploring combination approaches with a small molecule Lp(a) that is in our portfolio in Phase I, and it also allows us to easily combine with statins, which is standard of care.

We were thrilled to see that with combinations, we were able to bring 80% of patients on study to their LDL-C lowering goals. And so, we think that we're in a very solid place in the competitive landscape. Now of course, we'll be watching Merck's data to understand how we can continue to meaningfully differentiate ourselves in this landscape as we continue to work on our go-forward plans. We remain very positive about the potential for laroprovstat in this environment and for the potential to really meaningfully change patients' lives because dyslipidemia is not yet solved.

We know the majority of patients aren't reaching their LDL-C lowering goals. And so, there's still a major unmet medical need in the marketplace.

Thank you, Sharon. So, we still have quite a number of questions. So, can I suggest that we go one question per person, and we on our side will try to be short in our responses. So the next one is Seamus Fernandez. Over to you, Seamus.

So my one question is on the competitive developments and the evolution of the treatment of asthma and COPD. Just hoping, Ruud, if you could comment on your, I guess, primary competitors outside of Dupixent, but GSK specifically making moves to advance long-acting agents both depemokimab and their potential long-acting CSLP program. Can you just help us with your thoughts specifically on the value of having long-acting agents in that marketplace? And how your own -- whether it be pipeline pursuits or separately, your own existing portfolio is built to defend against that?

Yes. Thank you so much for your question. And let me first emphasize that, where we are as a company with both Fasenra and Tezspire, is very pleasing. We have for the second quarter -- consecutive quarter, sales of above $0.5 billion for Fasenra. So, the product is now annualizing of more than $2 billion a year.

And the reason I'm mentioning it is that, in all the market research and our own experience in the last few years across all geographies, clearly, efficacy is the #1 reason to prescribe products. And I think that's very important in the choice of physicians.

Having said that, there's always room for further other modalities. And AstraZeneca is putting a lot of effort in order to generate the first inhaled T-slip molecule, which is quite exciting in order to broaden the patient access for severe uncontrolled asthmatics. We think there's a high unmet medical need. For the simple reason that still too many patients are suffering from severe asthma and are not eligible for injectable.

So, moving earlier in the treatment paradigm with an inhaled T-slip if it is working, of course, and we will know that in the course of 2026, I think will be a huge advantage for so many patients still suffering. But all in all, it's clear that there are great products. We are in a very good position. We're the market leader in new-to-brand prescriptions, as I mentioned in my prepared remarks, but there's still an enormous opportunity to further accelerate the bio penetration. And last but not least, we are a verge in order to launch Fasenra in China, which is another very important growth driver for us as a company.

The next question is from Matthew Weston at UBS.

Thank you, Pascal. I think it's probably a question for Dave, but you flagged in your comments that '25 has been or seen a very significant benefit from new patients due to lower Part D co-pays. Of course, that's allowed companies to bring free drug patients into paid coverage. As we think about '26, do we need to consider a significant slowdown in the underlying growth of some of your assets as that free drug warehouse bolus runs out? And if yes, which product should we be most aware of?

Dave, do you want to cover this?

Yes, Please. Thanks, Matthew, for the question. So, I think just to take a small step back, if we compare what we'll expect to see in Q2 -- excuse me, Q1 '26 versus '25. First, we'll have a good, if you will, apples-to-apples comparison because both quarters will include the impact of the Part D liability.

Secondly, I think also we will continue to see benefit of patients staying on commercial medicine who had switched over this year or were otherwise abandoning. So, I think that one of the things that is really important here is that if you take a look at the oral medicines Tagrisso and Calquence in particular, although it's also true of Lynparza. They have fairly long durations of therapy, CLL with treat to progression, Tagrisso in terms of the early settings but also indeed what we see with FLAURA2. So, I would expect that patients who've come over to commercial medicine as opposed to being on free drug that we'll continue to see the benefit of those patients and the TRxs come into 2026.

The bolus patients who would have been your prevalent pool who came on as the co-pay cap went from the mid-300s down into the 2,000s. We may not see that repeat. But I really do think we're going to see demand coming forward from new patients, new indications. And I think that we'll see good oral growth moving forward on our assets.

Thanks, Dave. Maybe I could add that, a year ago, you may remember a number of people were worried about the impact of the part D liability on our growth rate. And you can see we've been able to manage that as we said we would, and Dave and his team have been doing an amazing job driving usage and growing our share and growing the volume, to compensate for this part D liability that we've had to absorb in 2025.

The next question is from Steve Scala at Cowen. Steve, over to you.

Actually, a question on Calquence. Is the upper end of the peak sales guidance of $3 billion to $5 billion is still achievable given the positive data from competitors Calquence's 2027 IRA negotiated price, which you presumably have by now and IMBRUVICA's IRA negotiated price. And related to all this, was the Calquence IRA price in line with your expectations?

Dave, I think it's for you again.

Steve, thanks for the question. On your last piece, we will share the IRA negotiated price on Calquence once that's public, which will be happening later this quarter. What I do want to comment on, though, with respect to your peak year sales question, recall that when we put forth the ambition for 2030 in 2024, we had visibility at that time into the fact that we anticipated that the Calquence would be an IPA. So that's absolutely consistent with the expectations that we had.

We expected that we would get positive data from AMPLIFY. That's come through and been part of what we've seen. And I think that we've seen really even better than we expected volume growth of Calquence, particularly within the United States.

So, in terms of the assumptions that went into the projections that we put forth or the ambition that we put forth in 2024, I think it's been positive news, against that and good momentum against those figures. I'm happy that we've seen good share growth in the United States this year on the work that we're doing.

We're seeing AMPLIFY in Europe with good initial uptake and we look forward to the AMPLIFY opportunity in the U.S. I do want to note that remember that there are no BTK/BCL-2 combinations for finite that are approved in the U.S. in frontline CLL. There's a large number of patients that are receiving a finite treatment that don't involve BTK at all, and we see this as an important opportunity for the asset going forward.

Thanks, Dave. So, still lots of growth coming from those approved or soon to be approved indications. And -- we also have escalate in DLBCL that is still to come.

Next question is Rajan Sharma, Goldman Sachs.

I just wanted to get your thoughts on Enhertu's trajectory from here, given that we now have the DB09 and the DB11 data and PDUFA next year, which have been seen historically as two of the largest opportunities. Some of our KOL feedback has suggested that initial uptake may be a little bit tentative to begin with. So yes, we'll just be keen to get your thoughts on that. And do you expect those potential approvals during the first half to drive an immediate step-up in Enhertu's growth in '26 and '27? And then just thinking further out, do you think you'll be reaching peak penetration in breast cancer as you approach your 2030 target?

Thank you. So question, we'll switch up to David, go ahead.

All right. We'll do. So first of all, I think as we take a look at 09 and the combination of both 05 and 11, let's take those in two separate parts.

DESTINY-Breast09 is clearly a very important opportunity to move Enhertu from the later line metastatic setting or the second-line plus metastatic setting that we're in today into a frontline setting.

The reason that, that is important is, first and foremost, many more patients will have the opportunity to benefit from an Enhertu. Because unfortunately, the number of patients that are able to receive a second-line therapy goes down just as patients unfortunately either pass away or they're unable to receive further treatment. So, opening up that population is going to be really important.

Secondly, the duration of therapies that we see because of the long PFSs within DB09 are really important. And that's as a result of this treat to progression, new paradigm that's being established. And I think that on this, it's important to note that one of the things that's been really well received by the clinical community is the lack of cumulative toxicity that is associated with Enhertu and what we're seeing within these studies. That cumulative toxicity is in large part why there's been discontinuation of the taxanes in some of the other metastatic settings.

And so, we're really looking for this to be an opportunity to make sure that we're driving to the way that DB09 was designed, which is treat to progression.

DB05 and DB11 in early stage, they represent a blockbuster opportunity together. This is a great opportunity to bring Enhertu into early settings. And I think that in terms of when will we expect uptake, certainly, the clinical community does follow guidelines. DB09, we anticipate coming into guidelines sometime soon, we would hope. Remember that the New England Journal of Medicine publication just came through just very, very recently. And we'll obviously look forward to making sure that the progress that we've made on the early studies gets published as well.

So, we'll try the last four questions in the time that remains. Let's go with one question per person and be short in our responses. Luisa at Berenberg. Over to you.

Thank you, Pascal. I wanted to return to the 2030 ambition. Because you've talked about and we've seen there's unprecedented success rate this year. So is the $80 billion now conservative? Can you comment at all on the mix that you're seeing with the success and what that means for profitability? And although the ex U.S., you're sticking at 50% ex U.S. contribution, are there any changes in timing of launches or the mix of the ex U.S. in light of that U.S. deal?

Thank you, Luisa. Not long ago, people were thinking the $80 billion was not achievable. Now it's going to be a soft goal. It remains an ambitious goal. And of course, we are very excited with all this new positive readouts. But it's a risky business. That's what I said not long, a few minutes ago. So, we have to remain cautious with the readouts that are coming next year. We don't know. I hope to God, we continue to have a high positive success readout -- in our readouts, but we can't be sure.

So, let's stick to the $80 billion. It's an ambitious goal. And if we can overachieve of course, we'll do our very best to overachieve.

Now in the second question with the profitability, we want to be a growth company until 2030, but also beyond 2030. So certainly, we can assume -- we can assume profitability increases, but you also have to understand we will want to continue investing in R&D. We have tremendous technologies in our hands, cell therapy, T-cell engagers, radioligands, which we haven't talked about today, all of those are making good progress. So, we certainly would want to invest in those from an R&D perspective, but also from a commercial perspective.

And beyond oncology, we have a lot to do also in biopharma and rare disease. So, we're not going to commit to any profitability target or improvement beyond what we've already said in the past.

Aradhana, anything you wanted to add to this?

No, not at all. It's a long answer, obviously, with all moving parts. So, maybe another time to reach out.

Good. so, the next question is from Gonzalo Artiach at Danske Bank.

Gonzalo Artiach at Danske Bank. I have one for Marc on gefurulimab and the data has been recently presented. It seems that the efficacy and safety signals have come fairly in line with Ultomiris in MG. How should we understand the dynamics between these two products in MG? And also I wanted to ask if you have any plans ahead for gefurulimab in other indications where Ultomiris is now approved. Thank you very much.

First of all, thank you very much for the question on the rare disease. So, if you remember what the trial of gefurulimab was done in patients earlier than the trials we have done historically with Ultomiris. You will remember that Alexion was a pioneer company to obtain the first approval with modern medicine in myasthenia gravis. And subsequently, we -- after Soliris, we developed Ultomiris and now we go one step earlier.

The other important factor of gefurulimab is a mode of administration, a subcut weekly provided in either prefilled syringe or an auto-injector that can be injected in 15 seconds. So, it's a very patient convenient, patient easy type of administration. And the speed of onset has been demonstrated in the study and also the sustainability is as good as it was for Ultomiris. So, that's what I can say about gefurulimab.

Thank you, Marc. And the last question is from Simon Baker at Redburn. Over to you, Simon.

Just changing the subject slightly. We don't ask many questions on. But one for Susan, could you give us an update on your confidence in sone vedotin as we come up to the gastric Phase III data in H1 '26? And also some thoughts on the broader scope of Claudin18 beyond gastric?

Thanks for the question. So, sone vedotin is a Claudin18.2 ADC with an MMAE tubulin-based payload. And we've seen encouraging response rate data in late-line patient populations. We are investigating this versus current standard of care, but we're also looking within the potential to take it into earlier line settings, including in combinations. And you all have seen, of course, that there are exciting opportunities for MMAE-based ADCs in combination with I/O therapy. So, that represents a significant opportunity to sone v.

Claudin18.2 is expressed in a high proportion of gastric cancer more than 50% of patients. So it's a much bigger opportunity than the HER2 high group, if you want to compare with what we've seen with HER2.

And I think, it's also expressed in pancreatic cancer. And we are looking at the data in pancreatic cancer as well. I mean, of course, there the bar is high. So, what we've done is go forward with the gastric cancer opportunity first, and we'll continue to explore the opportunity for this and also a topo-based ADC with a Claudin18.2 targeting also in pancreatic cancer, just to see which payload works best.

Thank you, Susan. So in closing, maybe a few words back to Luisa's question. I realized I didn't totally answer Luisa's question.

As the pipeline develops, you can see we'll have a lot of Specialty Care products moving forward. And of course, those tend to drive higher profitability as we know. But we also have products that will address conditions like weight loss, metabolic conditions, metabolic disease and those, of course, require more investment.

So, I think overall, you can suddenly assume improvement of profitability from a commercial viewpoint. The R&D, we want to continue spending at the -- in the low 20s, as we've done in the past. But as I said before, we will not commit to any direction of travel of our profitability, because we need to see how the pipeline develops, and that's what we've said in the past.

And more frankly, we've been good and lucky. We have had a very high success rate, and I hope it continues. And if it does, then we have to support all these products.

So with this, thank you so much for your great questions and your interest, and I wish you a good rest of the day.

Good afternoon, and welcome to AstraZeneca's H1 and Q2 2025 webinar for investors and analysts. Before I hand over to AstraZeneca, I'd like to read the safe harbor statement. The company intends to utilize the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Participants on this call may make forward-looking statements with respect to the operations and financial performance of AstraZeneca. Although we believe our expectations are based on reasonable assumptions, by their very nature, forward-looking statements involve risks and uncertainties and may be influenced by factors that could cause actual results to differ materially from those expressed or implied by these forward-looking statements.

Any forward-looking statements made on this call reflect the knowledge and information available at the time of this call. The company undertakes no obligation to update forward-looking statements. Please also carefully review the forward-looking statements disclaimer in the slide deck that accompanies this presentation and webcast. There will be an opportunity to ask questions after today's presentations. Please use the raise hand feature to indicate you wish to ask a question at any time during the call.

Now with that, I'd now like to hand the conference over to the Head of Investor Relations at AstraZeneca, Andy Barnett.

A warm welcome, everybody, to AstraZeneca's Half Year and Second Quarter 2025 Presentation Conference Call and Webcast for investors and analysts. I'm Andy Barn, Head of Investor Relations. And before I hand over to Pascal and other members of the executive team, I'd like to cover some important housekeeping items. Firstly, all of the materials presented today are available on our AstraZeneca Investor Relations website.

This slide contains our safe harbor statement, which I'd encourage you to take the time to read. We will be making comments on our performance using constant exchange rates, or CER, core financial numbers and other non-GAAP measures. A non-GAAP to GAAP reconciliation is contained within the results announcement, and all numbers quoted are in millions of U.S. dollars unless stated otherwise. This slide shows our agenda for today's call. Following the prepared remarks, we will open the line for questions.

As usual, we'll try and address as many questions as we can during the allotted time, although please limit the number of questions you ask to allow others a fair chance to participate in the Q&A.

And with that, I'll hand the call over to Pascal

Thank you, Andy, and welcome, everyone. I'm pleased to report that our strong growth momentum and excellent pipeline delivery continued through the first half of 2025. In the first 6 months of the year, total revenue grew by 11%, driven by continued demand for our innovative medicines. Core EPS grew 17%, reflecting the importance we place upon investing in our pipeline while driving operating leverage across our company. Since our full year results in February, we've achieved 19 regulatory approvals in key regions. and the pace at which we are bringing new medicines to patients around the world continues to accelerate.

In the year-to-date, our pipeline delivery has been excellent. We've already announced the results of 12 positive Phase III trials this year, including the first pivotal data for 5 new molecular entities. In the past few weeks alone, we communicated the high-level results for baxdrostat and gefurulimab, which both represent important potential contributors to our 2030 ambition. Please move to the next slide. Our diverse broad-based business continues to present an attractive risk profile, resilient to regional disruption.

And I'm pleased to report once again that we saw strong growth across therapy areas and geographies. In the first half, we saw double-digit growth across oncology and biopharmaceuticals and a return to growth for our rare disease business in the second quarter, which was up 7%. We also saw robust growth across geographies, particularly in the U.S. and the emerging markets outside of China. Underlying demand also remained strong across other regions, including in China, where the growth rate continues to be affected by Pulmicort generics.

Next slide, please. We continue to progress through a catalyst-rich period, and we've already announced multiple high-value trials with many more to come throughout the remainder of the year and into 2026. In oncology, we continue to grow our leading position in breast cancer, reinforced by positive trial results for camizestrant in SERENA-6 and Enhertu in the DESTINY-Breast09 and DESTINY-Breast11 trials. We are also expanding our presence in gastrointestinal and bladder cancers with the MATTERHORN and POTOMAC trials of Imfinzi. In addition, we saw positive overall survival data from FLAURA2 for Tagrisso plus chemotherapy, consolidating our leading position in EGFR-mutated lung cancer.

In biopharmaceuticals, the KALOS/LOGOS program has the potential to bring Breakthrough into uncontrolled asthma and the BaxHTN trial for baxdrostat represents an exciting opportunity to redefine treatment for patients with hard-to-treat hypertension. Finally, our rare disease pipeline is making excellent progress. We recently announced readouts for the CARES program of anselamimab in severe light-chain amyloidosis and the PREVAIL trial for gefurulimab in gMG. Including the trials highlighted here, the Phase III readouts in 2025 have the combined potential to generate well over $10 billion in peak year revenue on a risk-adjusted basis.

And this is why I've said many times in the past, by the end of this year, early next year, you will have a very good sense of the direction in terms of our $80 billion target for 2030, which we believe we are on track to achieve at this stage. Next slide, please. We continue to make exciting progress with our transformative technologies, which have the potential to drive our growth well beyond 2030. At ASCO this year, we shared the first combination data for our IO bispecific rilvegostomig in combination with Datroway as we seek to displace both first-generation IO checkpoint inhibitors as well as traditional chemotherapy. Since ASCO, we've moved yet another ADC using our proprietary platform into the clinic, furthering our ambition to replace chemotherapy across a broad range of cancer types.

And with that, please advance to the next slide, and I will hand over to Aradhana.

Thank you, Pascal, and good morning, afternoon, everyone. As usual, I will start with our reported P&L. Next slide, please. As Pascal highlighted, total revenue increased by 11% in the first half. Product sales increased by 10% with sustained strong momentum across key brands and alliance revenue was up 38%, driven by growth in shared profits of Enhertu, Tezspire and Beyfortus in regions where our partners book product sales. Next slide, please. Turning to our core P&L. We saw a total revenue gross margin of 83% in the first half, benefiting from product sales mix and favorable FX impact in the first quarter, which somewhat reversed in the second quarter.

As previously stated, we anticipate that the total revenue core gross margin will decline by around 60 to 70 basis points in 2025, driven by factors such as Medicare Part D redesign, Soliris biosimilar competition and increased profit share related to partnered products. We anticipate a gross margin in the second half of the year driven by these factors as well as the usual seasonal pattern for medicines such as FluMist. Total operating expenses increased by 9% in the first half, below top line growth of 11%. Core R&D costs increased by 17% and represented 23% of total revenue, driven by accelerated recruitment into our clinical trials, the additional costs relating to medicines acquired through business development and a step-up of investments in transformative technologies.

As mentioned at our ASCO event in June, we now anticipate core R&D costs for the full year to land at the upper end of the low 20s percentage range of total revenue. Core SG&A costs increased by 3%, growing at a much smaller rate than total revenue. We are anticipating continued operating leverage and margin improvement this year. Similar to prior years, we expect a lower margin in the second half, primarily relating to the gross margin effects previously mentioned. Core tax rate was 18% in the first half, which benefited from a favorable settlement in the first quarter and is anticipated to remain 18% to 22% for the full year. Core EPS of $4.66 represents 17% growth. Next slide, please.

As I just mentioned, the increase in R&D costs was driven in part by accelerated clinical trial recruitment with more than 50% of our trials recruiting significantly ahead of plan. We have seen a growing number of patients in our clinical trials. And by the end of the second quarter, the total had reached 56,000 patients. We also saw increased investments in our transformative technologies, including in our IO bispecifics, our in-house ADCs, cell therapy as well as our growing portfolio in cardiovascular renal medicines. We continue to make investments not only to achieve our 2030 ambitions, but also to drive continued growth beyond 2030. Given the breadth and depth of our portfolio, we anticipate R&D costs to remain in the low 20s percentage range of total revenue for the longer term.

On the SG&A side, I'm pleased to report that we're making great progress, and I would like to thank all our teams globally. We are seeing productivity gains from initiatives undertaken in the last few years, including the redeployment of resources, utilization of shared service centers and investments in digital and AI, all of which have led to SG&A costs increasing by only 3% in the first 6 months despite the high number of new launches. Next slide, please. We are reiterating our guidance for the year, where we anticipate a high single-digit percentage increase in revenue and low double-digit percentage increase in EPS. We have had strong performance in the first half and expect that momentum to continue in our core products. But note that the Brilinta LOE, Soliris biosimilar and products like FluMist are more second half weighted, and there's uncertainty regarding Farxiga.

Also note that the year-on-year growth rate in the second half will be skewed by the $600 million Lynparza-related milestone received in the fourth quarter of 2024. Net cash flow from operating activities increased by 27% to $7.1 billion in the first half. As previously communicated, we expect CapEx to increase by 50% this year with $1.3 billion spent in year-to-date. As a reminder, our total CapEx, including both tangible and software-related intangible assets, was $2.2 billion last year. Earlier this month, we announced a new multibillion-dollar manufacturing facility in the U.S. that will produce drug substance for our innovative weight management and metabolic portfolio, including our oral GLP-1, Baxdrostat, oral PCSK9 and combination small molecule products.

This facility makes a part of the recently announced $50 billion investment plan in the United States, which also includes R&D spend, operating expenses and investments across several of our existing sites. These investments are in line with our previously stated objectives to increase both our manufacturing and R&D footprints in the U.S. Deal payments of $2.3 billion in the first half included Enhertu milestone and an approximately $400 million upfront payment for the EsoBiotec acquisition, which closed in the second quarter. Net debt increased by $650 million in the first half, driven by the dividend payment made in the first quarter. We remain comfortable with our current level of debt and decrease in the net debt-to-EBITDA ratio to 1.4x reflects our improving operating cash flow.

With that, please advance to the next slide, and I will hand over to Dave, who will take you through our oncology and hematology business performance.

Thank you, Aradhana. Next slide, please. Oncology total revenues grew 16% in the first half to $12 billion, underpinned by strong double-digit growth across the U.S., Europe and emerging markets. Growth in the U.S. was particularly notable, up 19%, with demand growth substantially offsetting the impact of the Medicare Part D redesign rebates, which started at the beginning of 2025. Turning now to quarterly performance for our key medicines. We saw double-digit growth across all key brands this quarter. Tagrisso delivered 12% growth in the second quarter, reflecting strong demand across all indications. The market share for the FLAURA2 regimen continues to expand and the recently announced positive overall survival results reinforce Tagrisso's position as the frontline standard of care in EGFR-mutated lung cancer.

Overall, we anticipate continued sequential growth across all indications through the remainder of the year. Calquence remains the leading BTK inhibitor across major markets with total revenues increasing by 10% to $872 million in the second quarter. In the U.S., we saw growth in new patient starts, having secured preferential formulary placement in CLL across several commercial plans, driving frontline share gains. We also saw strong uptake in the first-line mantle cell lymphoma following the approval of Echo in January. Looking ahead, we see meaningful growth potential for the fixed duration AMPLIFY regimen in CLL following its recent approval in Europe and filing acceptance in the U.S. Lynparza remains the leading PARP inhibitor globally with 11% growth in the second quarter.

In the U.S., we saw new share gains in both prostate and breast cancer alongside robust growth in Medicare. We anticipate further volume growth globally to partially offset potential impact of VBP inclusion in China anticipated later this year. Truqap delivered $170 million in second quarter revenues, reflecting 84% growth compared to Q2 last year. We continue to see growing demand in the core second-line patient segment. And as we reported last quarter, we've achieved nearly 100% market share in the AKT-P10 biomarker altered population. Further growth will be driven by increased uptake within the PIK3CA population and additional global launches.

We saw particularly strong growth of Imfinzi and Imjudo in the second quarter, up 26% and 18%, respectively. In the U.S., there's been rapid early uptake of new Imfinzi regimens, ADRIATRIC and AEGEAN lung cancer and NIAGARA in bladder cancer as well as continued momentum in the established lung and liver indications. The strong launch of ADRIATRIC in small cell lung cancer in Europe more than offset the increased competitive pressures in biliary tract cancer in Japan. We remain focused on driving further adoption of Imfinzi and Imjudo with additional launches for NIAGARA, ADRIATRIC and AEGEAN expected in the coming months and with MATTERHORN and gastric cancer set to contribute significantly to growth in 2026.

Enhertu total revenues grew 42% in the second quarter, reflecting sustained market leadership in both HER2-positive and HER2 low metastatic breast cancer. We're seeing strong initial uptake in China with Enhertu on the back of very rapid and broad hospital formulary listings following NRDL enlistment in January. We see accelerating uptake for DESTINY-Breast06 with momentum building in the U.S. and early use in the chemotherapy-naive segment emerging in European markets following approval in April. Datroway is gaining traction in hormone receptor positive, HER2-negative breast cancer with early positive signals and share gains across key markets.

We expect growth to accelerate through the remainder of the year following the recent U.S. approval and NCCN guideline inclusion for patients with previously treated advanced EGFR-mutated lung cancer. With strong momentum across our portfolio, we are well positioned for continued growth through the rest of the year as we deliver innovative oncology medicines to more patients across the globe.

With that, please advance to the next slide, and I'll hand over to Susan to cover R&D highlights from the quarter.

Thank you, Dave. This year at ASCO, AstraZeneca delivered multiple data sets with the potential to transform clinical practice, including 2 plenary presentations. This marks the seventh consecutive year our science has been selected for the ASCO plenary session, highlighting both the caliber and consistent impact of our research and underscoring the value our data brings to patients, to clinicians and the wider oncology community. The SERENA-6 data represent the first Phase III results for camizestrant, our next-generation oral SERD and complete ER antagonist, which is an exciting new molecular entity with best-in-class potential.

A key first-line treatment objective for patients with hormone receptor positive advanced breast cancer is to prolong the time until disease progression whilst maximizing quality of life. In this interim analysis, camizestrant plus a CDK4/6 inhibitor reduced the risk of progression or death by 56% compared to an aromatase inhibitor plus CDK4/6 inhibition and showed an encouraging trend for improvement in second progression-free survival. Camizestrant also demonstrated a very well-tolerated safety profile with a discontinuation rate due to adverse events of less than 1.5%.

And it meaningfully prolonged the time patients maintained their quality of life by a median of over 16 months. The significance of these findings is reinforced by the recent breakthrough therapy designation granted by the FDA. The DESTINY-Breast09 trial moves in HER2 one line earlier in the treatment of metastatic HER2-positive breast cancer into the first-line setting. The trial demonstrated that combination of Enhertu plus pertuzumab resulted in a median progression-free survival of more than 3 years with a 44% reduction in the risk of progression or death compared to the standard of care 3-drug regimen, THP.

There was also a strong trend to second progression-free survival benefit and an early trend towards overall survival benefit. Treating HER2-positive breast cancer at the earliest opportunity with the most effective therapy is critical as approximately 1/3 of patients diagnosed with metastatic disease don't go on to receive a second line of therapy. These data establish Enhertu as a potential first-line option for HER2-positive breast cancer and their value has been recognized by the FDA, who recently also granted this data set breakthrough therapy designation.

MATTERHORN demonstrated a significant improvement in event-free survival for perioperative Imfinzi plus FLOT chemotherapy compared with FLOT alone, with 2/3 of patients with resectable gastric or gastroesophageal cancer remaining event-free at 2 years and with a strong trend towards improved overall survival. This represents the third perioperative regimen for Imfinzi after AEGEAN and NIAGARA and introduces a new treatment approach in a disease where options have traditionally been limited. We're delighted that MATTERHORN has been granted priority review by the FDA. This quarter, we also reported 3 key high-level data readouts, DESTINY-Breast11, POTOMAC and FLAURA2 overall survival. DESTINY-Breast11 moves in HER2 into the neoadjuvant early breast cancer setting, where the chance for cure is at its highest.

The trial focuses specifically on patients with high-risk disease where there's a large unmet need with nearly half of patients not currently achieving a pathologic complete response to treatment and many struggling to tolerate current standard of care combination chemotherapy regimens. Enhertu followed by THP demonstrated a statistically significant and clinically meaningful improvement in pathologic complete response rate compared to standard of care with a trend to improve event-free survival and an improved safety profile versus dose dense doxorubicin and cyclophosphamide followed by THP. The full data will be presented at ESMO later this year.

Data from our other early breast cancer in HER2 trial, DESTINY-Breast05, which looks at adjuvant in HER2 in high-risk patients post surgery are also expected later this year. In addition, we recently initiated our first trial of subcutaneous in HER2, which has the potential to further improve the patient experience across our broad range of indications. POTOMAC moves Imfinzi into the earliest treatment space of non-muscle invasive cancer with Imfinzi plus BCG induction and maintenance regimen demonstrating an improvement in the time until disease recurrence or progression compared with BCG alone.

These data will be presented later this year. Alongside the trials we have in muscle invasive disease, the recently approved NIAGARA trial and the ongoing VOLGA trial, POTOMAC potentially broadens and reinforces Imfinzi's position in bladder cancer. Both DESTINY-Breast11 and POTOMAC underscore our commitment to bring transformative treatments into the earlier lines of care to maximize the chance of cure. Finally, I also want to briefly highlight, as Dave mentioned, the recent announcement that FLAURA2 demonstrated a statistically significant and clinically meaningful improvement in overall survival versus Tagrisso monotherapy. These data reinforce the impact of Tagrisso and its role as the backbone therapy across all stages of EGFR-mutated lung cancer, and we also look forward to sharing these data later this year.

And with that, please advance to the next slide, and I'll pass over to Ruud to cover biopharmaceuticals performance.

Thank you so much, Susan. Next slide, please. Our biopharmaceuticals medicines continued to deliver strong performance in the first half with double-digit growth of 10%, taking total revenue to $11.2 billion. R&I continued its impressive momentum with total revenue of $4.2 billion, up 13% with growth medicines now making up 60% of the therapy areas revenue. CVRM achieved total revenue of $6.6 billion, growth of 8%. We are consistently seeing robust performances from our key medicines in R&I each quarter. Fasenra grew 18% to $502 million in the second quarter. We have now launched Fasenra in China.

And in the United States, we saw strong uptake in the new EGPA indication where Fasenra has already achieved leading share of new-to-brand prescriptions. We also had the positive readout for the NATRON trial in hypereosinophilic syndrome in June, and we are awaiting the results of the RESOLUTE trial of Fasenra in COPD due in the second half of this year. Tezspire grew by 65% in the second quarter and has achieved leading new-to-brand biologics share in asthma across key markets. The regulatory review of the WAYPOINT data in nasal polyps is well underway, and we are looking forward to launching this new indication in the second half. Tezspire is also being investigated in COPD with its Phase III program ongoing. Breztri was up 20% in the second quarter, benefiting from growing adoption of inhaled triple therapies in COPD and now has the potential to expand into asthma following the positive readout from the KALOS and LOGOS trials in May.

Demand for Airsupra remains impressive with the clinical proposition in moderate asthma strengthened by the BATURA trial, results of which were published in the New England Journal of Medicine in May. Saphnelo grew by 48% this quarter and has steadily gained share among systemic lupus erythematosus patients treated with intravenous infusion, and we are looking forward to the results of TULIP-SC, our subcutaneous trial later this year. CVRM grew by 3% in the second quarter. With continued demand for Farxiga and Lokelma, offsetting the expected impact of Brilinta generic competition in the United States and European markets. Farxiga's strong trajectory continued with revenues up 10% to $2.2 billion in the quarter. In the second half, we expect demand to continue to increase.

However, revenues in China are expected to be impacted by the VBP implementation. Lokelma delivered another impressive quarter with revenues of $175 million and growth of 27%. Lokelma is the leading potassium binder in chronic kidney disease and heart failure. We firmly believe that Lokelma has blockbuster potential, giving opportunities for further regional expansion. Wainua delivered $44 million in the quarter, including the first sales in ex-U.S. markets. We are excited for the CARDIO-TTRansform trial of Wainua, the Phase III trial in ATTR cardiomyopathy, which is due to read out in the second half of 2026. This is the largest trial in this population and has the potential to address key questions regarding the optimal use of silencers and stabilizers to treat this debilitating and deadly disease. And finally, we were particularly excited to see the first positive Phase III readout for Baxdrostat earlier this month.

And with that, I will hand over to Sharon.

Thanks, Ruud. Next slide, please. I'm pleased to share the positive high-level results from the BaxHTN Phase III trial of baxdrostat in uncontrolled resistant hypertension, which were announced earlier this month. Hypertension is a leading modifiable risk factor for heart attack, stroke, heart failure and kidney disease, and it remains a huge unmet medical need. Currently, nearly 50% of adults in the U.S. live with hypertension and half of those patients still have inadequately controlled blood pressure despite taking multiple medications.

With no new treatments for over 2 decades, baxdrostat has the potential to be a first-in-class, highly selective aldosterone synthase inhibitor that targets the hormone driving elevated blood pressure, leading to increased cardiovascular and renal risk. It's designed to reduce aldosterone production at its source, delivering a highly targeted approach that may help avoid the hormonal side effects often associated with current therapies. In BaxHTN, 796 patients with uncontrolled or treatment-resistant hypertension were randomized 1:1:1 to receive 1 mg or 2 mg of baxdrostat or placebo on top of standard of care without the need for dose titration.

The primary endpoint was change in ceded systolic blood pressure or SBP, measured at 12 weeks using automated office blood pressure readings. Secondary endpoints included assessment of ceded SBP after randomized withdrawal of treatment from weeks 24 to 36, ceded SBP in the subpopulation of patients with resistant hypertension and the proportion of patients achieving SBP below 130 millimeters of mercury at week 12, alongside safety and tolerability measures. We are delighted that both doses of baxdrostat demonstrated statistically significant and clinically meaningful reductions in SBP at 12 weeks, and the trial also met all secondary endpoints. Baxdrostat was generally well tolerated in the trial with a favorable safety profile.

The robust trial design of BaxHTN gives us great confidence in the data, and these results add to the compelling body of evidence supporting baxdrostat's clinical promise in addressing a critical unmet need in this hard-to-treat population. We look forward to presenting these data at the upcoming European Society of Cardiology Meeting in a late-breaking hotline session next month and are working at pace to share these data with the regulatory authorities. Our ongoing Phase III development program for baxdrostat is broad with 6 additional clinical trials enrolling more than 20,000 patients. We believe the long half-life of Baxdrostat is a key differentiator for this potential medicine, supporting 24-hour systolic blood pressure control, and we are looking forward to confirming this in the BAX-24 trial due to read out later this year.

We are looking to extend the potential reach of Baxdrostat across the globe, and BaxAsia will provide us with data for the Asian population in the first half of next year. We are also in the process of initiating a new trial, BaxPA in primary aldosteronism. This is a condition where excess aldosterone is driving hypertension, electrolyte imbalances and longer-term cardiovascular risk. Beyond this, we are rapidly advancing the combination of baxdrostat and dapagliflozin with 3 Phase III trials ongoing, 2 of which are outcome studies. BaxDUO-Arctic investigates whether the combination can slow the progression of chronic kidney disease. BaxDUO-Pacific initiated in 2024, looks at whether the combination reduces the risk of kidney decline or failure and cardiovascular death.

PREVENT-HF started this year is the first of its kind trial and investigates whether the combination results in reduction of heart failure events and cardiovascular death. We are very excited with the strong momentum across our CVRM pipeline, underpinned by multiple novel approaches and our ability to explore unique multi-mechanism combinations to address interrelated CVRM diseases.

And with that, please proceed to the next slide, and I'll pass over to Marc to cover rare disease.

Thank you, Sharon. Can I get the next slide, please? Rare Disease Medicine returned to growth in the second quarter with total revenue up 7%, resulting in 3% growth in the first half to $4.3 billion. In the second quarter, Ultomiris grew 23%, driven by patient demand across indications, including the competitive generalized myasthenia gravis and paroxysmal nocturnal immunoglobinuria markets. Soliris revenues continued to decline due to the successful conversion to Ultomiris as well as biosimilar pressure in Europe.

This decline was partially offset by order timing in tender markets. Beyond complement, both Strensiq and Koselugo grew 15% and 18%, respectively, driven by continued patient demand. Please advance to the next slide. We recently reported Phase III readouts for 2 new molecular entities, gefurulimab and anselamimab. We are excited by our Phase III PREVAIL trial investigating gefurulimab, or dual binding nanobody targeting C5 in patients with generalized myasthenia gravis, meeting all endpoints. Gefurulimab demonstrated a statistically significant and clinically meaningful improvement from baseline in myasthenia gravis activities of daily living total score at week 26 compared to placebo.

The PREVAIL trial was conducted in a broader gMG patient population compared with prior trials of C5 targeted therapies, and we are highly encouraged by gefurulimab rapid, complete and sustained complement inhibition with improvements in both patient and practicitioner reported outcomes. Gefurulimab is self-administered subcutaneously once a week with the potential for 2 delivery options, a prefilled syringe and a first-class auto-injector. We believe that with the strength of this data and convenient administration, gefurulimab has the potential to become a new first-line therapy following corticosteroid immunosuppressant treatments.

The gMG market has expanded significantly over the past 3 years with new branded entrants increasing disease awareness and diagnosis rates. Currently, less than 20% of patients are on branded treatments, and we expect this to increase to approximately 50% in the next 3 years. Additionally, self-administered medicine represent only a small part of this market today, and we expect this segment to grow substantially. Moving now to anselamimab. We recently provided an update on our Phase III CARES program in patients with severe light chain amyloidosis. While the result did not achieve statistical significance for the primary endpoint in the overall patient population, anselamimab showed a highly clinically meaningful improvement in all-cause mortality and cardiovascular hospitalization in a prespecified patient subgroup on top of background standard of care.

We are continuing to evaluate the full results from CARES to further characterize the efficacy and safety of anselamimab, and we intend to share this data with global health authorities. It is important to note that this is the first Phase III trial to demonstrate that targeting amyloid fibrils for depletion with specific antibodies can be highly effective in reducing death and hospitalization in an amyloid-driven disease. This bolsters our confidence to develop novel therapy that depletes amyloid. We're also investigating another fibril depleter, [indiscernible], previously known as ALXN2220 in transthyretin amyloid cardiomyopathy. The DepleTTR Phase III trial has now completed recruitment with more than 1,000 patients enrolled more than 1 year ahead of plan.

This is an exciting year for our rare disease pipeline with additional key trials expected to read out in the second half. The registrational trial of Ultomiris in HSCT-TMA represents an important commercial opportunity and would be the first indication for Ultomiris beyond the Soliris label. Asfotase alfa, our next-generation enzyme replacement therapy, which is studied in broad hypophosphatasia patient population has the potential to reach between $3 billion and $5 billion in peak sales revenue. Importantly, much of this value will be unlocked with the studies expected to read out this year.

And finally, you may recall AstraZeneca and several partners spearheaded efforts to secure an update to the One Big Beautiful Bill Act, which broadens the scope of orphan drug exclusion from Medicare direct price negotiation. The Orphan Cures Act is a significant positive for rare disease patients. Companies will no longer be deterred from innovating in orphan indication or investigating medicine across multiple rare diseases. We are now working with CMS to understand the implementation process, but we believe our current and future rare disease portfolio would be protected by this legislation.

And with that, please advance to the next slide, and I will hand back to Pascal.

Thank you, Marc. Next slide, please. In conclusion, our company has continued to deliver strong growth in the first half of the year, driven by sustained commercial and pipeline momentum with multiple positive data readouts and important advances across our late-stage pipeline. Year-to-date, we've seen above industry success rates in our late-stage portfolio. Looking ahead, we have several exciting readouts over the next 6 months across oncology, rare disease and biopharmaceuticals.

Next slide, please. We're making significant progress towards our 2030 ambition and are confident in our growth trajectory beyond 2030 as we invest behind transformative technologies that have the potential to change medical practice. We want to be a growth company to 2030 and beyond. And for that, we need to invest in technologies that will actually transform the future of medicine, but also drive the company forward over the next decade and beyond. And that explains why we continue to invest heavily in research and development. Additionally, as Aradhana mentioned, we are continuing to drive operating leverage across the company while not compromising on our investment in R&D and high-priority medicines, as I just said. We've already launched 9 new medicines towards our target of 20 by 2030.

And with pivotal data for 5 NMEs announced this year, we are very much on track to meet or even exceed this objective. Please advance to the next slide, and we'll now move to the Q&A. As Andy mentioned at the start of the call, please limit the number of questions you ask to allow others a fair chance to participate. But also online, please use the raise hand function on Zoom. With that, let's now move to the first question which is from James Gordon at JPMorgan.

James Gordon, JPMorgan. The first question was on Datroway and AVANZAR and the 2030 revenue target. So just putting Datroway and AVANZAR in context. So how much do you now need AVANZAR to work to deliver your $80 billion in 2030 revenue target? What was baked in and what's required? And we've seen quite a lot of Phase III readouts since the $80 billion target was set last year. So most [indiscernible] aside, are you more or less confident? How has confidence changed in things outside oncology, such as, say, baxdrostat IL-33 or anselamimab which just was talked about? So that's the first question. How derisked are things beyond Day? And then the second question was on VEGF bispecifics.

So VEGF is a mechanism that has got quite a lot of interest recently for lung cancer. And I've seen you started a trial of [indiscernible] PD-1/TIGIT with a CTLA-4 with or without bevacizumab, so a single-agent VEGF. So I guess how exciting is VEGF? You're doing VEGF. So are VEGF agents exciting for combos for lung cancer? And is it better to do a mono? Or what about bispecific? I don't think you have a bispecific. So do you think it's better to be bispecific and get the 2 together or do them by themselves?

Thank you, James. So maybe I'll cover quickly the first question. Susan, you might want to take the VEGF question. So on your first question, James, the answer is straight. No, we don't need AVANZAR to deliver our $80 billion target. Of course, we hope and we believe AVANZAR will be a successful trial and will drive that way. But as we've said many times before, our $80 billion is a risk-adjusted number across the totality of the portfolio. And as we progress, we derisk projects, Baxdrostat was at least from an R&D perspective, recently derisked.

We now have, of course, to launch it and commercially succeed, but the risk from an R&D viewpoint, gefurulimab, an important product, just derisked. We have many other studies that we've just mentioned in the last few minutes that are not derisked and basically no longer have to be risk adjusted in this forecast of $80 billion to 2030. So we don't need AVANZAR. The last point I will make is Datroway is not only about AVANZAR. We already have approval in breast cancer indication. We have approval in EGFR patients post EGFR inhibitors and chemotherapy. So Datroway is more than AVANZAR. Having said that, of course, I hope that AVANZAR is a positive trial. So Susan, over to you for VEGF.

Yes, sure. Thanks, Pascal. So in terms of the bispecifics, obviously, as you're aware, we've got our PD-1 and TIGIT, rilvegostomig and PD-1 with CTLA-4 volrustomig as the core components of our bispecific portfolio. And what we're doing is combining those extensively with the rest of our portfolio. The profile that we've seen with rilvegostomig, I think, is differentiated from other agents out there because you've got the ability to inhibit both molecules with one molecule, both targets of one particular cell with one molecule.

And I think that's important. What we also see because of its efficacy silent or reduced design is really excellent safety, particularly in combination with very low discontinuation rates. So we're looking at that both in combination with chemotherapy, but in combination with our extensive ADC portfolio as well. There are clearly some indications where VEGF mechanism of action has been shown over many years to have some added benefit. And we're looking at that in combination with rilvegostomig, for example, in the HCC and the gastric GEMINI trials. I think there is some potential for that activity also in lung cancer, and we're also going to be investigating that in lung cancer trials as well, looking at combinations with ramucirumab.

So I think there's some potential, but the key thing is that the real value of rilvegostomig is its combinability across many different indications and with our ADC portfolio, and that's what we're focusing on doing there. And one final point on AVANZAR. That's an event-driven trial. I would just point out that we completed accrual for that at the end of 2024, actually well ahead of schedule. It's often the case that you have to wait for the events to come. That's sometimes a positive thing.

The next question is from Sarita Kapila, Morgan Stanley.

One on Imfinzi, please, and the second on Enhertu. So on Imfinzi, could you talk about how large the revenue opportunities are for Imfinzi across bladder cancer as well as gastric cancer? And how are you viewing the emerging competition from KEYTRUDA cancer? I believe there's competing data in the NIAGARA and VOLGA settings expected in 2027.

And then secondly, on Enhertu. Could you help us understand how you expect Enhertu to be integrated into the first-line HER2-positive setting in breast cancer? Are you expecting majority of patients to use Enhertu in line with the DB09 protocol? Or could you see Enhertu move more to a maintenance treatment -- I'm sorry, an induction treatment versus maintenance as your competitor has been highlighting? And if you could just touch on the confidence of the Enhertu monotherapy arm and when we could expect data, please?

Thank you, Sarita. So Dave, 2 good questions for you.

Sorry about that, Pascal. Thank you for that. Sarita, thank you for the questions on this. Just an opportunity to reiterate here that the growth that we saw in the quarter on Imfinzi, which was quite strong, really did come from the new indications that we were launching. You call out within one of those bladder cancer and NIAGARA, and we were really pleased to see the uptake that we saw there. In terms of the size of the bladder cancer opportunity, if you look across the various studies that we have, NIAGARA, POTOMAC, and then we look forward to the VOLGA readout, bladder cancer is a blockbuster opportunity.

And certainly, the potential for competition is one that we're aware of. EV and PADCEV has an important role, but that's the reason that the VOLGA study is also such an important part of all of the portfolio of bladder cancer studies that we have. So far, the uptake that we've seen with NIAGARA has been strong, and we look forward to hopefully building on that with a readout from VOLGA and have an opportunity for that to go forward. And I think that depending upon the readouts, it's -- we'll see exactly how EV does. There's multiple different scenarios that could play out. One of them is that Niagara continues to remain the primary standard of care going forward. Another is that the incorporation of EV is important, and that's why we've got a study within this setting.

Within gastric cancer and specifically, we talked about the MATTERHORN study Again, I think MATTERHORN is in and of itself a blockbuster opportunity. Obviously, this is something that we need to move forward with approval, but I think that we heard a very positive reception at ASCO from the discussant characterizing D-FLOT as a new standard of care moving forward. And I think that, again, when you take a look at the incidence of gastric cancer across the globe, this is an opportunity certainly for a very, very important opportunity forward and U.S. priority review for MATTERHORN, together with the guidelines updates, I think, speaks really well to the opportunity there.

On Enhertu, our expectation is that with the transformative 40 months in progression-free survival, clear superiority on a PFS basis over THP -- and really that, that was done in a treat-to-progression context that we will see the utilization of DB09 in line with the clinical study. I think on top of that also that the CR rates of 15% versus 8% is something that has really struck the investigator community as something really, really important. And you don't know which of those patients might get those complete responses. And what we do know is that treat to progression is the design of the study that resulted in the clinical benefit that we saw within DB09 in the Phase III.

So there is certainly some interest and hypothesis and understanding certain subsegments and how duration of therapy might be modulated within those. But I don't expect that at launch that that's what we're going to see. And I would also just point to that we've seen treat to progression as the primary behavior that we see with 03, 04 and 06 in the marketplace. And while DB09 is a slightly different context, I again expect that, that to be the predominant behavior that we'll see forward so that patients get the best chance to achieve the results that we're seeing within the studies.

Thanks, -- maybe let me ask a couple of quick comments. As it relates to Enhertu induction versus maintenance. I mean, of course, everybody can always speculate all sorts of things. But in the end, medical practice has to be driven by data. So you can speculate. It's a useful hypothesis, but then you have to test it with the clinical trials. Until you have data, it's a little bit dangerous, I think, to speculate. Patients' lives depend on those treatments and doctors should really stick to the data.

The other comment I would want to make is maybe taking advantage of the Imfinzi question is I personally think that because there are so many indications that are developed for Imfinzi new indications, some of them are smaller, some others are bigger. Overall, it looks like Imfinzi has been a little bit -- the potential of Imfinzi has been a little bit underestimated maybe because possibly it's difficult to forecast all those indications. But if you look at the first half, I mean, Imfinzi grew 21%.

And for the second quarter alone, we had a growth of 26%. And if you look at our top products, of course, Ruud is still leading the race with Farxiga, Tagrisso is the #2, but Imfinzi is our #3 product. So it's a very large product, very important product for us and of course, for patients. So I think it's important to really sort of consider all those smaller indications that collectively will actually fuel the growth of this important product.

The third question is from Gonzalo Artiach, Danske Bank.

The first one I want to ask is on tozorakimab on the COPD program with readouts coming in H1 2026. We recently saw Astegolimab and Itepekimab from Roche and Sanofi reporting somewhat mixed data in COPD, putting some questions around the IL-33 pathway in COPD. So I was wondering if you could give us some words on your view on tozorakimab given the recent events in the space? And my second question is on anselamimab.

As you, Marc mentioned, you recently reported that the program did not meet primary endpoint, but there is a subgroup where you see positive outcomes. I was wondering if you could expand a bit on that, on who are these patients and how big this population is and give us some flavor on what is in your eyes, the likelihood of FDA approval for the subset of patients with data you have now?

Thanks, Gonzalo. So Sharon, do you want to take the first one, and Marc will take the second one.

Sure. So about your question regarding tozorakimab and COPD, I will say broadly that not all molecules are the same. And we believe that we have a differentiated profile in tozorakimab as our IL-33 monoclonal antibody. One of the features that differentiates tozorakimab is that it can inhibit signaling through both the ST2 pathway as well as the RAGE/EGFR pathway. And we think that's incredibly important in COPD because RAGE/EGFR helps drive epithelial remodeling and mucus production.

We know that's important in CPD because mucus is driving exacerbations and exacerbations are driving mucus production. Remember that we had a Phase II stud,y, FRONTIER-4, which is a small proof-of-concept study in patients with COPD recruited irrespective of blood eosinophil counts. And we saw a clinical benefit in lung function and reduced risk of COPD worsening in both current and former smokers. So we look forward to the readout of the LUNAR program next year, and that includes the OBERON, TITANIA and MIRANDA trials for tozorakimab.

Regarding anselamimab, so let me remind you that we conducted 2 clinical studies, Phase III clinical studies in Mayo Stage III, one in IIIA and one in IIIB. Both studies were an add-on to plasma cell dyscrasias, [indiscernible], but also daratumumab was possible. And the third remark I would like to make this -- obviously, this condition is very severe with fatality and severe morbidity. Now to answer your question more directly about this prespecified subgroup, I'm not going to comment further today, but I can only say that this is a sizable minority and the clinical benefit that we have seen is very meaningful.

Thank you, Marc. Next question is Sachin at Bank of America.

I one and then one respiratory, if that was okay. So firstly, on Datro AVANZAR TL07, any color on timing of AVANZAR relative to TL07? Raises a question is how do you view the probability of those 2 studies? I think investors have been more cautious on 07 given PD-L1 cutoffs and lack of QCS. And then the second question was just going back to the prior one on [indiscernible]. So Sharon, thanks for answers on RAGE and the Phase II data. But I wondered if you've looked at the event rates you're seeing within that study and any ability to change here given that's been the issue that both the competitors have had.

Sharon, do you want to start with the second one and then maybe Susan, you'll take the AVANZAR one?

Sure. So I'll continue with the topic of tozorakimab. We won't comment on event rates in our ongoing studies. I am aware that some of the other companies noted that they saw a slowing of events during COVID-19. We can't comment on the ongoing study. But as I mentioned earlier, we remained very positive about the potential for tozorakimab to become a new medicine for patients with COPD. We're doing that based on the encouraging outcomes from our FRONTIER IV studies, and we continue to move forward recruiting at pace for our program. And so we look forward to that readout next year.

And so thanks for the question on Datro AVANZAR Obviously, the TL07 study, given it's also a first-line study in -- you might expect that the event rates for AVANZAR are going to be reflected in event rates generally across the first-line studies for the combinations of Datro plus IO. So we'll have to wait and see. I mean, I would just comment that AVANZAR completed accrual at an earlier time point. So that's one piece just worth bearing in mind. And I think as well, the learnings that we've had across the program from a biomarker perspective, we're looking to see how we can think about how those might be used across the program for Datroway as well.

Thank you, Susan. Next question is from Seamus at Guggenheim time.

So 2 questions very quickly. So Dave, I think historically, when we talked about the opportunity for Enhertu the numbers that we could comfortably get to in our own models, we're north of $10 billion, especially considering the success that we've seen within Enhertu so far. Can you just help us understand a little bit the path to numbers north of or at $10 billion for this opportunity. I think it's also starting to show through a little bit that AstraZeneca's own market performance in some of the direct reported markets is actually outperforming perhaps what we may have assumed in partner markets. So just trying to get a better understanding of the future of Enhertu as we look at the overall growth trajectory.

And then just the second question, as we think about the opportunity in cardiovascular disease, PASCAL, we've really seen opportunities emerge from AstraZeneca over time in several categories where you were either third to market or came on very strong from a fourth or third to market position and ultimately became the third or second largest product in category, Imfinzi being a great example. What do you see as the opportunity in obesity for AstraZeneca's existing product portfolio in that context, particularly as some of the large, very established second players seem to be stumbling.

Thanks. Dave, do you want to take the first one?

Yes, it would be my pleasure. So Seamus, let me start just first with. One of the really important dynamics that we've seen on Enhertu globally across regions within 2025. At the end of last year, we were commenting that DB-06 coming online and NCCN inclusion and guidelines was going to be an important catalyst along with DB-09, DB-11, DB-05 towards really reinvigorating growth beyond what we had seen so far with 03. And I'm really pleased that we've seen strong sequential growth, not only in Q1 but also continuing into Q2. And I think that, that's double-digit sequential growth that we're seeing on Enhertu is coming as a result of really driving across the various growth opportunities that we've got within the marketplace.

So within the U.S. specifically, we see DB-06 driving launch growth along with contributions coming from the tumor-agnostic label as well as DB-03. Within Europe, we're seeing DB-03 growth along with continued opportunities as we're making inroads into the HER2 low. And then again, the EM progress that we're making and really driven by China in no small part, I think, has been really, really very, very encouraging to see. So if we take a look at the opportunity for Enhertu in terms of where could we get to if we imagine at peak, I think that we can very much see that we'll see contribution across regions and then in addition to that, I think that DB-09 represents a very, very important opportunity to move into the frontline setting, as Susan mentioned in her comments, there are many patients who don't get an opportunity to be able to see a treatment in the second line.

So there are more patients available in the front line. And that's why DB-09 represents an important growth opportunity above and beyond what we've been able to achieve with those 3, of course, also the duration of therapy is something that we would expect to be longer. 11 and 05 together represent near blockbuster opportunities as we move into the early setting. And there's still clearly a lot more opportunity that we've got to move forward in the ultra-low segment for the successes that we've had in DB-06, Seamus, ultra-low remains a place where we still have opportunity for continued progress, and I expect that we'll be able to make that. And then finally, we see combinations as part of the future, combinations with our novel IO bispecifics being an opportunity for growth down the road. So Enhertu is really delivering nicely against our vision to be able to be one of the largest medicines in our portfolio.

Thanks, David. So your second question, Seamus, it's a great question actually because it gives me a chance to recognize the incredibly talented team we have in this company, not only commercial, commercially, I mean, the commercial teams around the world are really absolutely exceptional. You've just mentioned yourself that Enhertu is doing better than you would -- you expected and David and his team are doing incredibly good job everywhere. Ruud and his team are doing a great job, same in rare disease. So if we now look at your specific question, one aspect is really the quality, the talented teams we have in every geography. And quite frankly, it's taken us 10 years to build the team we have today in every country because it's not that simple.

So that's number one. Number two is we have a tremendous footprint. And our motto is, of course, we follow the science, but it's also that we bring our medicines to as many patients as possible around the world. And so that means the emerging markets, that means China, that means every single country around the world. We want to bring our medicines to those people. And we should remember that there are many, many more people living outside the U.S. and Europe than inside those 2 important geographies. And if you look at Farxiga, it's a good marker of this. a great majority of our sales these days, they come from countries that are not the U.S.

The U.S. is very, very important, of course. But still as soon as you have a medicine that is affordable, easy to take like an oral agent, then you can reach out to the millions, hundreds of millions of people around the world who need our medicine. So the talent, the footprint, the way we develop those products, I think we always try to be innovative. An oral agent is a different route, of course, compared to an injectable, it will be easier, cheaper, but also our clinical development programs. We leverage the combinations. People who suffer from obesity.

And I hate this word obesity actually because at the end of the day, what it is about is abdominal central, what you call central obesity. I mean, in fact, you can be someone who doesn't necessarily look obese, but you have central fat, you have abdominal fat. And abdominal fat is really what drives insulin resistance, inflammation and all the secondary considerations that you can think about. So then these people typically, they suffer from other complications, hypertension, cholesterol dyslipidemia, kidney disease, et cetera. So we really try to look at how do we address all the components of this metabolic syndrome by combining our products.

So our offering will be not only an oral agent, but it's also going to be combinations and addressing all the risk factors. So what we try to focus on is less the sort of what you might call the cosmetic obesity market, which is a consideration for some people. But we believe the most important piece is really central fat and the insulin resistance and all the consequences of this. But I'd also like to ask Ruud maybe to tell us a little bit about what we're going to do with this cardiometabolic franchise.

Yes. No, thank you so much, Pascal. And I think you have summarized it quite well. We truly believe we have a differentiated strategy here. We have a long heritage, as you already mentioned, in this disease area. There's a deep understanding from a science perspective. And I have to say we have excellent relationships across the world with top cardiologists, internal medicine physicians -- and I think the combination and the different mechanism of action is a true differentiator.

There are so many people who are overweight and have very serious risk factors like the ones you mentioned and the fact that we have in our portfolio, I think, a quite unique oral PCSK9. Sharon discussed the potential of Baxdrostat. We discussed our own SGLT2 Farxiga. It also means that if everything works and the oral GLP-1 is, let's say, is in medicine, it's relatively easy to combine it. And it will also be then easily accessible for so many people around the world. So I think it's a truly differentiated strategy. We are committed to it. We are investing a lot of, let's say, resources, money into it because we truly believe that we can change the trajectory of so many people around the world with cardiovascular and renal diseases.

Thank Ruud. Peter Verdult at BNP Paribas.

Pascal, your Board asking this question, but latest thoughts on tariff dynamics and where expectations or your expectations sit on what the current administration is cooking up with respect to Part B and/or reforms. Secondly, just for Sharon or Marc, on Baxdrostat and the C5 data, I realize you can't go into any sort of quantification, but there are public data sets from competitors out there.

So can I push you on how the data stacks up in your view? Is it the overall profile of efficacy, safety and convenience? Or can we dream that there is superior efficacy on either asset? And then lastly, if you don't mind, just a third one, Sharon Pascal, just because most people on the call today have probably hopped over from Novo's profit warning call earlier. You've got a clear strategy for obesity. It's not going to play out until next decade. But it's likely that investors are going to increasingly question obesity market value expectations going forward. So can I just confirm that when you think about future pricing, it's at a materially lower level than the current GLP-1 price?

Thank you, Peter. So I had the word board at the beginning. I'm not sure if I captured your question. I think your question was about tariffs and also MFN. So maybe tariffs, Aradhana you want to take that one?

Sure. So I think your question was whether the tariffs that we expected are in line. Clearly, the tariffs between U.S. and Europe have been announced. I think it still is a question of timing and what happens with the administration when they get implemented, et cetera. We had mentioned on our first quarter call that we have pretty good and segregated supply chains. And therefore, there's only a handful of products where we do import some products from Europe into the U.S.

We do already have capacity for those products in the U.S., and we've already started some of the tech transfers, which obviously will take a little bit of time. But we will not be significantly impacted by tariffs. We reconfirmed the guidance this year. And this year, obviously, we're managing through inventory and so forth. But any impact, even if there is, is going to be very short-lived since we've already started the tech transfer process.

Thank you, Aradhana. On the MFN, maybe I can take this one. And we've had, as you can imagine, many interactions with the administration at different levels. The industry has had all the companies. And we, as a company, have had several interactions that certainly personally had many interactions. And we've basically shared what we think could be done because I do believe a rebalancing equalization, if you want to call it this way of pricing, a rebalancing of pricing around the world is necessary. The U.S. can no longer pay for the R&D for the world. I mean it's not sustainable.

So we need to have a fairer sharing of the cost of R&D in our industry across which countries. And of course, poor countries, we need to be more flexible with price, but which countries need to share and then share -- and you have to consider GDP levels, et cetera, for sure. So we've actually made a number of proposals. Of course, as you know, the pricing structure in the U.S. and the U.S. market is a huge market. It's a complicated market. Pricing is very complicated. So there's a lot of technicalities involved. But we did make our proposals, which we believe could achieve what the President is trying to achieve, but we also need Europe to increase their share of GDP allocated to innovative pharmaceuticals.

I mean if you think about it, today, the U.S. spends 0.8% of GDP in innovative pharmaceuticals, 0.8%. The U.K. and many countries in Europe, Germany is better, but many countries in Europe spend 0.3% of GDP. That's not enough. They need to increase it. And actually increasing it would be good not only for patients because we talk about price, but it's not only a question of price, it's a question of access. In many countries in Europe, people, patients wait for years to get access to medicines that could save their lives. So it's a question of access, not only price.

The second reason that would be good for Europe is we believe our sector is a great sector in terms of science, innovation, creating jobs and economic value. So today, innovation -- I mean, I started in the industry a long time ago. And at the time, innovation was driven out of Europe, and we were selling pills really. Today, innovation is driven out of the U.S. There is an explosion of technologies, as you know, that is driven by all these investments that has taken place. China is ramping up, as we've talked about before, very rapidly. And sadly, Europe is falling behind.

So I think this rebalancing needs to take place, not only for the industry, but also -- and not only for the U.S. pricing level, but also so that Europe can actually contribute to this innovation and then benefit from it in terms of value creation and economic development. But the administration is considering all these things, and we'll see what comes out of all these proposals that different companies may have made.

On the C5 data, I'll ask Marc to comment, but I want to make a quick comment. We really want to be respectful of congresses and data presented at the Congress. We don't want to disclose data ahead of the Congress because -- we want to be respectful of the processes that are in place and the right of Congress to keep the data until it's presented. But maybe Marc in a minute wants to make a few points. The last point I will make about the so-called obesity. I've never really liked, as I said, the word obesity for me, it's about weight management because actually, at the end of the day, for me, it's not about how you look.

I mean, you look the way you want to look, quite frankly. The question is how much abdominal fat do you have and how much inflammation do you create around your liver, around your pancreas, around your heart in your body and how much that drives multiple conditions, in particular, metabolic conditions. So our approach has always been to target this central fat, this abdominal fat and the -- I mean, metabolic syndrome is not the right term because it's never been a recognized indication, but let's say, this insulin resistance. And that's really what we target. We believe it's a big market.

We believe it's a market that needs to be addressed with prices that are affordable. And then payers and patients around the world should benefit and then should be reimbursed because if you address that, you're going to really help patients. But at the end of the day, these are chronic treatments. And essentially, you have to be easy to take and you have to be affordable so people can take these medicines for a long time. Sorry to talk a little bit long. But Marc, over to you for the C5 data.

Yes. So as you advised, Pascal, I'm not going to be able to talk about detailed data. What I can say on top of what I've expressed in my prepared remarks is that the rapid onset in patient-reported outcome is going to be a strong point of this gefurulimab. And overall, for our C5 franchise, I think it will be a very good -- it will complete the injectable franchise, infusion franchise that we have with Ultomiris and Soliris in myasthenia gravis. So we see it as a complementary product in addition to the strong franchise that we have today.

Mark Matthew Weston, UBS.

Two questions, if I can. The first on the C5 franchise. Marc, I'd be very interested to understand the dynamics in the market with the first launch of Soliris biosimilars. Are we seeing any signs of payers in the U.S. or ex U.S. introducing step edits or therapeutic substitution forcing patients back down to biosimilar Soliris away from Ultomiris?

And then a question for Iskra on Farxiga VBP. Can you remind us how much of Farxiga is in China? And also, I realize you don't know yet what the potential financial impact is. But in the past, Astra has previously given guidance on other VBP products suggesting that potentially sometimes there are commercial measures that may offset the impact of VBP. And I just wondered whether that was something that you expected to see here.

Thanks very much. Marc, do you want to take the first one?

To try to address your question, I think the continued progression of Ultomiris and the increasing also conversion from Soliris to Ultomiris, I think brings part of the answer. So we do not have -- we do not face a sort of a back to biosimilar Soliris from payers. Once the conversion has been established in any given indication or any given market, usually Ultomiris has a very sustainable growth.

Thanks for the question. So as you know, Forxiga represents a very important growth driver for our CVRM portfolio in China and both in diabetes as well as in CKD and heart failure indication. As we already communicated and Ruud already mentioned, we do expect VBP for Farxiga as part of batch 11 with the impact in the second half of this year. Your question is very, very right. There are definitely the different implications of the usage of the drugs in a post-VBP setup. And you know that VBP is usually driving much broader utilization and broader access for many more patients.

And given the unmet need in China, I'm sure the Forxiga and SGLT2 class will be widely used, which means that in the short period, you can anticipate the reduction primarily driven by price. But equally, you can expect the tail and the potential increase volume driven as we saw in many other brands in the post-VBB time in China. So basically, we anticipate very similar trend to the brands like Crestor, for example, in the past.

And actually, Matthew, you referred to commercial activities. In fact, it's what we call consumerization in China. To be honest, it's actually very similar to what companies are now considering in the U.S., and they call go direct or direct-to-consumer. It's essentially selling directly to patients who, of course, receive a prescription. And if you look at Crestor, that's what we have been able to achieve. Patients get a script from their doctors and more and more, they get an electronic script these days through video consultation.

And then they get their Crestor delivered to their home. And a lot of people prefer to pay $25 or $30, I think it costs delivered to their home rather than go to the hospital and queue to have it for free. So we think we can actually do a similar approach in with Farxiga in China. Of course, sales will be lower, but ask said, there will be quite a tail. And actually, quite interestingly, you see in some parts of the U.S., similar behavior. Sometimes people can't put up with all the hurdles of getting reimbursed and they decide just to pay out of pocket and be done with it. So if the product is at a price that is affordable and you can get it delivered to your home, of course, you need a script, but it's a convenient option for patients.

Rajan Sharma at Goldman.

So just on the rare disease side of things. So one of the key catalysts this year is obviously efzimfotase alfa. Could you just help us understand what the target profile is for the drug, particularly in the context of Strensiq in the same setting? What's the residual unmet need there?

So thank you for this question on efzimfotase alfa. So first of all, efzimfotase alfa has been developed in both the adult and pediatric indications. And our goal is to achieve a much wider geographic coverage than we have with Strensiq. The coverage of Strensiq is strong in a few countries, but the access and the reimbursement has been slower in other parts of the world.

Now if you look at the 2 products, efzimfotase alfa will be one administration, one injection every 2 weeks. And if you compare this to Strensiq, you have either 6 or 12 injection in the same period of 2 weeks. So it will have a greater patient benefit. As I said earlier on, we will have the results of our Phase III trials towards the end of the year. And we look forward to bringing this new therapeutic solution to many countries around the world.

Thanks, Marc. Michael Leuchten at Jefferies.

Quick question on the Part D redesign, please. One of your European competitors talked about how the volume uplift in the second quarter was below their expectations and the overall impact from the Part D redesign, maybe not as hoped. Your oncology franchise overall performed very, very strongly in the second quarter. I was wondering if you could talk to, was that despite the Part D redesign maybe not having the volume effect? Or did you not see that slower uptake and you're quite happy with what you saw?

Dave, I mean, it's really mostly an oncology question. Do you want to cover that?

Yes, it would be my pleasure. So Michael, I commented last quarter that the Part D redesign really was a rebasing event as we saw the gross to net impact take place for paying for the offset for the co-pay capping. And we've also talked about how we've seen an offset in addition to that with fewer patients on free drug, lower abandonment rates. And so some of these elements are really coming into play to help to offset the additional liability that we face. I also commented that after that rebasing, we would see sequential growth pick up and that we would see growth from there, not only on the existing medicines, but also from new launches.

I'm really pleased that we saw that with Calquence and with Tagrisso. So with Calquence, we saw sequential growth of 15% in the United States. With Tagrisso, we saw sequential growth of 12%. And in both of those instances, demand was the overwhelming driver of the growth that we saw. And so as we take a look at the opportunities in front of us, Tagrisso, we're going to continue to drive FLAURA2, which we've been having very nice success with alongside with ADAURA and LAURA.

With Calquence, we look forward to the opportunity to continue to take advantage of the leading share position that we have and moving forward with that and getting ready for the AMPLIFY launch as we move to a finite option. So I would say that this is playing out consistent with our expectations and how I believe that we've been talking about it for the last year or so.

Thanks, Dave. We'll take one last question, Luisa Hector at Berenberg.

Thank you, Pascal. A big picture one really. So I mean, it's intriguing that the diversification of Astra is very clear, and we've heard a lot of it through the call today. You've also seen an unprecedented number of positive trial readouts. But there's still a bit of a leaning towards oncology. I mean, great that we now see Imfinzi with so many uses in cancer, potentially on track to be your highest selling drug.

So I'm just wondering 2 things really. Has the mix of your 2030 revenue ambition shifted? And how confident are you that you now have the right number of therapy areas at Astra and that your end-to-end pipeline filling is sufficient to sustain the company through to the next decade. So I guess it's really where are the gaps that you see given all of the infilling that you have very successfully achieved?

Thanks, Luisa. I'm not -- I suspect actually Ruud would take offense of that comment because, I mean, in the first half, if you look at it, oncology was almost $12 billion, $11.95 billion and biopharma was $11.2 and still growing. So it is a very important part of our company. And I think it shouldn't be -- what shouldn't be underestimated is the fact that in the emerging markets, in particular, the foundation of our presence is actually biopharmaceuticals.

And it's key because that creates the platform to then launch products in oncology, in rare disease. If you start from very little, it's hard and you don't have the talent. I mean in many geographies, I was in the Middle East, Southeast and many geographies, we've been able to build really, really talented people -- teams because we've got this presence and we've attracted those people. And then on this foundation of biopharmaceuticals, we actually can add oncology, which is really a great opportunity for -- is in the emerging markets. but also rare disease where Marc and the team have been driving growth.

So that's one aspect. The second aspect is, if you actually look at the pipeline, there are several medicines that are actually going to drive our future in what we call biopharmaceuticals. In respiratory disease, we have several products. I mean those are commercialized growing and then new ones. And in cardiovascular medicine, we have quite a number of products that can be big. I mean an oral PCSK9, if it works the way we hope it will work, has enormous potential around the world. PCSK9 are great products, but they are injectable, they are kind of expensive -- outside the U.S., the use is limited. If you bring an affordable oral agent, you have a huge potential.

Hypertension, huge potential. A lot of people across the world have, again, this sort of central fat, even though they may not look overweight, they are central fat and then insulin resistance and they have hypertension, huge potential. Same for, of course, the oral GLP-1. So I think over the next few years, if our pipeline delivers the way we are hoping it does, and we started well with Baxdro, you'll see a great growth in cardiovascular disease. So as to the point about do we have enough therapy areas, I think, yes. We can always go and explore new things. But the big -- what are the biggest killers in the world.

Cardiovascular disease, number one. Respiratory disease, people forget always that mortality from asthma attacks or COPD attacks is high. And the third is oncology. So we are actually addressing the 3 biggest -- when I say oncology, I mean, oncology, hematology, we are actually addressing the 3 biggest killers in the world. And -- and the science is exploding, not only in oncology, but now in cardiovascular and respiratory disease and immunology. So I think we have enough, and we are very focused on changing medicines in those areas with new technologies and to grow post 2030.

So with this, thank you so much for all your great questions and your interest, and I will wish you a great day.

Welcome, ladies and gentlemen, to AstraZeneca's Meet the Management Event ASCO 2025.

Before I hand over to AstraZeneca, I'd like to read the safe harbor statement. The company intends to utilize the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Participants on this call may make forward-looking statements with respect to the operations and financial performance of AstraZeneca. Although we believe our expectations are based on reasonable assumptions, by their very nature, forward-looking statements involve risks and uncertainties and may be influenced by factors that could cause actual results to differ materially from those expressed or implied by these forward-looking statements.

Any forward-looking statements made on this call reflect the knowledge and information available at the time of this call. The company undertakes no obligation to update forward-looking statements. Please also carefully review the forward-looking statements disclaimer in the slide deck that accompanies this presentation and webinar.

[Operator Instructions] Now please stand by while I connect you to the auditorium in Chicago.

Good evening, everybody. Thank you for joining us. Welcome, and we'll start sharp on the hour because Dr. Tolaney and Prof. Turner need to leave us at 7:50. So again, welcome, and I hope you have enjoyed the ASCO as much as we did so far over the last couple of days.

So this is our forward-looking statement, nothing special here. You know it. This is our agenda. And we are privileged to have, as I said, Prof. Turner and Dr. Tolaney joining us. And you will have a chance to hear from them what they think of this data, but also answer your questions. And of course, you have a number of us from the leadership team.

Let me just start with reminding you what our ambition is. Our ambition is to become a leader in cancer care and -- but also in cardiovascular disease, respiratory disease. We're building immunology. And of course, we want to remain a leader in rare disease. Our goal is to achieve $80 billion by 2030 through science and through innovation and building a pipeline of products we have. But we're also working on what we call the day after tomorrow. And you've probably seen some of the early data we have on some of our new technology products.

As you can see here, we are making good progress across all our key priorities, whether it is about weight management and the risk factors, we have now 3 Phase III studies that have either started or in the process of starting, supporting our oral PCSK9. We also have the Phase II program supporting the oral GLP-1.

Now if you look at oncology, whether it's ADCs or IO bispecifics, cell therapy T-cell engagers also, we're making very rapid progress. We now have 6 specific AstraZeneca ADC in the clinics. We're also making progress with our radioligand programs. We have a large Phase III program supporting our IO bispecifics. And finally, as you can see on this chart, we're making also very good progress with our cell therapy and our T-cell engagers.

We -- I should have mentioned one thing important, very important that Cristian would not be happy if I didn't remind you this. 50% of our trial -- more than 50% of our trial are enrolling ahead of plan. And it's important to keep this in mind for 2 reasons. First of all, it's good news. We are really executing very, very well, and Cristian and his team are doing extremely well. But the second aspect of it is you have to expect, of course, our R&D expenses are following this trend of accelerated enrollment in our clinical trials.

Now we are still staying with our guidance for the year, of course, and just wanted to keep you informed of our progress. But for the full year, you should expect us to land at the upper end of the lower 20s. As we always said, we are targeting lower-20s percentage of turnover in terms of our investment in R&D.

But this investment is actually a good investment. If you look at the progress we're making, we've had a whole series of positive studies and important ones since the beginning of this year. Of course, 3 of those we're presenting here, 2 plenaries and 1 special session, and there's more to come. More to come this year, as you can see on this chart, more to come next year.

So it's really important to keep in mind that we have a very heavy readout programs over the next number of months. And that's why I've said many times, and I want to say it again tonight, by the end of this year or early next year, you'll have a good sense for whether we are on track with our 2030 goals of $80 billion. First of all, you'll see the momentum in the existing portfolio, but also you will see how we deliver on the pipeline.

We're also investing in both manufacturing and R&D sites. So an important message here for you relates to tariffs. The biggest part of our manufacturing footprint is in the United States, and we have been building it over the last few years because we always thought we have to have a specific footprint for China, but we also have to have a specific footprint for the U.S. That allows us to manage the potential tariffs if they were to be implemented for pharmaceuticals.

There's a couple of products, as we have communicated before, that we believe would still be impacted by tariffs, and we are moving the manufacturing of the U.S. supply to the U.S. And if any impact of tariffs we would have, it would be only temporary. So on the manufacturing side, we are well covered. We have invested recently in a cell manufacturing plant in Rockville, Maryland. So the tariff is something we can manage.

Just very quickly because today is a meeting about oncology and the data we presented. For those of you who are interested in MFN, we don't have a lot more to say than what we've said before, which is we actually agree that there has to be some form of equalization. Europe and the wealthier nations around the world need to pay a bigger share of the innovation. And probably there has to be a rebalancing of the cost of this innovation and the pricing of our products across the world. But there's not much more we could talk about today about MFN. Let's try and focus on the great data that we've been developing.

And we're also relying on a very strong network of R&D centers. As you know, we invested in a new center in Beijing, which we believe will really help us continue building the pipeline. And we hope to continue on this great series of ASCO plenaries that we've experienced over the last 5 years. Of course, we remain humble, as always, but we are also very proud to see those numbers, 8 plenaries, and I'm not even counting the special sessions, over the last 5 years since 2020.

So with this, I'll hand over to Susan, who will take you through our progress and the themes here. Over to you, Susan.

Thank you, Pascal, and welcome, everybody.

So just as a reminder, on the left-hand side of this slide are some of the themes that we are driving in terms of the strategy for oncology drug development that we talked about at the Investor Day last year. So first of all, of course, the opportunity to improve on the backbone of chemotherapy and radiotherapy with the advent of antibody-drug conjugates and radioconjugates; the segmentation of the currently defined IO-sensitive tumor types with the next wave of IO agents; the expansion of that space with the introduction of T-cell engagers and cell therapy; putting these together into key combinations that can have the potential for transformation of outcomes; and then driving the early intervention in the disease where the opportunity for cure and long-term benefit is greatest.

I'm also very proud of the consistent delivery of ASCO plenaries over the last several years, which just demonstrates the value of the AstraZeneca team. And you see many of the R&D team that are responsible for this here in the room with us today. So again, in terms of our presence at ASCO this year, it's not just about the plenary sessions that I'll talk -- we'll talk more about. But we have 82 abstracts accepted, and we have many other oral presentations that have gone on, which are just demonstrating our progress against those key themes that we're driving for our strategy; and 8 simultaneous publications during ASCO, including 3 in the New England Journal of Medicine.

So what does this do in terms of helping to move us against those themes. First of all, we're going to hear a lot about the SERENA-6 and DESTINY-Breast09 studies, which demonstrate our leadership moving into the first-line treatment of breast cancer in the hormone receptor-positive breast cancer setting with SERENA-6 and in the HER2-positive breast cancer setting with DESTINY-Breast09.

We're also establishing improvements in outcomes and transformational outcomes in gastrointestinal cancers, which is something that I don't think everybody pays as much attention to as perhaps is needed. So really delighted with the data from the MATTERHORN study in the perioperative regimen. Again, another example of a perioperative regimen that can have this potential for improving the long-term outcome and the potential for cure, but also DESTINY-Gastric04 confirming a HER2 benefit in gastric and GEJ cancers in the second-line setting. And then again, Phase II data from our GEMINI study in hepatobiliary cancer showing the role of rilvegostomig.

And then in lung cancer, where we really have bold ambition and already have a leadership position, we have the ambition to treat 1 in 2 lung cancers by 2030, and good progress against that in terms of further data that was presented here with the NeoADAURA and data with the NeoCOAST-2 in the neoadjuvant setting, TROPION-Lung02 in the first line and TROPION-Lung04 for the combination of rilvegostomig with dato. And I'll talk a little bit more about those.

So where do all of these fit in the lung cancer landscape? And you can see, this is the overall map. I've highlighted in the yellow boxes those studies that we're going to talk a little bit more about here. And again, as said, we've established leadership in lung cancer with agents in many different segments of the lung cancer map. And what we're presenting in terms of the data here at ASCO shows how we're moving towards that ambition of treating 1 in 2 patients.

So the new data that we have with Datroway and IO in QCS gives both better confidence in how we can use the QCS biomarker in the first-line setting in combination with IO agents. And the data that we've got with NeoADAURA shows how we -- it's really important to be testing patients with EGFR-mutant lung cancer at the time of diagnosis and, together with the data that we've got from the SAFFRON and SAVANNAH studies, really reinforces that Tagrisso is the backbone therapy for EGFR-mutant lung cancer across all stages of this disease.

So let me show you a couple of snippets of these data with the NeoADAURA data here. Again, neoadjuvant treatment of EGFR-mutant lung cancer does not, with chemotherapy, does not result in a meaningful pathologic complete response rate. What we hear -- the primary endpoint in this study was the major pathologic response rate, and this was clinically meaningful in this setting. You had a significant improvement in both the Tagrisso monotherapy and the Tagrisso plus chemotherapy arms compared with placebo plus chemotherapy. So again, this reinforces that you really should be testing all patients with lung cancer for EGFR mutations before starting an neoadjuvant therapy because the currently established treatments there of chemotherapy or chemo plus IO do not work.

And what the early data for event-free survival from this study showed, as you can see on the right-hand side, is actually that you are seeing a trend to improvement for the Tagrisso plus chemo and the Tagrisso monotherapy arms compared to that standard of care. And what Jamie Chaft, the PI for this, also showed is that endpoint of major pathologic response was predictive of this EFS outcome in this patient population.

In terms of the other data that we showed for Datroway and IO, first of all, on the left-hand side, we built on the data that we had shown at the World Congress on Lung Cancer, confirming the pathologic complete response rate of 35%, a major pathologic response rate of 63% for the combination of Datroway and Imfinzi, which is around double the responses for both path-CR and NPR that we saw with Imfinzi plus chemotherapy in the AEGEAN setting. And again, what we also saw there, as you've seen in many other studies, is when you do get a path-CR, that predicts for the event-free survival outcome. So this is very encouraging.

In the middle panel, what we showed with the TROPION-Lung02 data is more data on the Datroway plus pembrolizumab with or without platinum chemotherapy in this study. And the most important takeaway from this is that the QCS biomarker that we showed from the TROPION-Lung01 data is also predictive of the outcome in this setting in a first-line setting in combination with IO with or without chemotherapy for both PFS and OS.

And on the right-hand side, you see the data from the TROPION-Lung04 study with the combination of Datroway plus our PD-1 TIGIT bispecific rilvegostomig, again, showing deep and durable responses with around half of these patients having ongoing responses at the current time.

So again, if you put all of these data in context now of the breast cancer landscape map, what you can see is that we are moving into this first-line setting and changing and redefining how breast cancer is treated in that first-line setting with a very innovative study that is SERENA-6 that Nick Turner will talk about and also the DESTINY-Breast09, which really changes the game for first-line HER2-positive breast cancer.

And so with that, I'm delighted to hand over to our key external experts to walk you through this data. And I'll hand over now to Nick Turner to talk about the SERENA-6 study. Thank you.

Well, thanks for that introduction, Susan. So it's a pleasure to show the results of SERENA-6.

So SERENA-6 was a Phase III double-blind study in hormone receptor-positive HER2-negative advanced breast cancer in the first-line patients who are on aromatase inhibitor and CDK4/6 inhibitor for at least 6 months with any of the 3 approved CDK4/6 inhibitors who had ESR1 mutations detected in circulating tumor DNA and without any evidence of disease progression and testing to identify the mutations was carried out every 2 to 3 months at approximately the same time as staging scans. We randomized 315 patients 1:1 to continuing the AI, continuing the CDK4/6 inhibitor and the placebo for camizestrant or switching over to camizestrant, continuing the CDK4/6 inhibitor and the placebo for AI. And the primary endpoint was PFS by investigator assessment.

So we saw a substantial improvement in PFS as the primary endpoint. So we saw median PFS improved from 9.2 months in the control group of continuing AI to 16 months in the switch to camizestrant group with a hazard ratio of 0.44, highly statistically significant, so over a doubling of PFS. And the curve separated early and stay separated. And importantly, at 24 months, only 5% of patients were without progression who had continued on AI, but that increased to 30% who switched to camizestrant, I think with clear evidence of a tail emerging. And I think it's really important to place this in the context with what we've seen with oral SERDs in the second or third line, where we've seen a delta of the median of only 2 months, whereas here, we're seeing a delta of 7 months. So really quite a favorable comparison with the data we're seeing in this setting.

We've also looked across a number of prespecified subgroups, clear evidence of consistent efficacy of camizestrant across all subgroups. And importantly, we've boxed out the 3 CDK4/6 inhibitors. So all CDK4/6 inhibitors were represented in the study with clear evidence of efficacy across all 3 of the CDK4/6 inhibitors.

Now really importantly, we also looked at patient-reported outcomes in SERENA-6. And so this is the time to deterioration in quality of life, and that improved from 6.4 months in the control group up to 23 months in those who switched to camizestrant with an adjusted hazard ratio of 0.53, and we also saw a time to deterioration in pain. And so I think this is really picking up what progression actually means for patients. It causes substantial symptoms, and it's also a considerable psychological blow for patients. Many patients are on their first-line AI and CDK4/6 inhibitors for years. They're back to normal life, but that first progression event is quite an unpleasant, unfortunately, pointing for them that this isn't going to last forever. So avoiding progression really matters, and I think that's what we pick out in this data.

We also looked at PFS2, so time to progression on the second-line therapy. At this point, this data is really quite immature. But nonetheless, there's a really encouraging hazard ratio of 0.52 at this point, and we'll need longer follow-up. And PFS2 is a very important endpoint because it's going to very likely show that, that benefit we saw on PFS1 will carry through. But there are some limitations on the data at the moment, in particular, in the camizestrant arm, many patients are still on treatment. So we've only really had the bad actors that have progressed on the camizestrant arm and are contributing to PFS2. So I think with longer follow-up, we would very much expect PFS2, if anything, to get better with longer follow-up, and we'll certainly look forward to those future analyses.

In terms of tolerability, camizestrant was very well tolerated. There were similar rates of serious adverse events in the 2 groups. The discontinuation rates were universally low across the study. Only 1% of patients had to discontinue camizestrant due to adverse events. There's more detailed analysis of the AE profile on the right-hand side. So there was a modestly increased rate of neutropenia in the camizestrant group. But this, of course, is the characteristic side effect of the CDK4/6 inhibitor partner and is asymptomatic. And this modest increase simply just reflects that they were on their CDK4/6 inhibitor for longer.

Then if we look at symptomatic adverse effects, broadly, they are very similar between the 2 groups. The one that was higher is photopsia. So that was present in 20% of those on camizestrant, 8% of those on AI. But photopsia is brief flashes of light in the peripheral vision. It had no impact on patients in this study. And bradycardia, we only saw at very low rates. Bradycardia was sinus bradycardia and was asymptomatic. And I think what we really see coming out of this big first Phase III of camizestrant, that the side effects of photopsia and bradycardia were really not clinically relevant. And certainly, that matches my personal experience with my own patients.

And then just to look at the conclusions, switching AI to camizestrant whilst continuing the CDK4/6 inhibitor, guided by the emergence of ESR1 mutations during first-line therapy ahead of disease progression, significantly improved PFS in patients with hormone receptor positive/HER2-negative breast cancer. That PFS benefit was consistent across the CDK4/6 inhibitors and all the clinically relevant subgroups.

Switching to camizestrant substantially delayed the time to deterioration in quality of life. Camizestrant was well tolerated with a very low rate of discontinuations due to AEs. And SERENA-6 is the first global registrational Phase III study to demonstrate the clinical utility of using ctDNA monitoring blood tests to detect and treat emerging resistance in breast cancer. And we think that this hopefully is a new way of refining first-line treatment for patients with advanced breast cancer that has a significant potential to improve their outcomes.

Thank you.

Well, now we're going to switch directions and talk about HER2-positive disease. So these are the data from DESTINY-Breast09. So DESTINY-Breast09 is a randomized Phase III study of trastuzumab deruxtecan with or without pertuzumab compared to a taxane plus trastuzumab and pertuzumab for first-line therapy of metastatic HER2-positive breast cancer.

So this was a trial for patients who have not had any previous therapy in the metastatic setting for HER2-positive disease, and they were randomized 1:1:1 to receive trastuzumab deruxtecan plus placebo or trastuzumab deruxtecan plus pertuzumab or a taxane plus trastuzumab and pertuzumab. And the trial was really designed to assess if trastuzumab deruxtecan plus pertuzumab is better than THP and was also designed to look to see if trastuzumab deruxtecan alone is better than THP.

And so here at ASCO, we presented the results of the interim analysis comparing trastuzumab deruxtecan plus pertuzumab to THP, given that those data did meet the stringent criteria set at the time of the interim analysis for success. The T-DXd monotherapy arm did not meet those stringent criteria. So those patients on the T-DXd plus placebo arm continued to be followed until the primary PFS analysis.

So here are the data for the primary endpoint of progression-free survival comparing T-DXd plus pertuzumab to THP. And what you can see is that the combination of T-DXd and pertuzumab led to a statistically significant and, I think, very clinically meaningful difference favoring T-DXd and pertuzumab compared to THP. So the median PFS for T-DXd and pertuzumab was 40.7 months compared to 26.9 months with a hazard ratio of 0.56 and a p-value that was less than 0.00001.

And I think what's really interesting is you can see that these curves separate early, but they really continue to widen over time. And in fact, because our follow-up time is about 29 months at this time point, you can see that there are very few events at the tail of the curve. And so it does mean there's some instability at that tail. And so we do still have 46% of patients that remain on study treatment with T-DXd and pertuzumab. So it does suggest that this median is likely to evolve with further follow-up.

You can see that the benefit for T-DXd and pertuzumab when compared to THP was really consistently seen across all the subgroups, and that included our stratification factors, which are highlighted in yellow, which looked at prior treatment status, hormone receptor status and PI3 kinase mutation status, again, showing benefit across all these groups.

The objective response rate was also numerically higher for T-DXd and pertuzumab, around 86% compared to about 79% for THP. But what I thought was very important, too, was that the complete response rate with T-DXd and pertuzumab was almost twice that of THP. So the complete response rate was 15% for T-DXd and pertuzumab compared to 9%.

And when you look at the overall survival data, I think it's important to remember, survival data is very immature and is only being presented descriptively. There was no formal testing for OS at this time. There are only 16% of survival events that have occurred at the time of the interim analysis. But even so with very limited follow-up, you do see that there's already a trend favoring T-DXd and pertuzumab with a hazard ratio of 0.84.

When you look at the safety and toxicity, you can see that, in fact, the rates of Grade 3/4 adverse events and the rates of serious adverse events were actually similar between the 2 arms. There were more dose interruptions and dose reductions with T-DXd and pertuzumab compared to THP. And there were numerically a few more deaths with 5 deaths on the T-DXd and pertuzumab compared to 1 on the THP arm.

To the right, you can see the most common toxicities by arm with the most common toxicities for T-DXd and pertuzumab, including nausea, diarrhea and neutropenia; and for THP, including diarrhea, neutropenia and anemia. So very consistent with the known toxicity profiles of the individual agents used.

So just to summarize, T-DXd and pertuzumab demonstrated a statistically significant and very clinically meaningful improvement in progression-free survival with a 44% reduction in the risk of disease progression or death. The duration of response was also substantially longer with T-DXd and pertuzumab, and the complete response rate was almost double. And while the overall survival data certainly are immature at this time, you already see a trend favoring T-DXd and pertuzumab.

And we also looked at PFS2, so looking at the time from randomization to progression on second-line therapy. And you can see that, that also is supportive of the impact on longer-term outcomes. The safety data were consistent with the known toxicity profiles with no new safety signals identified. And so I think these data really do suggest that T-DXd and pertuzumab should be considered a potential new standard of care for first-line HER2-positive metastatic breast cancer.

Thank you. I will pass it over to Sunil Verma.

Thank you, Dr. Tolaney. I'm going to keep my remarks short because I think we have some time for Q&A before Dr. Tolaney and Prof. Turner have to leave.

I think it's really important to see, we just heard 2 really remarkable presentations looking at transformation in first-line treatment of metastatic breast cancer. So how do we put this into context? So let's take a look at really the meaningfulness of the HR-positive breast cancer segment, as highlighted by the great presentation that Prof. Turner did at the plenary presentation.

So the first thing, AI plus CDK4/6, of course, is the standard of care. There hasn't been any substantial changes in that standard of care for many years since 2012 when the first data came out. And SERENA-6 is the first and only next-generation SERD with Phase III data in the first-line setting. There's a lot of excitement, of course, about this field, but this is the first data that we have seen. So I think this was one of the key reasons why this was also included in the plenary.

And if we take a look at the data and how it sort of shapes up, there's about 85,000 patients in G7 that are treated with first-line HR-positive breast cancer. About 50% of them receive AI plus CDK4/6. There's another 20% or so that get fulvestrant plus CDK4/6 and another segment that get chemo or ADCs in that setting. Of those patients who get AI CDK4/6, about 3/4 of them do not progress and are able to stay on treatment for beyond 6 months, and that's the patient population that really was enrolled in the SERENA-6. And 30% of these patients will drop ESR1 as point of molecular progression before radiological or clinical progression. And that's this patient population that really camizestrant was shown to be superior to AI in combination with CDK4/6.

A few things. There was a healthy debate, of course, discussion that happened at the plenary, but it's important to note that ESR1 testing is already established. And now we're using that established ESR1 testing and using that as part of routine blood test and, as Prof. Turner showed, as part of the routine visits that these patients have every 2 to 3 months. And I think that's an important principle about integration and how this could be integrated within routine clinical care.

Now I think the results of this are certainly very meaningful in the first-line setting. But beyond that, they actually support the role of camizestrant. It's a safe regimen, as Prof. Turner showed, and that gives us a lot of confidence as we have a very expanded clinical development program. We're looking forward to SERENA-4 results that broader -- that broaden the camizestrant use in the first-line HR-positive advanced breast cancer setting. And of course, that's an all-comer approach.

And then, of course, we have a very significant program in the adjuvant setting with CAMBRIA-1 and CAMBRIA-2, both looking at early as well as late adjuvant setting, and those studies are enrolling very well. And we're looking forward to, of course, bringing this camizestrant in early-stage disease. And again, I want to underscore the safety and the efficacy really positions us very well for this expanded development program. We remain confident with the overall potential of camizestrant, and it's a $5 billion-plus peak-year opportunity with this program that we have.

Further moving on to another breast cancer subtype, HER2-positive, as you just heard from Dr. Tolaney, DESTINY-Breast09 really marks another milestone in the treatment for first-line therapy. Now this goes back many decades, as it was presented by the discussant, the standard of care used to be around 4 months PFS with chemo alone in 1998. And we now have exceeding 3 years, nearly 10x the progression-free survival that we saw nearly 3 decades ago. And it's building on the efficacy that was very strong with CLEOPATRA. So this gives us a lot of confidence that this is going to address, of course, the clinical care.

Now there's nearly 23,000 patients who are receiving first-line HER2-positive metastatic breast cancer in the G7. And this demonstrates not only activity that is very definitive with a strong PFS, as shown, and supportive evidence for PFS2 and overall survival, but also shows the consistency of treatment effect across key subgroups, including hormone receptor positive and hormone receptor negative.

And the reason for really moving it up earlier is there's about 1 in 3 patients that don't go on to receive second or later lines of therapy, again, showcasing the benefit of starting with the best therapy upfront, as Dr. Tolaney highlighted. So we believe and we remain confident that this first-line data further represents the multi-blockbuster opportunity that we have for Enhertu across the lines with AstraZeneca and Daiichi Sankyo.

And furthermore, you heard, of course, the release that we shared in May about DESTINY-Breast11, which is looking at neoadjuvant approach with Enhertu followed by THP. And that further underscores our ambition to move Enhertu into early stage. And of course, we are all eagerly awaiting the results of DESTINY-Breast05 as well, where we think that we have the potential to take the Enhertu and the power of Enhertu that we have seen in late line, in first line and beyond.

So with that, I think we'll take Q&A. Thank you, Dave.

Okay. Thanks, Sunil. All right. Great. Sorry, just so I can keep track of time here, so we've got about 15-plus minutes to be able to ask questions. Right now, I would request that where possible, we focus questions for Dr. Tolaney and Prof. Turner. You get to hear from us a lot. You've got 12 minutes of precious time or 15 with our 2 guests.

And I think that it looks like, Emily, you've got a microphone. So why don't you start and then Rachel will come by. And if you can just give your name before you ask the question, that would be super. And we'll also take some online, Andy?

2 mics.

Oh, 2 mics, all right, very well. Okay. Perfect. Please, Emily.

Emily Field from Barclays. KOL we spoke to this afternoon indicated that the rate of de novo metastatic disease in DESTINY-Breast09 was higher than the real-world setting. And this particular doctor was, therefore, somewhat complex that the ORR rates were not higher than what was shown in D-B03. So just wondering if you could comment there.

And then I guess this question is for Dr. Tolaney since we heard from Dr. Turner yesterday. Obviously, a robust debate with the discussion in terms of waiting for PFS and OS data versus the point of the quality of life data presented yesterday. So Dr. Tolaney, I'd be curious on your thoughts on which of those points you would value more.

Yes. So I'll start with the question about metastatic HER2-positive disease. So in DESTINY-Breast09, the number of patients with HER2-positive disease was just slightly over 50% of the population. In fact, if you were to look at the rate of de novo metastatic disease in the United States, it's actually rising. So probably in the U.S., it seems most of our real-world data is suggesting it may be as high as 70% because all these HER2 drugs are doing such a wonderful job at curing our early-stage patients. And with T-DXd, that may be getting even better as it moves into the early-stage setting.

So I think the proportion of patients that we see upfront, at least in the United States, is becoming more de novo. And as you saw in DESTINY-Breast09, the benefit was actually very consistently seen both in the de novo subgroup as well as the recurrent group with very similar hazard ratio. So I think it shows it works in both populations.

With respect to SERENA-6, I think the data that we saw was really I think it is a paradigm shift in the way we think about breast cancer. We have never really thought about switching therapy prior to anatomic progression, and to be able to switch with molecular progression, I think, is quite innovative. And I will say, it's hard right now because the PFS2 certainly isn't -- is immature.

But I think what really got me was the quality of life data that you've not only profoundly improved the progression-free survival in the first-line setting, but these patients are living better in addition to having their disease controlled longer. And I think it goes hand-in-hand, right, that if we can control people's disease better upfront for longer, they're going to have a much better quality of life. And so I think it was very consistently seen. And it seems like PFS2 is also going to hit given the trend. So I think really, it is a really innovative strategy for a patient.

Thanks, Dr. Tolaney. Emily, I just would offer that I had heard, consistent with Dr. Tolaney's comments, commentary that they were pleased to see that there were as many de novo patients in the study because that is a more accurate reflection of what they're seeing than had it been actually a fewer number.

Microphone. Yes, please.

It's Rajan Sharma from Goldman Sachs. Just on SERENA-6, do you have a sense of the time window between ESR1 mutation emergence and then progression? I'm just thinking if there's an opportunity to potentially reduce the time period of testing, so I think the discussant talked about that as being burdensome yesterday.

So we don't have that data yet from SERENA-6, and we're certainly going to look at that. We know ESR1 mutations don't emerge before 6 months, and that's why all patients on the study have been on for 6 months at least, and they then emerge most likely in the next 2 years after that. But all our patients come in for blood draws every 2 to 3 months anyway whilst they're on treatment.

And so actually, I think adding this on to that blood test could easily become routine in our clinics. And actually, my experience is from all the studies we've done in this and similar that actually, patients find it really reassuring that you're monitoring their disease more carefully. So there might well be a bit of result anxiety for the few days before the blood test. But actually, that's outbalanced by that much longer-lasting reassurance that you're monitoring the disease better.

Simon?

Simon Baker from Redburn Atlantic. A question for Dr. Tolaney. The discussant was talking about the potential for sequencing managing effect with toxicity. Do you -- in how you will implement the results of this study with your patients, do you think there's any role for that? Or does the data support simply following the outcome that we saw in the study?

Yes, no, it's a good question. In fact, it's kind of a good problem to have that we had such a prolonged progression-free survival that we can now even think about these questions, right? I mean, in essence, the combination of T-DXd and pertuzumab is doubling the progression-free survival. And in truth, we don't even know what that median is really going to be. It could be even longer.

And so I think that's why this question is being brought up because it could be that patients have their disease controlled for so long. Does it really make sense to continue to keep them on T-DXd and pertuzumab? Certainly, this trial cannot address the question. All we can say is that we know with the treatment the way we gave it, we're having a profound impact on outcomes.

But I think it does bake the question, are there ways to optimize therapy? And I think while I find that it's very important, I also don't want to compromise the outcome because we doubled complete response rates, and there is a chance that we could be curing some of these HER2-positive breast cancer patients. So I think we have to be careful about how we think about optimization.

And so I think it will be interesting to dig into D-B09 a little bit better because we'll be able to see, well, when are people really hitting CR? Are there opportunities to look at timing of a ctDNA clearance? Are there ways we could think about doing this in a more educated manner? So I hope it will lead to studies to help us to understand that.

Thank you, Dr. Tolaney. Prof. Turner, we'd be interested in your perspective as well on the same question.

Yes, I think it's -- I think we're at a really exciting time in HER2-positive breast cancer, which Sara just brought up, which is I think we're well on the way to starting to cure a significant number of patients with HER2-positive metastatic breast cancer. I don't think we've really been confidently able to talk about that with metastatic breast cancer before, but we start to see it with the CLEOPATRA regimen of taxol and dual-HER2 targeting. We're perhaps around 10% are cured. And I think what really excites me in D-B09 is the tail on the curve to me suggests that we actually might be starting to cure more patients with HER2-positive breast cancer. And it's great then that gives us the opportunity to be more ambitious in the future as well.

Thank you very much. Please, Christopher?

Christopher Uhde from SEB. So I guess this is a -- it's a layered question. But the first part is, I guess, something to be addressed perhaps by both the Professor and Doctor and leadership. So could you please share your confidence to the extent to which you're confident in a positive OS benefit for both SERENA-6 and D-B09? And I guess, perhaps it's worth commenting for -- to give Mr. Market some comfort on the reasons for the gap -- the big gap in investigator-assessed and BICR PFS in D-B09.

I mean it's also -- it's clear there's an expectation that PFS will increase with longer median follow-up, but what about duration of treatment as well? And are you more confident today in Enhertu Perjeta than Enhertu monotherapy hitting OS? And to what extent might the Enhertu arm have been hurt or helped by the low concurrent use of endocrine therapy compared to the THP arm? And what does SERENA-6 tell us about the odds of success in SERENA-4 and CAMBRIA?

Those are really lot of good questions.

Let's see if I can help on that. We have issued yellow cards in the past for 5 questions, but we'll let you go away on this one. Why don't we start first with maybe we can have Dr. Tolaney, if you want to talk about the gap in BICR or the differences between BICR and investigator. Also, I think if you could address whether or not you have an expectation of duration of therapy to also increase as the population or the study continues to mature. And then if you want to comment on overall survival thoughts, and maybe we can also ask Susan to do the same.

Sure. Thank you. So you're completely correct that there was the difference -- a slight difference in performance of PFS in the control arm by investigator assessment in BICR. So you saw around 20 months with investigator assessment and around 26 months with BICR. So at first, when you look at that, at least when I first saw it, I thought, well, if it was not blinded, people knew they were on THP. So you could imagine and think, well, maybe there's some bias that patients on the investigator arm may come off early because they want to transition on to get another therapy like T-DXd in the second-line setting.

So what we did is we looked at the rate at which investigator-assessed PFS was occurring prior to BICR PFS in both arms, and it's actually the same rate. So that's suggesting it's not due to bias, right, because it's occurring in the same rate on the T-DXd and pertuzumab arm. And so what happens is if a patient comes off for investigator-assessed PFS and they change treatment, we continue to follow them with serial scans until they hit a BICR PFS.

So let's say I was on THP and I went on to T-DXd, I'm going to keep getting scans while I'm on my T-DXd until I progress and then that counts as my BICR PFS. So there's going to be a very big lag in time between your investigator PFS and your BICR PFS in that case. And when there are a lot more PFS events in the THP arm relative to T-DXd-P that will drive this difference to make BICR PFS longer. And so we actually looked at this with our statisticians, and that was exactly what drove that difference. So I think it made sense.

With regards to the duration of treatment, so at this time with the 29 months of follow-up, we had a median duration of treatment that was almost 22 months for T-DXd and pertuzumab, and our PFS was almost 41 months. And so one could say, well, why is there such a difference there and what will happen to the treatment duration? But you have to remember, when you only have 29 months of follow-up, you cut your treatment duration at that time. So that treatment duration is going to get much longer. It's just kind of where we are at the snapshot in time. And so that will change again with longer follow-up.

And then with regards to overall survival, at this time, we only had 16% of survival events. So we just don't have maturity. But I think the fact that you're already seeing a trend is supportive, and there's a lot of data to suggest that PFS2 very much correlates with overall survival. And with a hazard ratio of 0.6 for PFS2, I think it's highly likely that you'll hit a survival difference.

Dr. Tolaney, could I also just ask, there was one other that was in there, which was a commentary on the mono arm. And so just are you any -- do you have any more confidence in the pertuzumab-containing arm versus the mono arm? And is there any extent by which Enhertu might have been hurt or helped because of the concurrent use of...

Of pertuzumab. Yes, it's an interesting question. So I will be honest, I was a little surprised when T-DXd pertuzumab hit and not T-DXd because we'd already seen data in DESTINY-Breast03 that T-DXd has a 29-month PFS in a pretreated population, so obviously, expected to be much greater. But then you look at the statistical design of what's required to hit success at this interim time point and is extraordinarily stringent, and so just a few events could make you not hit.

And so when you think about that, then you think, well, it's a little bit of chance that we probably didn't hit in the T-DXd monotherapy arm just, again, given the extraordinarily stringent criteria. And so I think I have expectations that it will hit at the time of the final PFS. And so I would hope that we'd actually potentially have 2 approvals in the future for T-DXd and T-DXd-P. And I do not think there is any detrimental effect. We actually already have data from DESTINY-Breast07, where we actually saw that the 18-month PFS was actually identical in small numbers, but you saw 80% of people were free of progression with T-DXd-P and T-DXd in the first-line setting. So I think it looks very good.

Perfect. Thank you. We're going to take one question, which I think we have time for online, and then we're going to let our guests catch their flights. James Gordon, JPMorgan, please go ahead.

James Gordon, JPMorgan. Two questions on camizestrant and SERENA-6. So the first one was on testing. So the discussant at the conference noted the burden of testing and talked about patient reluctance. And I think the patient side has been addressed just now. But what about funding for the frequent testing that needs to be done? Could that be a challenge, particularly ex U.S.? Is that going to have a lower cost? And is that something that Astra would be able to help with? Or could that be a problem in terms of getting funding for doing this testing?

And the other question about the study was just quality of life. So there was some talk about scan anxiety, but what about the benefit on quality of life? And is that likely just because of slower disease progression? Or is that also about side effects for the drugs? Like how burdensome are AIs? And what about the side effects you get with a SERD like cami? Are those side effects likely to be a challenge for patients?

So Prof. Turner, I'd suggest, if you want to answer the second question, we'll take care of the first one.

Okay. So the question was about the quality of life benefit we've seen. I think this is likely driven by the side effects of disease progression of pain that is experienced as well as all the other symptoms that come, and this often does predate the actual confirmation of progression on the scan. And I think we're seeing that in the study where you're starting to see the quality of life falling in the control arm a little bit before you see it on the scan. So I think that fits.

I don't think this is driven by differences in side effects. Camizestrant overall we're seeing is very well tolerated broadly. The symptomatic AEs are the same in both subgroups. But we will be able to drill down much more into the quality of life data, the individual sub-domains, and we've got plans to show that soon in a future congress, in a future meeting. So I think that will be really important.

Great. Thank you very much. I will -- then just, James, with respect to the reimbursement aspect of things, now that we've seen results such as these, it allows for us to have conversations with payers across the globe on the opportunity to be able to think about reimbursement. And so we're already engaging in those discussions.

Certainly, there's also multiple avenues that are taken. There's the companion diagnostic route, which is the one that in the United States is the best route, lab-developed tests, and there are multiple of those that we're seeing now really in earnest being developed ex U.S. And so it's individual country approaches that are going to be taken, both with respect to access and also reimbursement for the ESR1 mutation testing. And what I would say is that we've got a pretty good track record of working on those things across the globe. Most of the medicines that we've launched have been precision medicines that have had a companion diagnostic, and we'll employ the same here.

I want to ask all of us to thank our guests, Prof. Turner and Dr. Tolaney. And you may go. We know you need to catch flights. So thank you very much. So with that, as they leave, I'm going to turn it over to Cristian Massacesi, who's going to take us on to the next section. Thank you.

Thank you, Dave. So let's change the organ, GI. So I will go briefly through the key presentation that we had that was very rich for our GI portfolio. Before going there, I want to show and share with you, like Susan said and showed with lung cancer, breast cancer, a tumor map for gastric cancer. This is an indication that for us is becoming absolutely in strategy.

If you start from later line, you can observe that, of course, at this conference, we presented DESTINY-Gastric04 that confirmed in a randomized fashion the role of Enhertu in second-line gastric cancer, HER2 positive after, of course, the approval based on DESTINY-Gastric02 in the context of a single-arm study.

We are also running in parallel in a very second important segment of gastric cancer, Claudin18.2-positive, a Phase III study in the same setting, second, third line with our Claudin18.2 MME ADC. The nick name is sone-ve. This is the drug that currently we are comparing against standard chemotherapy. The study is ongoing, is actually recruiting, as Pascal was telling at the beginning, ahead of schedule.

We have then moving -- the plan is moving these ADCs in the -- where they can potentially bring even further benefit in first line. In HER2 positive, we are testing Enhertu in combination with fluorouracil, capecitabine in combination with IO in HER2-positive setting. And we decided to run in agreement also with Daiichi Sankyo, we run 2 studies with 2 different IO backbone, pembrolizumab, and this is DESTINY-Gastric05; or rilvegostomig, our PD-1 TIGIT.

There are supportive data for both trials, and we believe that this can strengthen the position of Enhertu in frontline study and, of course, help us also to position our PD-1 TIGIT in this important space. Both studies are ongoing and actively enrolling. Of course, there are plans also to move our Claudin18.2 ADC in this space, in this case, will be a combination with fluoropyrimidines and rilvegostomig.

Then of course, the line of sight is where MATTERHORN is, what we presented here. So we are creating and generating these very powerful regimens with novel IO backbones and better chemotherapy, the ADCs, and the idea is to bring where we can cure more patients in the early stage where MATTERHORN has been run.

Let's go to MATTERHORN. This is the design of this study, is first of all, very important to highlight is the third positive perioperative study that, as AstraZeneca, we are delivering after AEGEAN in non-small cell lung cancer and NIAGARA in bladder cancer. It's a resectable setting. The patient can be resected, but the disease is high risk, so Stage II-IVa. And so the patients are receiving an induction and treatment with a FLOT that is the best chemo backbone, is a cocktail of 4 drugs: fluorouracil, leucovorin, oxaliplatin and docetaxel. And then after the surgery, the patients receive other 2 months of FLOT.

What we did in this trial is adding durvalumab during the chemotherapy phase and then adding 10 cycles, 10 months of durvalumab as maintenance. The primary endpoint of the study is EFS. Of course, the key secondary endpoint are overall survival and pCR. pCR is an endpoint that is not very well defined in gastric cancer, resectable gastric cancer like, for instance, in non-small cell lung cancer or triple-negative breast cancer, but it's something that can help to understand the outcome of these patients.

We presented, if you recall, pCR data from NIAGARA for MATTERHORN in previously in 2023 because, of course, there was a readout that happened earlier. And there was a benefit. We see a benefit. We saw a benefit with a delta of 12% FLOT D versus FLOT. The results of this ASCO show that also EFS is clinically and statistically significant. The other ratio was at 0.71. The median EFS for FLOT arm was 33 months, not reached for durvalumab FLOT. It's very meaningful because this is an early setting. And if you see the 18 months and 24 months rates, you see that you go from 64% to 73% and 59%, 67%. In an early setting, it's an important delta.

What is even more intriguing is this early OS benefit, very strong trend. The other ratio for OS was at 0.78. We already reached the median OS in a comparator arm, it's 47 months, not reached for durvalumab FLOT. This is a descriptive analysis. We didn't plan because of the maturity that we were expecting a formal testing analysis for OS. So this is why this analysis is not statistically significant. But of course, when the right maturity will be reached with adequate number of events, it will be formally tested with full alpha.

Safety, very, very important in these specific settings, early settings and very reassuring. What we have seen with -- in this trial once more with durvalumab in early setting is a very consistent safety profile that we were expecting. Actually, I would say, here, if you see most of the adverse events were driven by the chemotherapy backbone. There were not significant differences in terms of all grades and Grade 3-plus events between the 2 arms. And ultimately, durvalumab was very, very well tolerated across all the adverse events experienced by the patients.

Let me move now to DESTINY-Gastric04, that is the second presentation -- oral presentation in gastric cancer. This was Enhertu in HER2 positive. This is an important trial because it confirm how Enhertu is effective in these gastric cancer patients, second line, also because it needs to take into consideration that this was the best comparator arm. Ramucirumab, paclitaxel is probably the best standard of care you can have for patients in second line, and Enhertu was able to increase the overall survival more than 3 months. Very meaningful results, safety profile as expected. As you know, in gastric cancer, we have a 6.4-milligram dose. But overall, these data are reinforcing the positioning of Enhertu as a global standard of care in second line.

Let me close with some Phase II data in another disease, that is cholangiocarcinoma, biliary tract cancer. We're very proud to have TOPAZ positive some time ago where we were able finally to bring to these patients with metastatic biliary tract cancer a new treatment that double the survival rate at 3 years. But despite that, the medical need is still huge. You see there are less than 50% of patients that are alive after 3 years with the TOPAZ regimen.

This is why we want to improve upon it. And we want to do that using, again, a potentially better IO backbone. And these are the data that we presented at this conference with rilvegostomig, our PD-1 TIGIT in combination with standard chemotherapy, gemcitabine and cisplatin, that show a good median PFS, a good response rate with the durability of these responses. So you see the spider plot, please consider the study is ongoing. These are data that patients that continue to receive treatment.

One important aspect is, as we learned with the rest of rilvegostomig program, the activity was even better in patients with tumors expressing PD-L1. And we -- the second important learning, the safety profile. Once more, rilvegostomig is very well combinable with standard chemotherapy. We have seen this in non-small cell lung cancer, in gastric cancer and now in biliary cancer. So this is a drug that will represent our backbone for most of the combination that we will run.

So based on this data, as you know, we have now 2 Phase III studies ongoing, one in adjuvant with rilvegostomig versus placebo post surgery; another one in metastatic setting that is the combination of rilvegostomig and Enhertu in first-line BTC patient HER2 positive.

Dave, I think you're going to conclude this session.

Thank you, Cristian. All right. So just one last slide for me to put into commercial context the data specifically from MATTERHORN that Cristian just walked us through.

So we've been working really to build on the tumor presence that we have in lung and in breast cancer to really move into GI cancers. And we believe we've got a portfolio of cancers that really will allow us to advance transformative treatments that are going to change outcomes for patients, and MATTERHORN is really a great example of this.

As mentioned earlier, this is our third perioperative opportunity for Imfinzi. This is relevant not just because of the number of times that we've been able to do this, but because of the experience that we're building, working together with multidisciplinary teams, surgeons, medical oncologists, all of those who come together to make decisions on how to best think about neoadjuvant, adjuvant, perioperative approaches to treating these patients that are in curative-intense settings.

This has the potential to be the first and the only perioperative IO-based regimen in Stage II-IVa gastric/GEJ cancer. There are a large number of patients, 43,000 that are within the G7. And we know that 50% of those patients undergo perioperative treatment today. So perioperative treatment is the standard of care.

I'd also note that it is important that FLOT is the primary standard of care being used. And in fact, more importantly, I think these data, and you heard this from the discussant yesterday, really underscore that FLOT should have an even increasing role as the backbone that we see across the globe for this very, very important treatment. And it's 55% today. I would expect that to grow in terms of the percent of patients that are getting FLOT, and that would be true across regions.

This is a blockbuster opportunity for us. And really, again, I think that the discussant summarized quite nicely and well when the discussant speaks about D-FLOT and talks about D-FLOT because of the fact that the EFS and the OS is being seen across subgroups, where OS is obviously still at this point only a trend, but that's quite important.

DESTINY-Gastric04, it supports the existing Enhertu indications that we have. It's already established, that is Enhertu is the standard of care in second-line HER2-positive gastric and GEJ in many countries. This reinforces confidence in Enhertu, converts conditional to full approvals in markets where we pursued an accelerated path to market.

It enables a move into earlier lines. We've heard this consistently. More patients, therefore, have an opportunity to benefit the earlier you move up durations of therapy because of time to progression are longer, and this is good for patients and an important opportunity to, therefore, to make sure we're moving our best therapies as early as possible, which support reimbursement. And we're moving Enhertu into frontline gastric cancer. DESTINY-Gastric05 will come along with ARTEMIDE-Gastric01 in the 2026 time frame.

So with that, we will move now to Q&A, same format that we had, had previously within this.

And without further ado, we can move straight into it. And please, a question in the back.

It's Ben Jackson from Jefferies. Two questions from me. The first, just coming back to the SERENA-4 discussion afterwards talking about the no crossover to the Enhertu -- sorry, to the camizestrant plus CDK4i in SERENA-6, talking about whether that causes any problems for assessing whether the benefit is actually seen when they progress on the ctDNA, the emergence of ESR1 versus actually the radiographic progression. Can you talk to us and just whether you see that as either a problem to uptake or a problem to whether that actually could be an issue with the FDA approval of the indication?

And then secondly, just really quickly on SERENA-4, you're obviously looking at the combination with palbo there. Could you just talk us about the rationale and the belief in the -- a broad indication across all CDK4/6s?

Susan, so maybe you can speak to discussions and whether or not you anticipate the crossover is having any impact with agency. You can also then talk about palbo and SERENA-4. And Sunil, if you have anything to add on uptake for SERENA-6, that would be great. Susan?

Okay. So in terms of crossover, obviously, camizestrant is not yet approved anywhere. So you can't have it crossing over to a second line when you don't have it approved in the second line. It was possible for patients to obviously go on to second-line therapy as appropriate, and you saw that broken down in the trial design. But I don't think it's a relevant discussion.

What you've heard from what Prof. Turner said is there's 2 things that really underpin the confidence in the approvability of SERENA-6. First is a very strong and very clinically meaningful improvement in the PFS 1 endpoint. Second is a very strong trend to PFS 2, which shows that you've got the carry-through to that second-line scenario of the effect that you saw in the first line.

And the third is in terms of what patients feel of function, which is a key part of the regulatory approval thing, you're actually seeing an improvement in the quality of life, which is very durable because you're avoiding that progression on to symptomatic disease progression, and that is meaningful in this setting. I think it's further reinforced by the fact we have announced that we've got breakthrough therapy designation by the FDA. That is a recognition of the impact of the potential for this new method.

And I think the final point that I would just say is if you -- that hasn't been discussed at great length is the safety profile that we saw in SERENA-6 is excellent. You've got a similar discontinuation rate to the discontinuations that you see on an aromatase inhibitor, some 1%. You really don't have any meaningful toxicities in terms of GI side effects or the other things that can cause issues. And I think that predicts well not just for the potential for the broader first-line indication, but also in the adjuvant setting. And it's really gratifying to see when we saw that about that profile because it really was at the top end of our set of expectations.

So in terms of the relevance of SERENA-6 for SERENA-4, I'd just remind you that out of all of the second-line studies, the profile that we've seen in the SERENA-2 study, which was a Phase II study, looks really good, competitive with all of the others. We did see an overall benefit in the overall population, not just in the ESR1. And in the endocrine-sensitive wild-type population, this drug is also active, as you would expect, because it is a degrader of the estrogen receptor regardless of whether it's wild-type or ESR1.

So again, we have to wait for the results of the SERENA-4. But given the profile that we've seen, I think we've got confidence going into the SERENA-4 in terms of the safety profile and the potential for efficacy. So I'm delighted with the camizestrant program.

Just specifically to answer your question on why palbo in SERENA-4, I think, because it was part of the question. I think when SERENA-4 was designed, palbociclib was the standard of care. And we were generating the combination data with ribociclib that we're not ready to go directly in Phase III. This is the reason why we were able to introduce ribociclib, abemaciclib and, of course, palbociclib in SERENA-6. But SERENA-4 would have been too late to amend and to introduce another CDK4/6 inhibitors.

What you did see in SERENA-6 is that there's a very similar effect size regardless of the -- across that group. So I think that's reassuring as well.

So just I think a brief summary point. I mean I think that the crossover point is really trying to get to a sequencing question. And so I think that it was pretty well addressed today in terms of the value of moving that decision into an upfront and not waiting, and that was at least the view that we heard from both Prof. Turner and Dr. Tolaney that were here.

I think I'd also just like to add on SERENA-6, I mean a couple of points that I think are important. If approved, this will be the first next-generation SERD to move into the frontline setting. It will be, we hope, with a broad CDK4/6 label based upon the data that we saw within the study. ESR1 is part of routine blood testing that's taking place today, and it's the first opportunity to move into this $5 billion-plus opportunity that's in front of us.

Okay. Please.

This is Zach Dunn from Guggenheim Securities on behalf of Seamus Fernandez. So I'm going to shift over to lung cancer. Hopefully, that's okay. So starting with the QCS data that was shown today, it looks like the NMR+ also selected for more non-squamous, and there was a slight increase in the percentage of PD-L expression high. So I'm wondering, considering those 2 factors, how does this play into your confidence from the data presented today overall in the QCS and using this as a biomarker? And then tagging on to that, what do you think is the bar for success in AVANZAR? And is KEYNOTE-189 a good reference point?

Okay. So Susan, I think those are good questions for you. I mean, again, remembering that we've focused our efforts on looking into non-squamous and refining also the QCS algorithm within that population. But with that, Susan, if you want to build on that?

Yes. Just a reminder, the primary endpoint is in the non-squamous population in AVANZAR. Obviously, the data that we saw in TL02 with the same cut point as we saw with the retrospective analysis from TL01 also showed an enrichment for both PFS and OS in the biomarker positive. And again, you would -- from the data that we had in TL01, you might expect a bigger effect in non-squamous than in squamous, although those numbers are small.

I think that overall profile, therefore, predict -- increases the confidence just because you've now looked at data not just as monotherapy, but with the IO combination with and without platinum for both PFS and OS in a first-line setting, right? Those numbers are still small, of course, right? So we have to wait for the AVANZAR data, but that's what gives us confidence.

In terms of the bar for success, again, AVANZAR has a primary endpoint in both the ITT and in the biomarker positive part of the population. We increased the sample size following the results of the TL01 and focused on the non-squamous so that we're adequately powered for PFS in both of those analyses, and I think that's what gives us confidence. And yes, we would have -- expect that we need to beat the IO plus chemo standard of care backbone in that setting.

Can I add something, Susan? The bar KEYNOTE-189, of course, is a benchmark, but it's not the only benchmark because it's important to remember that AVANZAR is probably enriched for a population that is PD-L1 medium expressed or low or negative expressed because, of course, in more than 50, here, you have chemo backbone in both arms. So there are -- we expected to have less high PD-L1 positive patients. So it needs to be taken into consideration when you think how you benchmark the comparator arm.

Thanks, Cristian. So just for clarity, when we talk about the ITT population in AVANZAR, it's non-squamous. And so we've got 2 shots on goal in that study. There's the non-squamous and the subset of non-squamous that's the biomarker positive. Right.

Okay. Other questions? And we can also take questions online, of course. Right behind you here.

A short one. rilvegostomig, Susan, I'm starting to come around. The BTC data, you previously said the PD-L1 high is kind of an important indicator of where to use it, but the data look very, very good in BTC that we saw here. Is that still a factor? Or are you evolving in your thinking? And what do you expect OS to look like post PD in BTC?

Post PD in BTC, okay. All right. So just a couple of comments on rilvegostomig in general, right? Obviously, it's a bispecific. So the intent is that this antibody will bind both targets on the same cell, which is different from co-administration of 2 different separate antibodies and can produce different biological effects. We did publish a poster at SITC last year, looking at an ex vivo model system that we call the enable system, which basically takes patient-derived tissue from organoids that you can grow for a few number of days. We used interferon gamma as a measure of the potential for T-cell activation in that setting. That shows, in that context, the importance of that bispecific modality. And I think we'll continue to build out that data set and show that.

I think it also shows the importance of the Fc attenuated design of rilvegostomig, which I think may also help to explain its differentiated safety profile, particularly in combination with chemotherapy agents. So the data that we've then shown, I mean, the relevance of PD-L1 high as a biomarker for predicting the response to IO differs by tumor type, I would think. And of course, we do have the durvalumab indication in biliary tract in the first line based on the TOPAZ study. So what we were looking for in the trial here was something that could improve on that.

And I don't know if you want to make any comment, Cristian, about the...

Yes. I think rilvegostomig require a little bit more discussion. I think we are -- Susan explained very clearly the differentiation that this bispecific bring versus when you put the 2 antibodies together, okay? This drug has an Fc that is reduced. This is also can explain some of the efficacy and safety that we are observing.

We have now 4 data sets. We have ARTEMIDE-01 that is the monotherapy data in frontline non-small cell lung cancer. We see very compelling activity, more than 50 in terms of response rate in PFS. We see good activity, very good activity, superior what you expect to a PD-1 in 149 response rate in PFS. We see good activity in gastric cancer in combination with standard chemo in biliary, as you see before. And we will start to generate data also in combination with our ADCs.

So these are the data set that, of course, along the year, we will release when they are ready to be presented. But this is reinforcing that what we are doing is supported by data. The drug is very well combinable with standard chemotherapy with ADCs. And currently, we have 8 pivotal studies ongoing with this drug as a backbone.

Thank you, Cristian. I'm going to take 2 calls -- or questions, excuse me, online, and then, Emily, we'll come back to you in the room. So first, Colin White from UBS.

Colin White from UBS here. When the discussant from SERENA-6 was talking about the challenges in assessing clinical utility in the study, she mentioned imbalances in post-progression treatment and imbalances between the arms and the lines of therapy, which could impact the PFS2 measures and OS data. And not thinking about in terms of approval, but I was just wondering if you could comment on whether or not that might -- you think that might impact the perception of the robustness of those measures when we get the data.

And then the second question I had was on DESTINY-Breast09. The discussant seemed to be suggesting that it might be -- it could be used in patients that might do less well on THP. Is that your expectation of how Enhertu will at least initially be used in the first-line setting? Or do you anticipate rapid uptake?

Thank you. Cristian and Sunil, maybe I ask you both to answer those questions.

Okay. Maybe I can get started and, Cristian, please, jump in. So let me take the D-B09, and it reminds me of last year's late-breaking abstract with D-B06. If you may recall, we had a very similar discussion about the discussant saying that there may be patient subgroup and patient segments where D-B06 may be used with Enhertu versus standard of care with chemotherapy. And I think what we have seen is we have seen a strong uptake of D-B06 in HR-positive in a broader patient population.

And I think we heard the same in the discussant here. Initially, there is sort of who is the right patient population. And as clinicians get comfortable, that expands. And I think the data that Dr. Tolaney shows was very definitive for PFS, for complete response rate and, of course, for PFS2, suggesting a strong trend for overall survival. So that, I think, is going to lead to a broader uptake.

There is a segment of HR-positive where [ patina ] consideration is there. But we again think that upfront use of Enhertu is the right approach, what we're hearing from the clinicians so that clinicians don't have to wait to see whether patients progress or not and they use the best therapy upfront. So I think that definitive data is very strong.

I think for SERENA-6, and it's related to the question that was asked previously, you can't really force somebody in the second-line HR-positive setting to have a defined treatment. There's multiple therapeutic options available for that patient, including endocrine therapy, including chemotherapy and, of course, ADC. And what we saw from SERENA-6 is a representative patient demographic and a representative distribution of the type of therapies that are available.

So I think that is generally reflective of the current clinical care rather than a forced that I don't think would be well received in the clinical trial setting or in interpretation of this study. So I think both of those factors lead to a much more generalizable result that we have seen from SERENA-6.

Just one more comment on that. Progression-free survival is measured by definition, by progression events, not by the treatment changes. So if you're getting the overall time on before you're actually having that progression, that really matters because you heard from Prof. Turner, it matters because actually patients get sicker and lose quality of life when they progress.

And pain is an important part of that. A lot of these patients progress due to bone metastases, and that induces pain. And that affects your quality of life from the moment that you have that. So I think when you're looking at it, I don't think it diminishes the confidence in PFS2. It's still a relevant point.

Obviously, SERENA-6 is a relatively small study arm. So in terms of the powering for an overall survival benefit in such a patient population, you're unlikely to have adequate power for that. But what I think is going to be needed is some more maturity on the PFS2 and the trend to OS. And again, what the shift is that we're seeing in that curve on PFS2 gives you confidence that you're going to be able to achieve both of those.

I encourage you to also go back and listen to the discussant from the FLAURA conversation. We also engaged in a sequencing conversation at that point. It's not uncommon for the question to be asked. I do think that what is particularly unique here, and it's powerful because Prof. Turner said it and not us, to hear about the concept of cure being incorporated into advanced breast cancer in the HER2-positive setting is a pretty remarkable place to have been able to arrive to.

And so the fact that you don't know who those patients are going to be that are going to get the 15% complete response, I think, is something that's going to drive a great urgency to make sure that the best therapy, the best regimen is being used upfront. And I think we're also, on SERENA-6, going to see that the patient groups are going to be keen on making sure that they have the opportunity to avoid a progression conversation.

Just to make this human, when you talk to patients, the worst news that they get is the news that they've been diagnosed with cancer. The second worst news that they get is if their disease has progressed, and they have to get that news alongside all of the other physical realities that they go through.

Rajesh Kumar, over to you for the next question, please.

First one is on SERENA-6. Thank you very much for explaining why you're confident about approval. If approved, how do you perceive the adoption curve would be, especially given that you need to incorporate a diagnostic in the pathway? So do you anticipate a slow initial ramp-up followed with a network effect, which ramps up a bit faster? Or do you expect a more linear ramp-up as you already have plans to incorporate diagnostics in the next 2 or 3 years? That's the first question.

And second, slightly off topic. Thank you for all the various presentations you've done during ASCO. Just listening to a lot of presentations and recent deal flows, could you help us understand how your next-generation bispecific strategy is altered by all the news flow around VEGF? Clearly, there's a lot of excitement around the mechanism. Would love to understand what your thoughts are on the mechanism and how do you see that space evolve? And how do you intend to play in that space?

Thanks, Rajesh. Much appreciated. So we've got 5 minutes left. We're going to try to answer those 2 questions and 2 more in the room. So first, Sunil, can you comment on expectation for adoption curve and what we'll be focused on in order to drive up that? And then Susan, I suggest for you to handle the VEGF bispecific question.

So I'll keep it short. So maybe just 3 quick points. I think the first one from clinical adoption, there's a clinical perspective and a patient perspective. And I think, Dave, you highlighted the importance from a patient perspective, they want to take control of their disease. They don't want to be controlled by cancer, but they want to take control of their disease. And there's strong interest. We saw that in clinical trial enrollment and we see here from the patients. And that, I think, adoption is coming from the patients.

The second thing that I want to highlight is the ESR1 testing is routinely done right now with more than 60% of patients getting that upon progression. So it's already established. And now, as Dr. Turner said, this could be integrated as part of routine blood test every 2 to 3 months.

And then the final thing about adoption, you have 2 different populations where the benefit can be seen and they were enrolled. So one is the incident patient population that is newly diagnosed and are on AI CDK4/6 and not progressed in the first 6 months.

And then the second population, which is a prevalent patient population, those patients who are 6 months and up to 2, 3, 4 years and have not progressed. And it's important to note that in this study, the first test showed ESR1 positivity in 50% of the patients. So I think that's going to drive adoption as well. So I think those are the key tailwinds that will lead to hopefully rapid uptake.

Thanks, Sunil. Susan?

Okay. So again, our bispecific strategy is focusing rilvegostomig on the more IO-sensitive tumors in some of the combinations and volrustomig as the PD-1 CTLA-4 in the PD-L1 lower or particularly CTLA-4 sensitive. There are some tumor types that have some sensitivity to VEGF. We are testing the combination of rilvegostomig VEGF-directed therapies in HCC, for example, on lung cancer in Phase II studies.

It's not yet clear that the bispecifics give you differentiated biology versus the combination of an IO and a VEGF together. And actually, the data that we have from rilvegostomig in the ARTEMIDE-01 study have very similar trend to PFS as what you see with ivonescimab in the PD-L1 high group.

So I think there are multiple approaches to improving on the current standard of care. And by focusing the bispecifics on the different segments, we hope to optimize the profile that we have there. And where necessary, we'll look at the combination with VEGF in VEGF-sensitive tumor types.

Thank you, Susan. Yes, please.

My name is Miki Sogi from Bernstein. I have a question regarding the TL02, the QCS analysis. And in the abstract, you shared with us the data from the subpopulation of non-squamous, squamous without actual QCS. And that data really showed a really high promise for the -- based on the duration of response, that was much stronger comparing to PFS. So we were really hoping that to see the QCS analysis within non-squamous to see the actually duration of response actually translating into the PFS in -- with this the further subpopulation analysis.

So my question is, first of all, why you didn't disclose that? It was probably too small a sample size. And if that's the case, and now we are, of course, all expecting for AVANZAR results coming in the second half of the year. So which data we should be really focusing on?

Okay. So again, I think the TL02 data set is best looked at really as an overall group because otherwise, if you're sub-setting it, it's hard to interpret endpoints like PFS in 2 small groups. So what you saw overall is that as a doublet or a triplet for both PFS and OS, you're seeing an improvement when you look at the QCS-positive group and enrichment there.

And I think that gives us confidence, again, as I said, because it's now a first-line population, it's an IO combination with or without chemotherapy that you still show that enrichment for QCS. Again, we focused on the non-squamous in AVANZAR. So you're right that, that is the more relevant subgroup. But I think that's the effect size that you expect to see. And if you just subset by non-squamous within the doublet and the triplet, you really do get down to tiny numbers.

Thank you.

So -- and also on TL02, another thing that was very striking was really strong doublet data. And I actually asked this question just earlier to Daiichi Sankyo team, whether they are planning to do a doublet in the trial in first-line setting. And their answer was, well, we are already doing this with the TL07, but that doesn't include a QCS analysis. So I just wanted to ask the same question to the AstraZeneca team.

So again, just a reminder, the rationale for including platinum is to increase the depth of response, which may be particularly important in the PD-L1 low group, which is what you'd expect to end up with more of in the AVANZAR study.

And also remember the cross-comparison between the doublet and the triplet is challenging because there were actually quite different patient populations that were enrolled. There's a higher rate of brain metastases in the patients in the triplet and actually a much higher proportion of those patients had a lower dose, the 4 mg per kg dose rather than the 6 mg per kg. So I don't think it's reasonable to project that the doublet is superior in any way. I just think that was just the nature of those cohorts that was in TL02.

Susan, there's a difference in platinums as well, yes?

That's also an important point, right, which is that TL02 included a significant proportion of patients that were on cisplatin. We're including the carboplatin, which is best tolerated in the AVANZAR study design. Thanks, Dave.

All right. Perfect. Emily, if we can be fast, we'll fit you in.

Well, and maybe switching gears, I know you haven't had that long, but how has commercial uptake been in the other perioperative Imfinzi approvals of NIAGARA and AEGEAN? And how would you expect this to be similar or different from MATTERHORN?

So on both of those, we've been really pleased with the pace of uptake that we've been seeing. We see, as we would have hoped to have seen, that when you move into earlier settings that there is an urgency to bring on the best therapies possible. AEGEAN is doing well and contributing, as is NIAGARA, and I think that we'll look forward to having an opportunity to share more on sales trends and some KPIs that are there, but both have been moving well. And I also think that I expect that there will be conversations on Tuesday morning about MATTERHORN happening as well in practices certainly within the U.S.

So with that, I want to end where we started, which is at the beginning of this year, we talked about this being a catalyst-rich year. We came out of an ASCO where we had an opportunity to talk about 3 of those catalysts that were all from positive studies in really important areas, both for patients and the outcomes, but also in terms of the sales opportunity that they represent with SERENA-6, DESTINY-Breast09 and MATTERHORN, together with some of the other important readouts that we've already seen, high-level results that we know that we've announced from DB11 from POTOMAC. Those are very, very exciting places for us to be as we then set our chart for 2030 and the progress that we want to make.

Thank you all very, very much for joining us. Safe travels back from Chicago. We appreciate it. Bye.

Good morning, good afternoon, and good evening, everyone. I am Pam Cheng, Executive Vice President of Global Operations and Information Technology and Chief Sustainability Officer at AstraZeneca. It is my pleasure to welcome you to AstraZeneca's 2024 Sustainability Highlights Call. Thank you to all who have joined us today. The presentation slides are available on our website, and a recording of this call will be available after we have concluded today.

Please advance to the next slide. These are our usual safe harbor statements.

Next slide, please. I will begin with some prepared remarks focused on the substantial progress we have made across our sustainability targets in 2024, then I'll be joined by members of our sustainability leadership team for a live Q&A session. [Operator Instructions]

Next slide please. At our Investor Day last May, we announced our bold ambition to reach $80 billion in total revenue by 2030. Since then, we have made great progress towards this goal. 2025 is an unprecedented catalyst-rich year for our company, and we have already reported 8 positive Phase III readout in the year-to-date.

We have also launched 9 new medicines, rapidly progressing towards our goal of delivering 20 new medicines by 2030. Looking ahead, we continue to make substantial investments towards transformative technologies like antibody drug conjugates, cell and gene therapies and in our weight management assets that have the potential to evolve the care of many diseases and drive our growth beyond 2030.

Next slide, please. At AstraZeneca, everything we do is grounded in science. Across our broad portfolio, our focus remains on disease and disease areas that place an enormous burden on people's lives, economies and the health of our planet. Across AstraZeneca, sustainability has remained a fully integrated part of our business strategy and play a crucial role in achieving our ambition to build a healthy future for people, society and the planet.

Please advance to the next slide. We set ourselves ambitious sustainability targets, and we are proud of the progress we have demonstrated towards achieving these goals in 2024.

Across our business, the vast majority of our targets remain on track. Our access programs are excelling. We will surpass the targets we set for ourselves for people reached and are tracking well for training of health care workers across our flagship programs: Healthy Heart Africa and the Young Health program.

But we aren't stopping here. In November of last year, we introduced our health equity strategy on which I will dive deeper in the coming slides. We have also demonstrated great progress on our commitment to reducing our scope 1 and 2 greenhouse gas emission in 2024. And we continue to reduce our reliance on water and minimize our waste in efforts to help protect our planet.

All of this outstanding progress is made possible by our people, 84% of whom believe AstraZeneca is a great place to work, and we are delighted to see the recognition of our leadership externally.

Next slide, please. In light of an evolving regulatory and reporting environment, we have evolved our sustainability disclosures, which includes the publication of our double materiality assessment for the first time integrated within our 2024 annual report. The assessment identifies sustainability-related risks and opportunities as well as impacts on people and the environment.

Leveraging a variety of sources and aligning with AstraZeneca's overall risk appetite, we determine our material sustainability topics, which includes accessible and affordable health care, business conduct, climate change, cybersecurity and data privacy, patient safety and product quality, pollution, sustainable innovation and lastly, talent attraction and retention. We will expand on these topics over the course of the presentation.

Please advance to the next slide. As I've mentioned, sustainability is embedded across AstraZeneca through our continued commitment to following the science and prioritizing patient outcomes. We have evolved our 3-pillared approach of assets to health care, environmental protection and ethics and transparency to a new strategic framework.

Recognizing the process we have made to date, the interconnection between business growth and resilience and the need to address the major health challenges of our time, our sustainability strategy now focuses on how we make a sustainable impact, taking action on climate and nature, health equity and health system resilience and how we do business, guided by our values and investing in our people to create long-term value, resilience and trust by operating responsibly, ethically and with robust governance.

Next slide, please. I'd like to now take some time to highlight the sustainable impact that AstraZeneca has made in 2024.

Next slide, please. Moving first to climate and nature. Through our Ambition Zero Carbon program, we are decoupling our Scope 1 and 2 emissions from our strong business growth and have achieved a 77.5% reduction in absolute Scopes 1 and 2 greenhouse gas emissions since 2015. We are working collaboratively across our value chain and are proud that 1 in 10 suppliers with science-based targets are working with us, which reflects our industry-leading efforts to drive actionable and scalable change.

Recently, we've expanded an industry-first renewable power purchase agreement in China and have now made this platform accessible to our suppliers. Unlocking assets to wind and solar power for suppliers is really important. It supports our own Scope 3 targets and enables value chain decarbonization.

Additionally, we are unlocking 225 gigawatt hours of renewable energy annually, which could result in potential annual emission savings of 250,000 tonnes per year. AstraZeneca has co-led this initiative through the sustainability market initiative, or SMI; and its health system task force, which our CEO, Pascal Soriot, chairs.

Please advance to the next slide. Several years ago, we committed to transitioning our pressurized meter-dose inhaler, or PMDIs, to an innovative next-generation propellant with near-0 global warming potential through our partnership with Honeywell. I am delighted to share that we have recently been granted an industry-first approval for Breztri or Trixeo with this new propelling in the U.K. and I'm excited to report that other regulatory reviews are ongoing. 78% of all inhaled respiratory medicines globally are PMDIs, and millions of patients around the world rely on these important life-saving medicines to manage their respiratory conditions.

And as a reminder, our PMDI medicines represent approximately 20% of our Scope 3 footprint today. So this marks an important milestone towards our broader Scope 3 ambitions. With our next-generation propellant, we are able to deliver these life-changing medicines to patients sustainably. We are continuing at pace to transition our broader portfolio of PMDI medicines, and we are on track to achieve our 2030 goals.

Next slide, please. At AstraZeneca, we continue to increasingly focus on nature. We recognize the health impact of climate change and biodiversity loss. Given the pharmaceutical sector uses resources from the nature to research, design and develop medicine, we have a business need and a responsibility to focus on our broader impact on nature.

In March, as an early adopter, we published our first task force on nature-related financial disclosures, or TNFD report, demonstrating our commitment to following the science and to deepening our understanding of our relationship with nature. As part of TNFD, we conducted our first LEAP assessment, which identify our key nature-related dependencies, impacts, risks and opportunities.

Through this work, we are identifying opportunities for investments in water storeship and nature projects connected to our value chain through our climate adaptation and Nature Fund with 3 projects supported in 2024. Furthermore, our AZ Forest program is progressing with 40 million trees planted to date, and we have seen an impressive 23% reduction in our water usage since 2015.

Next slide, please. Turning now to health equity. Another of our key strategic priorities. We are aiming to close health care gaps to give people everywhere, the chance to be as healthy as possible. Our strategy is to achieve impact across 3 focus areas by embedding health equity across our business from discovery to the delivery of health care. Firstly, in science, we are focused on increasing diversity in discovery, improving representation of clinical trial participants and ensuring post-trial assets to medicine products.

In health care delivery, we are focused on more equitable screening, earlier detection and diagnosis, while also expanding our programs to ensure affordable access to our medicines.

Lastly, in community investments, we are focusing on addressing the root causes of health in equities by investing in underserved communities. Our efforts in health equity are underpinned by our focus on capabilities and engagement to build trust with partners and purposes with employees.

Please advance to the next slide. Factors such as gender, geography, income level and the environment can affect the care individuals receive, and many people face barriers to screening, early detection of disease, precision diagnosis and treatment. At AstraZeneca, we are leveraging AI to help drive earlier disease detection, diagnosis and intervention.

We are partnering across our therapeutic areas to assess artificial intelligence-powered diagnostics to improve screening and detection of lung and cardiovascular diseases, particularly for harder-to-reach patient groups in lower to middle income countries or patients with limited access to hospital care.

Please advance to the next slide. We believe that everyone deserves the opportunity to live their healthiest life. Yet quality and timely health care remains out of reach for too many people around the world. Our vision is to work to remove barriers to health care across the entirety of the patient journey. Through our efforts, we aim to positively impact the lives of 1 billion people, including 400 million people from underserved groups.

This ambition marks a fundamental transition in how we think about and conduct our business and represents our vision to reach more patients, and we are holding ourselves accountable.

Please advance to the next slide. Now turning to health system resilience. We remain committed to building more sustainable and resilient health care systems across the world to prepare for the increasing challenges that continue to strain health systems, including the growing burden of disease, aging population and the impact of environmental crisis.

To support our commitment, we are partnering with health systems stakeholders to transform care by providing evidence-based recommendations and co-creating solutions through both policy change and practice change.

This year, we are celebrating 5 years of the partnership for health system sustainability and resilience, or PHSSR, which AstraZeneca cofounded alongside London School of Economics and The World Economic Forum. I am proud to say that PHSSR is now active in over 30 countries.

Please advance to the next slide. Sustainable funding of health care is another critical element to health system resilience. To help guide future investments, PHSSR facilitated the development of policy recommendations for EU-level health care funding. Additionally, AstraZeneca is also playing a trailblazing role through the sustainable markets initiative, which I have referenced earlier, to equip more than 10,000 medical students across Europe with the knowledge and skills to address the interconnection of climate and health as they become the next generations of doctors.

As part of the European network on Climate and health education, we led the way in co-designing and developing this partnership with universities that has now been implemented across 38 European medical schools. Partnerships like these demonstrate our commitment to contribute to more sustainable and resilient health systems.

Next slide, please. Now we will shift to discuss how we do business. Please advance to the next slide. Turning now to our governance and ethics. Inspired by our values, we are focused on accelerating the delivery of life-changing medicines that create enduring value for patients, society and planet and our shareholders. On the left side of the slide, you will see our values, which determine how we work together and the behaviors that drives our success.

These values, following the science, putting patients first, playing to win, doing the right thing and being entrepreneurial, are embodied in our code of ethics and its supporting standards, which are foundational to our global compliance, governance and ethical frameworks and practices.

To ensure and promote the long-term sustainable success of AstraZeneca, our Board of Directors is accountable to our shareholders to ensure proper business conduct and seeks to represent the interest of all stakeholders. Our Board is responsible for setting our strategy and policies, overseeing risk and corporate governance and monitoring progress towards meeting our objectives and annual plans via committees focused on audit, remuneration, nomination and governance, science and sustainability, all to support the delivery of our long-term ambitions.

Beyond our Board and Board committees, our compliance lead is a core member of our senior executive team and is responsible for ensuring that we do business the right way via an approach that helps us to introduce compliant behaviors through our code of ethics, policies and training.

At an employee level, we also conduct risk assessment activities and seek to foster a culture where individuals are encouraged to raise concerns without fear of retaliation.

Please advance to the next slide. I will now cover some further detail on other material topics for AstraZeneca, as highlighted through our double materiality assessment.

First, looking at patient safety and patient quality. Our business requires the supply of safe and high-quality medicines, which are constantly and carefully monitored throughout the entirety of their life cycle. We are dedicated to patient safety and base our behaviors and decisions on our belief that everyone deserves to have confidence in the safety quality and efficacy of our medicines.

In 2024, we have continued to deliver high-quality medicines across our broad-based global network. Across 31 manufacturing sites globally, we saw 0 critical findings from all health authority inspections in 2024. We did not experience any patient level recalls, and our product availability remains high, which once again demonstrates our commitment to delivering life-changing medicines to patients globally.

Next slide, please. Now turning to cybersecurity and data privacy. In an increasingly complex digital world, continuous and proactive discipline in cybersecurity is critical to prevent disruption to our business. In 2024, we did not experience any material cybersecurity incident or any material security breaches involving personal data.

Our cybersecurity efforts are vigorous and our actions are guided by the NIST Cybersecurity Framework 2.0. With the implementation of continuous and proactive actions to protect data and ensure cybersecurity, we remain vigilant and always seek to promote and enhance our cyber-first mindset across our enterprise.

Please advance to the next slide. Across our enterprise, AI is transforming how we work, helping us push the boundaries of science which enables us to deliver new medicines faster and improve the patient experience. In R&D, we are now using AI and data science across 85% of our small molecule programs from target identification to clinical trial design.

AI is also being used to design and develop other therapeutic modalities, including peptide or protein, nucleotide-based and cell-based therapeutics. In commercial, we are partnering with leading technology companies to apply AI to address global health care challenges.

In lung disease, for example, we are leveraging technology to advance lung cancer care in low- and middle-income countries through our collaboration with Qure.AI to screen patients with AI-enabled X-ray assessments. This is an effective and cost-efficient solution for screening, and we have achieved our target to screen 5 million patients by the end of 2025.

Beyond lung cancer, we are also collaborating with other partners, including InVision to bring to market novel AI software as a medical device to improve the diagnosis of rare diseases such as cardiac amyloidosis.

Lastly, in operations, technology is transforming our supply chain into an increasingly intelligent system with an emphasis on sustainability. For example, by implementing over 30 digital tools and AI solutions for selected processes and products, our plant in Wuxi, China, has achieved significant productivity and lead time reduction. These are just a few examples of how we continue to expand our competencies to maximize the potential of emerging technologies like AI.

We will continue to build these capabilities to support our growing future business. To ensure that we are using AI ethically, our robust enterprise AI governance framework aligns with evolving international regulations and standards.

Next slide, please. Finally, turning our focus to talent attraction and retention. In an increasingly competitive environment, attracting, retaining and developing talented individuals remains key to our success and will support our growth today, tomorrow and the day after tomorrow.

We continue to invest in our employee experience, support inclusion and diversity and foster growth and enterprise leadership. In doing so, we are expanding our core competencies and data science and AI engineering and are investing in our people to enable our workforce to maximize the potential of emerging technologies.

We value and reward innovation, entrepreneurship and outstanding performance and believe in the power of development to unlock potential, drive performance and foster an inclusive culture. In 2024, nearly 90% of employees said they have improved their existing skills, learned new skills or have had a development opportunity, and a central metric demonstrating how we are developing capabilities for the future across our business from early talent to enterprise leaders.

Please advance to the next slide. To close, I am proud of the progress we have made in 2024 and I'm impressed with how we are maturing our sustainability strategy and our approach to key priorities and material areas.

With that, we now will move to our Q&A session. [Operator Instructions]. Thank you very much. We now open to Q&A.

Fantastic, Pam. We've had a number of questions come through, so I'll read out some of the written questions to start with. Firstly, on your health equity ambition, what underpins the 1 billion target you have announced? And how do you define underserved populations as it relates to the 400 million target?

Thank you very much for the questions. I would like to pass to Stefan Weber to answer this question, please.

Yes. Thank you. Thank you, Pam. Thank you, Elizabeth. So this is a great question. And first of all, I just wanted to reiterate that when we said, the positive impact that we want to have with our Health Equity strategy is really on society, but then also on our shareholders and on AstraZeneca employees.

And so for orientation, the ambition really expresses part of the societal impact that we want to have. Again, 1 billion people, 400 million positively impacted from underserved groups. So now what is behind those numbers is really the key flagship programs that we have in Health Equity related to health education screening.

As you've heard from Pam, really important part of our Health Equity work is focused on prevention and early disease detection, including screening. But then also a second pillar of our work is really related to the access to our science, to trials to support more diversity in our discovery efforts. And we have programs related to that then are also captured as part of the ambition that we measure.

And the third element is really the amount of people that have equitable access to guideline-directed medical therapy, including AstraZeneca medicines. In each of these 3 pillars, we have programs such as YHP, the young health program, on education; we have many screening-related programs, which we are driving with a health equity lens; and then we have significant programs related to open science, trial diversity, diversity in our discovery efforts and so on.

So it's really in those -- through those programs that we drive the impact of 1.4 billion people by 2030. This is a cumulative total of annually reported numbers in those programs. Then the other part of the question was, how do we define underserved groups. This is a very relevant question because there is no universal definition for that.

So the way we are currently measuring it, we are, first of all, basing our definition on World Bank classification and we are taking all people reached in low- and mid-income countries, as part of that group of underserved people because, in general, the people in these countries face greater challenges in accessing high-quality care and achieving optimal health outcomes compared with those people in the high-income countries. Although we recognize that is not universally the case, this is a good general starting point for us.

But within high-income countries, we're also looking to identify underserved populations because they exist in any country even in high income countries. So we are basing ourselves on public health agency definitions in those countries and our own analytics and understandings of the care gaps that patients face in high-income countries from the U.S. to Australia and the countries in between. So we're really looking into insights on care gaps in lung diseases, in rare diseases or in oncology and that's why we -- that's how we are defining underserved group in a case-to-case basis.

Fantastic, Stefan. On to the next question, sticking with the theme of targets. With a number of AstraZeneca's targets rolling off at the end of 2025, how should we think about your areas of focus evolving in line with your updated strategy? Will there be any major changes to the KPIs that you report in the future?

Thank you. I would take this question. So we remain committed to our sustainability goals. And our insights and learnings over the past year will inform the setting of updated and evolved KPIs in the future. Sustainability topics as shared today are featured across the business. We will also be guided by double materiality assessment to provide us with areas of focus.

And we will continue to follow business trajectory with annual reviews of these metrics areas. We can expect to see evolve targets across climate in nature, health equity and health system resilience as well as other material topics like paper packaging, API, health equity, including Healthy Heart Africa and Young Health program. And we will continue to refine KPIs to best enable us to meet our ambitions while supporting the growth of our business.

Thank you very much for the question.

Thank you, Pam. The next question focuses on Scope 3. Specifically, when will the great work on Scope 3 reduction project start to show up in Scope 3 reduction. As in 2024, Scope 3 emissions were flat and are up on a 2019-2020 basis. Could you share more information about a Scope 3 trajectory to get you to the minus 50% by 2030?

Thank you for the question. As a growing business, I mean the spend in our value chain is increasing, of course. And consequently, our model Scope 3 footprint is also increasing. The great news is that we have worked very hard in the course of 2024 and an inclusive of currently in 2025 to have a great road map on Scope 3 of achieving 50% reduction by 2030 and ultimately becoming net-0 prior to 2045. So for the details of this question, I would like to pass it over to Lisa -- to Liz Chatwin.

Yes. Thanks, Pam, and good morning, good afternoon, good evening, everybody. Just want to remind that we were an early adopter of science-based target. We were actually the first company -- one of the first companies verified in 2021. And as Pam said, we remain committed to our net-0 and our Scope 3 reduction path. But as Pam said, it's important to remember, our business has grown. We've doubled our size, and we're on track, as Pam shared, to be an $80 billion company by 2030.

And of course, with growth comes a rise in our Scope 3 emissions through our investments and also because we are producing more volumes. As you saw, and I think you mentioned in your question, our net Scope 3 has increased by 3% versus 2019, but actually, our Scope 3 emissions intensity has reduced by 44%.

We know that reducing Scope 3 is challenging. It requires work with our suppliers across our value chain in the introduction of brain chemistry and of course, the successful transition to the next-generation propellent across our PMDI portfolio, while at the same time, patient numbers using these devices is growing.

So as Pam said, we've made great progress. We've had the first approval of the next-generation propellent this year, and we're set to transition all our PMDI portfolio by 2030. We've also made reductions in our Scope 3 emissions related to distribution, moving from air to sea and also our business travel.

We've also seen significant improvement in primary data from suppliers, which really helps us target decarbonization. And we've made great progress with our suppliers with the majority of these now commission to science-based targets. In fact, 1 in 10 suppliers with science-based targets are AstraZeneca suppliers. So we continue to work hard on this as our business grows and recognize, of course, we can't do this alone. We are partnering with our suppliers and also other organizations across our sector and beyond to achieve our emissions reduction targets.

Fantastic. Thank you, Liz. The next question relates to our next-generation propellant. I think the audience are pleased to see the great progress that we're making here. Perhaps we can share more about how this transition will take place with Breztri and the other PMDI medicines within your portfolio?

Thank you for the question. We are super excited, and we've been working on this for many years and very, very pleased to see this coming to fruition. As referred to earlier, we are tackling approximately 20% of our Scope 3 footprint through our commitment to developing PMDI using the next-generation propellant, HFO1234ZE to be specific, which has a near-0 global warming potential.

We are planning to transition Trixeo to the next-generation propellant in the U.K. in the coming months. Trixeo, with the next-generation propellant, will maintain the same COPD indication, same product strain and same dosage regimen as Trixeo with the current propellant, which is HFA134a.

Similar to previous inherence transitions, we are working closely with clinicians, societies, health and regulatory bodies and patient advocacy groups to ensure that people understand the important reasons for the transition to a near 0 global warming potential propellant and what to expect.

AstraZeneca is committed to doing the right thing by both patients and the environment. Therefore, no medicines will be wasted or discarded. Trixeo with a next-generation propellant will phase in as current pack stock levels deplete. Existing stocks will be utilized first and transitioned to NGP, next-generation propellant, as soon as possible.

The current propellant and next-generation propellant can be used interchangeably. Trixeo, with the next-generation propellant, will phase-in as current pack stock levels deplete. Existing stocks will be utilized first and transitioned as soon as possible. And we will carry on likewise for the rest of our portfolio. Thank you.

And the last question we have is a follow-up to the health equity piece. So maybe one for you, Stefan. Is the HealthEquity strategy being challenged in the current funding environment for health programs and tariffs?

No, that's an interesting question. Thank you, Elizabeth. So look, first of all, our vision and our ambition and strategy for Health Equity, they all align to the financial commitments we laid out at our Investor Day last year, with the $80 billion revenue target that we communicated along with our margin commitments. Health equity is deeply rooted in our day-to-day operation and aligns tightly with our strategic priorities.

It's really important what Pam said before that we have philanthropic programs, but our health equity strategy is really embedded in how we do business. And so the work that we're doing in -- particularly in high-income markets in identifying underserved groups and finding a way how we can close care gaps, this will result in a win for patient society but also our business.

And some of our programs already show the significant amount of upside potential there is in making -- in bringing people that currently don't have access to guideline-directed medical therapy or to screening in those markets that how much business value there is as well.

So when there's business value, right, it protects the investment. And our philanthropic programs, we're also partnering with many stakeholders. We're not doing them alone, we're even partnering with the government in co-funding some of these philanthropic initiatives.

So my short answer would be nobody is immune actually to the impacts of tariffs or to drastic shifts in government investment in innovative medicines, no one is immune, but our health equity programs, I think they're well protected because they are so rooted in how we do business.

Thank you, Stefan. One more question, shifting gears a little bit, relates to our packaging and bio-based plastics. The question is specifically, has AstraZeneca explored nonfossil fuel-based plastics such as PLA or PHA for your medical devices?

So thank you. It's a great question. So as a matter of fact, we've actually dispensed significant amount of effort. I'll pass it over to Liz in a moment to talk about specifics. We spend enormous amount of effort. We believe the best way not only replacing some of the current materials but the best way to eliminate emissions and carbon footprint is also start in product development stage.

So a couple of examples to share is that we are -- we have an active project, actually projects around the world to explore replacing packaging material, PVC packaging material to polypropylene, for example. We've actually announced a multi-$100 million project in China to actually build facilities to be able to be leveraging more sustainable packaging material like polypropylene for our packs, for example.

The other example that I would like to speak about is really the -- how do we go from the current solvents we use to biosolvents, more sustainable solvents. We're starting this early in development stage. So as you may know that the supply, the availability of biosolvents is quite scarce in the marketplace globally, so we are now also working on the possibility of increasing, expanding, working with our partners to expand biosolvents supply as well. But we are starting in the drug development stage of using more sustainable materials. Liz?

Yes, absolutely. I mean Pam has provided a really comprehensive answer. We do know that nonfossil-fuel-based solvent in plastic is a key part of our sustainability approach. And as Pam said, we need to start early in product development with that. I would also say that the use of bio-based materials is something that we're working on across our sector with the sustainable markets initiative knowing that a demand signal with more companies is going to drive improvement in availability and capacity. So something that we're working on as well across the sector.

Fantastic. One more has come in on a slightly different topic, specifically. Can you share a bit more around the work you have done on business resilience or risk assessment of AMR, such as the proportion of revenue that is depending on functioning antibiotics?

Thank you. Serious bacterial infections pose significant and growing threats to global health linked to estimated 7.7 million deaths a year globally, leading to increasingly mobility and mobility for patients and substantial burden on health care systems. At the ESCMID this year, the company will share preclinical data on investigational monoclonal antibodies mAb targeting 3 of these top 5 pathogens identified as urgent risks by the Center of Disease Control and Prevention.

So AMR puts many of the gains of modern medicines at risk making infection harder to treat and making other medical procedures and treatments such as surgery and cesarean sections and cancer chemotherapies much riskier. So this is indeed an important topic to address.

And one last question that's just come in relating to China. Has AstraZeneca reviewed it's business ethics processes and policies following the allegations faced in China? Has any area of improvement being identified?

Heather?

Thanks for the question. Yes. Thank you. Thanks, Pam. So we, on an ongoing basis, review our compliance program, the health and look for areas of improvement and learnings from across the world. We have the same standard for operations, no matter where we operate in the world based on our values. And we continue to be a learning organization. Thank you.

Fantastic. That concludes all of the written questions we've had in today. So Pam, I'll hand over back to you to close today's call.

Thank you. Thank you, Elizabeth. Thank you very much to all of you for joining us today. We appreciate the engagement. We appreciate the questions. We are very proud of our sustainability leadership in the sector and beyond, and we are happy to share our excellent progress with you today. Thank you very much. Have a great day or good night.