AstraZeneca Stock

Welcome, ladies and gentlemen, to AstraZeneca's Meet the Management event at the ASBMR Annual Meeting in Boston.

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 statement disclaimer in the slide deck that accompanies this presentation and webinar. [Operator Instructions] And with that, I'll now hand you over to the company.

Thank you, operator. Good morning, good afternoon, and good evening, everyone. I'm Marc Dunoyer, Chief Executive Officer at Alexion and Chief Strategy Officer at AstraZeneca.

I would like to welcome you, and thank you for joining us to hear about the efzimfotase alfa Phase III program in patients with hypophosphatasia or HPP, including the HICKORY data presented yesterday at the 2026 American Society for Bone and Mineral Research in Boston.

As always, the materials presented today will be published on the AstraZeneca Investor Relations website following this presentation. Next slide, please.

Here are our usual forward-looking statements, which I encourage you to read. Next slide, please. This is the agenda for today's call. We are delighted to be joined by Dr. Raja Padidela, Consultant Pediatric Endocrinologist and Metabolic Bone Diseases at Royal Manchester Children's Hospital, who will walk us through the Phase III HICKORY data presented at ASBMR.

Next slide, please. Before we discuss the data, I want to remind everyone of AstraZeneca's broader ambition and the role our rare disease portfolio plays in delivering our ambition. I will also cover our strategy contributes not only to 2030, but well beyond.

With this, next slide. This slide captures how we think about growth today, preparing for tomorrow and investing for the day after. Over the past 2 years, we have continued to deliver strong commercial performance and substantial pipeline progress, further strengthening our confidence in sustained growth through 2030 and beyond.

Rare disease remains an important contributor to our outlook. We will drive growth through new launches such as Ultomiris in IgAN and [ Klagfa ] in gMG, while advancing a pipeline of pioneering medicines, including Efzimfotase alfa, which we will discuss in more detail today.

In addition to the efzimfotase alfa data, we expect several high-value catalysts across our biopharmaceuticals and oncology therapy areas over the next 12 to 18 months, reinforcing the breadth of our pipeline and confidence in the durability of our long-term growth outlook.

Next slide. We view rare disease as one of the health care greatest areas of unmet need, defined by delayed diagnosis, limited scientific understanding and the absence of approved therapies for most conditions.

We believe these gaps require a pioneering approach to innovation, combining novel science, new modalities, advanced diagnosis and close partnership with patients to develop transformative medicine where few or no treatment options exist.

Next slide. Against this backdrop of significant unmet need, we focus our expertise across 5 disease areas where we believe we can make the greatest difference. Across each, we are pursuing medicines with the potential to be first or best-in-class or meaningfully change outcome for patients. Today, we are focusing on efzimfotase alfa, one of the leading assets within our bone and endocrine disorders portfolio.

To provide some context, Gianluca will first introduce HPP, discuss the significant burden this disease places on patients and provide an overview of the global Phase III program.

Dr. Raja Padidela will then walk us through the HICKORY Phase III data presented at ASBMR and share his perspective on the potential implications for patients living with HPP. Next slide. And with this, over to you, Gianluca.

Thank you, Marc. I'm Gianluca Pirozzi, the Head of Development and Regulatory and Safety at Alexion. HPP is a rare inherited lifelong disease caused by deficient alkaline phosphatase activity affecting patients in all ages.

The disease is heterogeneous and multisystemic with a range of skeletal and functional manifestation significantly impacting quality of life. In its perinatal and infantile forms, HPP can be life-threatening and is often fatal before age 2 without treatment.

In children, rickets, impaired growth, deformities and fractures can affect development throughout life. Adult patients with HPP in their disease is generally milder, but it's far from benign.

They may experience slow healing fractures, tooth loss, chronic pain, muscle weakness, fatigue and progressive disability, all of which can affect work, independence and daily activities.

Next slide, please. Efzimfotase alfa is a great example of patient-centered innovation, a second-generation enzyme replacement therapy developed from more than a decade of experience with Strensiq. Both medicines replace the deficient alkaline phosphatase enzyme, but efzimfotase alfa has 4 key differences to reduce treatment burden, improve tolerability and support broader patient access.

It has enhanced enzyme activity, allowing for a similar effect as Strensiq, but a lower simple weight-banded dosing regimen with a smaller injection volume. Its optimized Fc design reduces off-target interactions, while enhanced glycosylation extends the mean half-life to around 6 days, supporting dosing every -- once every 2 weeks rather than 3 to 6 times per week as per Strensiq.

Finally, an optimized manufacturing process improves production efficiency and reduces wastage, supporting broader global access. Next slide, please. Efzimfotase alfa development program was intentionally designed to capture all patients living with HPP.

Recognizing that pain and fatigue are among the most prevalent symptoms experienced by patients, the program expanded beyond traditional skeletal endpoints to evaluate outcomes that directly affect daily functioning and quality of life.

The Phase III program enrolled 196 patients across 22 countries, representing the largest clinical program in HPP to date. Importantly, it was the first to include patients with adult-onset disease and those without skeletal manifestation using tailored endpoint to generate data that reflects all patients living with HPP.

The program includes treatment-naive children in MULBERRY, children transitioning from Strensiq in CHESTNUT and treatment-naive adolescents and adults in HICKORY. Next slide, please.

These slides provide a recap of results from MULBERRY and CHESTNUT pediatric studies, which were presented at ICCBH in June. While today's discussion is focused on HICKORY data presented at ASBMR, it is important to consider these results within the context of the broader Phase III program.

In MULBERRY, efzimfotase alfa demonstrated statistically significant and clinically meaningful improvement in bone. At week 25, the median Radiographic Global Impression of Change score was plus 1.67 versus 0 with placebo with a p-value of 0.0003.

The Rickets Severity Score confirmed significant improvement, showing substantial ricket healing within 6 months, while placebo-treated children showed no change. Importantly, MULBERRY also evaluated outcome beyond bone health alone, demonstrating improvements in physical function, motor proficiency and quality of life, providing evidence of the broad and clinically meaningful treatment effect.

CHESTNUT investigated a safety switching between 2 enzyme replacement therapies. Adverse events were comparable between children who switched to efzimfotase alfa and those who remained on Strensiq. Clinical benefits were maintained across bone health, physical functions and quality of life.

Taken together, these studies provide important evidence supporting the potential of efzimfotase alfa across all pediatric patients with HPP. With that context, I'll now hand it over to Dr. Raja Padidela, who will walk through the HICKORY data presented yesterday.

Thank you very much, Gianluca. I'm Raja Padidela. I'm a pediatric endocrine and metabolic bone disease Consultant at Royal Manchester Children's Hospital. Good morning, good afternoon, good evening, wherever you are. I'm going to present to you HICKORY data.

You heard about the CHESTNUT study and MULBERRY data, and this would be data on HICKORY study. This study was performed in treatment-naive patients with hypophosphatasia. Patients were more than 12 years of age, so adolescent and adults were recruited for this study.

This is a randomized, double-blind placebo-controlled trial with randomization performed in 2:1 ratio. So 2 patients received efzimfotase alfa and one received placebo. Patient identification was based on documented confirmation of hypophosphatasia with ALPL genetic pathogenic variant as well as looking at the plasma pyridoxal phosphate, which is one of the substrates, which is elevated in hypophosphatasia.

It was also a requirement that the alkaline phosphatase values were below the age and gender adjusted normal range. So the primary endpoint for this study was to look at the 6-minute walk test.

The key secondary endpoints were to assess various functional and quality of life assessment in these patient group with hypophosphatasia. So this is the baseline characteristic. The demography was very similar in both the group of the patients receiving efzimfotase alfa and placebo.

The patients were randomized and the numbers were 84 patients received efzimfotase alfa and 40 patients received placebo. This is results of the primary endpoint, which is the 6-minute walk test. Efzimfotase alfa patients had numerically longer distance walked at 25 weeks, but this was not statistically significant from the placebo group.

When you look into the open-label extension, efzimfotase alfa continued to show improvement in the distance walked in 6-minute walk test. So overall, over a period of 49 weeks, the increase in distance in this group of patients was 61.9 meters.

The patients who were on placebo group were switched over to efzimfotase alfa at 25 weeks. And you can see that there has been an increase in the distance walked, which was 43 meters from starting efzimfotase alfa. There were some dropouts, but this was not impacting on the power of the study and the dropouts were not related to injection site reaction or any safety parameters.

With regards to the key secondary endpoint, there was clinically meaningful improvement in the lower extremity function scale, the pain severity scores and the FACIT-Fatigue score, of which only the FACIT-Fatigue was statistically significant.

Deep diving into other secondary endpoints, the pain score, there is a pain interference score, which looks into the pain which impacts on daily activities, and this was favorable and statistically significant in patients receiving efzimfotase alfa.

Treatment satisfaction is important, and this was again statistically significant and favorable in patients receiving efzimfotase alfa compared to the placebo group. Continuing on the open-label extension, looking at the functional -- physical function in these groups of patients, those who were on efzimfotase alfa continued to show progress with 30-second sit to stand and lower extremity function scale and this was clinically meaningful.

And so was the case in the placebo group after switching over from placebo to efzimfotase alfa at 25 weeks, there was clinically meaningful improvement in these functional assessments.

Similar results were found with the pain severity score and FACIT-Fatigue score. Those who were continuing on efzimfotase alfa showed steady progress and improvement in these scores.

It was clinically meaningful with pain severity score and such -- and similarly, the patients who switched over from placebo to efzimfotase alfa showed significant improvement in their pain score, which was clinically meaningful.

And similarly was the case with FACIT-Fatigue score. We had prespecified groups in this population. The prespecification was based on the onset of their symptoms. So pediatric onset of hypophosphatasia was defined as the onset of clinical signs and symptoms documented in the medical history before 18 years of age.

In this group of patients compared to adult onset, there was a clinically meaningful improvement in 6-minute walk test, 30-second sit to stand, lower extremity function scale and the pain severity score, of which the 6-minute walk test, 30-second sit to stand and pain severity score were statistically significant.

In the adult group, clinically meaningful improvement in lower extremity function scale and FACIT-Fatigue was found. Only FACIT-Fatigue was statistically significant.

We did have in the placebo group in the adult onset who had extreme values, which may have impacted in some of these assessments, especially with the 6-minute walk test results.

Overall, across 3 Phase III programs, MULBERRY study, CHESTNUT study, HICKORY study, efzimfotase alfa had a favorable safety and tolerability profile, including in patients switching over from asfotase alfa in the CHESTNUT study. Efzimfotase alfa is administered once every 2 weeks because it is more potent. It's got a longer half-life and patients achieved a median of 98.8% injection site reaction-free days while on treatment.

The annualized rate of injection site reaction was 5x lower with efzimfotase alfa than with asfotase alfa. To conclude from the HICKORY and the broader program, in the HICKORY overall population, clinical benefit was observed in physical function and pain and fatigue despite not meeting the primary endpoint of 6-minute walk test.

In the pediatric onset subgroup, 6-minute walk test showed nominally significant clinically meaningful improvement together with measures of pain and physical function.

Adult-onset subgroup, fatigue showed nominally significant clinically meaningful improvement. In the open-label extension, there is continued improvement in physical function, pain and fatigue in patients receiving efzimfotase alfa. HICKORY results were consistent with clinical benefits observed in MULBERRY and CHESTNUT study.

Overall, across all these 3 studies, positive results in a broad hypophosphatasia population more than 2 years of age with a favorable safety profile. Thank you very much.

Thank you, Dr. Padidela, for taking us through the results. Can I see the next slide? HICKORY represents one component of the broader efzimfotase alfa development program and evidence package.

I want to spend some time discussing the overall opportunity in HPP, how we think efzimfotase alfa is differentiated and the role it could play in the future management of this disease.

Next slide. As the only approved therapy in HPP, Strensiq has transformed disease awareness, diagnosis and patient care. However, as with many rare diseases, understanding the true epidemiology remains challenging.

Published prevalence estimates vary widely across geographies and are typically derived from relatively small data sets that are extrapolated across broader populations.

While prevalence estimates vary, available data suggests there are approximately 14,000 addressable patients across the top 8 markets. 20% of these are pediatric cases. 60% are adults with pediatric-onset disease and 20% adults with adult-onset disease, with approximately 43% of patients presenting with skeletal manifestations.

Strensiq established the treatment paradigm for HPP. However, approved patient population, reimbursement criteria and access restriction vary across markets.

Informed by years of clinical experience with Strensiq and insight from real-world evidence, efzimfotase alfa was studied across a broader spectrum of HPP, including patients with adult-onset disease and those without skeletal manifestations.

We believe this broader evidence base, together with the differentiated profile discussed next, has the potential to expand patient reach beyond where Strensiq is today. Next slide.

We believe the totality of evidence generated across the efzimfotase alfa Phase III program supports its potential to expand the treatment opportunity in HPP, and we see 4 reasons for that.

First, efzimfotase alfa offers a differentiated administration profile. Compared with Strensiq's weight-based dosing administered 3 to 6 times per week, efzimfotase alfa is administered once every 2 weeks using a simple weight banded regimen.

This results in approximately 12x fewer injections per year and significantly lower injection volumes, substantially reducing treatment burden and potentially lowering barriers to treatment initiation.

Second, we believe the improved tolerability profile has the potential to support treatment continuity. Efzimfotase alfa was associated with a substantially lower injection site reaction with 361 days per year free from ISRs.

When ISRs did occur, the majority resolved within 1 week with 80% resolving before the patient next injection and 4x fewer persisting beyond 28 days compared with Strensiq.

Reducing treatment burden is important for both patients and physicians, helping support treatment persistence. Third, the program has demonstrated improvement across a broad range of disease manifestations.

As discussed, HPP extends well beyond skeletal abnormalities and can have a meaningful impact on physical function, pain, fatigue and quality of life. The breadth of outcome observed across the Phase III program reinforces the potential for [ asfotase ] alfa to address the wider burden of disease experienced by patients.

And finally, we believe efzimfotase alfa has the potential to expand patient reach globally, a broader clinical evidence base, coupled with lower volume, less frequent dosing and enhanced manufacturing capabilities would help address some of the barriers that have limited patient access across geographies.

Taken together, we believe efzimfotase alfa has the potential to become the preferred treatment option for patients with HPP. We expect growth to be driven by both the transition of patients currently receiving Strensiq and the expansion of the treated HPP populations.

This underpins our peak year sales expectation of $3 billion to $5 billion for efzimfotase alfa. Next slide, please. Today's discussion has highlighted the potential for efzimfotase alfa as well as the strength of the innovation engine that sits behind our rare disease business.

As we look beyond this program, our focus remains on evolving the portfolio, advancing the next generation of medicines and building a pipeline capable of delivering sustainable growth well beyond 2030.

Next slide. This slide highlights our near-term opportunities we have across rare disease. Each of these program has generated [ three ] Phase III data and is either already approved in at least one market under regulatory review or approaching potential launch.

Collectively, they represent a series of near- and medium-term opportunities across multiple high-value, underserved rare diseases, including complement disorders, HPP and light chain amyloidosis.

This gives us confidence in our ability to sustain growth from our existing portfolio as well as add new sources of revenue. Next slide.

Finally, beyond these late-stage opportunities, this pipeline represents the next wave of innovation across rare disease. By combining deep scientific expertise with a diversified portfolio of modalities, we can pursue diseases that have historically been difficult to treat.

This includes next-generation complement therapies, amyloid depleting antibodies, multifunctional fusion proteins, cell and gene therapies and oligonucleotide-based medicine.

Together, this program reflects our commitment to pioneering the next generation of rare disease medicine, creating a broad and diversified pipeline designed to deliver transformative outcome for patients and sustainable growth for AstraZeneca well beyond 2030.

Next slide. And with this, let me open the line for the Q&A.

So the first person on the line is Luisa Hector at Berenberg.

I guess my first question would just be on how you're thinking about any regulatory risk here, how the FDA will interpret this data? And whether -- I mean, is this a case of the different patient phenotypes, so age of onset being relevant here. Would you expect the drug to have slightly different effect in the pediatric and the adult onset groups? Or is it a function of the endpoints not being quite right? So just to frame it how we should think about this given the regulatory side?

Thank you, Luisa, for this question. Gianluca, maybe you can help respond to Luisa.

Great pleasure. Luisa, thank you, Luisa. Thank you for the question. So first of all, I would like to say it's a little premature for us to speculate what the regulators will read in the data and how they will mention.

We have filed in major geographies we are currently under review. So I will not be able to speculate. But I can answer your question in terms of the -- our interpretation of data set.

First of all, the pediatric patient population, adult with pediatric-onset of adult have the same underlying disease. So mechanistically and genetically, there's no reason why there should be a difference in terms of response to treatment.

Our medication is an enzyme replacement therapy addressing the underlying genetic condition. And therefore, we do believe that the data, the drug would be effective across the entire spectrum of the patient population.

And therefore, we designed a broader program that includes all the spectrum of the disease. Having said that, we designed a study that had been tailored to be able to assess treatment effect by age group by measuring endpoints which are relevant of each specific age group.

In the pediatric patient population, we used endpoints of bone measurement, which are radiological endpoints, easy to measure, well characterized and also objective in the measurement.

And that data set, we saw exactly what we expected, a very strong and clinically meaningful treatment effect of the drug comparable to Strensiq, again, as expected, but with a much lower dose, much lower frequency of administration.

So all the advantages that were mentioned during the review. Now in the adult patient population, it's important to note, this is the first time that we actually study adult patients, especially adult with adult onset. There's very limited data sets on the adult with pediatric onset, and we started the broader patient population.

So we purposely included a broader data set because that's where the unmet medical needs lies the most. Adult with adult patients, no available treatment and therapies.

Obviously, we had to choose the endpoint to be able to do that, and we chose the 6-minute walk test. The 6-minute walk test is the only endpoint approved by regulators for the management and the measurement of the disease. That's why that endpoint was chosen. But it's very well known that the endpoint has some limitation both in terms of variability and in terms of the fact that a patient can self-acquire knowledge during the course of the clinical study, which leads also to potential confounding evaluations.

Now when I focus on the 6-minute walk test results, which I think obviously is the critical point here. Indeed, we did not meet the primary endpoint. Nevertheless, there are quite important explanation that we can contribute -- can explain these findings.

First of all, the explanation resides on the fact that the adult patient population with adult onset saw higher-than-expected improvements in this endpoint, 28 meters against the 10 meters observed in the adult patient with pediatric onset.

Several things contributed to that. Number one, a couple of patients in the adult patient population with adult-onset on placebo had unusually large improvements. They are clinically uncommon for HPP.

These 2 patients drove the [indiscernible] clinical results in the placebo patient population justifying the results. In addition to that, as I mentioned, we enrolled a broad patient population.

And the adult onset group was older, mean age of 54, had more comorbidities, several number of patients above 64-year old and with assisting devices. All the confounding factor can be important for the assessment and evaluation of the 6-minute walk test.

And then finally, the placebo arm started with 50 meters lower baseline. There was an imbalance, which also justified the finding on the 6-minute walk test. There was a long answer to say that the endpoint chosen in the Phase III justify the difference in the results, more -- we don't think there's a justification based on the mechanism of the drug. And -- but we're looking at the totality of the data of the Phase III, we see a directionally positive effect across all the secondary endpoints and with a clear understanding of the reasons why we see the 6-minute walk test data set and the lack of significance for the primary endpoint.

Okay. Michael at Jefferies, can you go up with your question?

Yes. Gianluca, if you could just go back to what you said. I'm just trying to understand, I get the difference in 6-minute walk and functional, but the adult population really only hit on fatigue. It didn't hit really on pain either.

So why doesn't that tell you that maybe the disease is different in adult versus pediatric onset? And then going back to the regulatory question. So I presume you had your pre-NDA meeting, you did get the FDA priority review given for patients above 2 years of age. That does suggest that the U.S. regulator does look at this as a continuation of disease across age groups? Or am I overreading that priority review in over 2 years?

Okay. Perfect. So I'll go back to the adult patient population. Just to clarify, when we say treatment effect in adult, we have to be careful by defining adult with pediatric onset, which includes also the adolescent patient population and adult with the adult onset.

In the adult with pediatric onset, which is about 50% of patients, 60 out of 124 were classified as pediatric onset. We do see a consistent treatment effect in the 6-minute walk test with obviously nominal clinical significance because we missed the primary endpoint.

So we have to be very clear that all, I'm talking about is nominal significance, but it's also clinically meaningful and pretty much consistent across all the endpoints we measured in the pediatric patient -- in the adult patient population with pediatric onset.

Now in the adult patient population with adult onset, we didn't hit the endpoint on the 6-minute walk test. And the reasons are the ones that I previously explained. Let me repeat them again.

A couple of patients within the adult-onset placebo had a very highly unusual improvement in the 6-minute walk test in the range of 200, which is largely higher and uncommon in the HPP patient population.

Remember, the number of patients in these studies are small. This is an ultra-rare condition. So we are talking about a total of 46 patients with adult with pediatric onset. So you can imagine that 2 patients with a very high effect on placebo can skew the data set and the interpretation of the data. That's the main element to highlight.

In addition to that, the presence of an imbalance at baseline is also important. Placebo patients 50 meters lower at baseline, which means they have a higher marginal improvement.

So what we see in 6-minute walk test in the interpretation of the adult with adult data is a confounding effect due to the use of the 6-minute walk test and the underlying characteristic of these patients.

I cannot deny that the important 6-minute walk test obviously [indiscernible] results, which did not reach significance or nominal significance. However, when you look at the rest of the data set, including fatigue and pain, which are the most relevant and the most prevalent also symptoms in this patient population, we see a nominal clinical effect and also a clinically meaningful effect in the adult patient population as well.

There was an additional question, I believe.

Yes.

In terms of the interpretation of the results from -- the priority review, yes. And I can confirm that the priority review from the FDA was assigned to the totality of the data set. So including pediatric and adult patients with pediatric onset and adult patients with adult onset.

Thank you, Michael, and thank you, Gianluca. The next question is for Peter Verdult at BNP.

Peter from BNP Paribas. Maybe can we go to Dr. Padidela, a little bit of crystal ball gazing. When you think about your views in the U.K. and whether you -- hopefully, you've spoken about the data with U.S. peers and colleagues.

Could you maybe just give us a little insight into the future? I mean, should an approval come through and let's assume best case scenario across both adult onset and pediatric onset.

Could you just give us a sense, assuming that reimbursement and cost is not an issue, how is this going to change your prescribing habits when you think about initiating therapy in naive patients as well as the switch and your willingness to switch patients from Strensiq onto efzimfotase alfa? Sorry, multipart question, but all to Dr. Padidela.

Yes, I'll try to answer. If I miss, then please do ask me if I missed any section. So the asfotase works, no question about that. But we do have challenges with asfotase alfa and one of the most important version is the injection site reactions. 40% of our patients have to stop their treatment with asfotase alfa because of injection site reactions.

And that is a huge number. And that is the group of patients where it is clinically beneficial, but the treatment site -- injection site reactions are so overwhelming that the patients decide actually, I would like to stop the treatment.

And I think that is one of the most important thing which I have seen with efzimfotase alfa. In the pediatric population as well, when you look into it, my patients struggle.

It is clinically effective. It helps in skeletal improvement, asfotase alfa, but they do struggle with injection site reaction. I do worry that, that does impact on the full effectiveness of the medication with asfotase alfa.

But with efzimfotase alfa, the data in pediatric population is very encouraging. It heals rickets, it heals all the skeletal manifestation.

It has got a similar safety profile to asfotase alfa in the patients who switched over.

But what is most important is the injection site reaction, -- significant reduction in the trial data in my patients who are taking part in the trial, it's been very helpful.

With regards to the pediatric -- with regards to the adult population, the adolescent and adult, one of the major problems is injection site reaction.

In younger children, it's the skeletal manifestation. So sometimes the patients take it because they cope with the side effects and take it because the skeleton manifestation will significantly worsen.

Whereas in adolescent and adult population, it is the pain, the fatigue, the quality of life, which is significantly reduced, need this medication for improving that. They see the benefit, but unfortunately, they can't continue because 40% of them come out of it because of injection site reaction.

So for my patients, with this medication, I would definitely switch over because I've got the safety and efficacy data, which is very encouraging, which is similar to asfotase alfa with regards to efficacy. And it is much, much, much better when it comes to the safety, especially the injection site reaction. Have I missed any other elements of your question?

Maybe just if I actually can add on, Dr. Padidela, given that I've got the mic, so to speak. Your view on not hitting significance in the adult on -- are you of the view that you're taking the totality into account? Or how convincing or not is not hitting the primary endpoint?

Yes. I mean the primary endpoint was not met. And again, Gianluca has mentioned various aspects which has led to that -- the outcome, what it is. But when I look into the totality of the data, when I look into the improvement -- the clinically meaningful change in pain, fatigue, and open-label extension as well, the placebo group does very well, the treatment group continues to improve. It is a heterogeneous disorder, it's a lifelong disorders and we are looking at just data on 49 weeks.

So I'm quite hopeful that this treatment would be beneficial for our patients. I do take the point that the 6-minute walk test wasn't met, but there are various reasons for that which Gianluca has already mentioned. There are 2 extreme values in the placebo group and various -- and older population with other comorbidities. But I'm quite hopeful -- I am quite positive that once the totality of the data is looked into by FDA and various other regulators in different parts of the world in this rare disorder, the approval should come through and the patients would benefit.

So maybe I'll turn to the next question. Rajan Sharma from Goldman Sachs. Would you like to ask your question?

I've got 1 for the company and 1 for Dr. Padidela. Maybe doctor, if you could maybe just firstly talk about your current treatment for your adult HPP patients given that Strensiq, technically, I guess, not approved in that setting? And then could you also just talk about how, if these patients are diagnosed and treated in adolescence or from pediatric, how that sort of journey evolves over time?

And then for the company, I hear your commentary on, kind of, the outsized placebo responses or the extreme placebo responses. But I think there was also an open-label trial with Strensiq, which was running, it showed that there was no statistically significant benefit on 6-minute walk test there as well. So just wanted to understand your confidence in the mechanism in the adult population or whether there's something in the underlying biology that makes an enzyme replacement not necessarily the correct intervention?

So I'll start with all the patient group. The most severe ones are the ones who are born with severe skeletal, neurological and respiratory manifestation. In this group of patient, treatment is lifesaving. Without treatment, the mortality is very high. When you look into the natural history study, without treatment, 85% of patients don't survive beyond 5 years of age. And with treatment, 27% mortality at 5 years of age. So it has changed that major manifestation of hypophosphatasia, that is asfotase alfa has changed that. It hasn't been currently studied in this group of population, less than 2 years of age.

But the same group of population, when they go beyond 2 years of age, this medication has been studied with the switchover. And we have found that it has got the same favorable safety profile with much reduced injection site reaction. And what we have also seen is that it continues the improvement which we have seen in the skeletal manifestation with asfotase alfa. So from the pediatric point of view, we do manage patients with skeletal manifestations with a more objective. But we do also have a pediatric population where pain and fatigue is the most prominent symptom. And in this group of population, we do give asfotase alfa, but the challenge is the side effects which impacts on the quality of life and sometimes they are more significant than the disease itself.

And this is where I feel that this will be beneficial. When it comes to the adolescent and adult, I don't look after patient beyond 20 years of age, but I do have -- I do work in a center where I transition my patients to my adult colleagues. So in adolescents, the main challenge is the injection site reaction. And I believe that with this treatment, there would be a significant reduction with that and then the compliance would be better and the tolerability to this medication would be better. With adult onset, and I have -- I work very closely with my adult colleague in managing this patient, transitioning them into the adult service.

The main issue at the moment, they -- in the U.K., we manage -- we can only give Strensiq medication to pediatric onset patients. So that documentation is required. But once that documentation is available, they receive treatment, and it is clinically effective, but the injection site reaction is a major issue with 40% of the patient dropping out because they can't take this medication. So for adult population with the pediatric onset, I remain satisfied.

With regards to adult onset, I'll let Gianluca discuss that with you.

Yes, absolutely. And I'll go back to your question. I think you mentioned the Strensiq data set. So I'm happy to answer that and provide additional perspective in the adult data set. So first of all, the study you're referring to was an old study, small in size, open label. There were a total of 19 patients and only 13 of them were adults. The control were much younger, more impaired patient with a larger marginal improvement. In addition, in that study, actually, the dose of the Strensiq was still under consideration, and we know that patients were underdosed in the study. So it's a very small data set in Strensiq, although we are very much aware of that. As you know, we were aware that before starting the study, and we did not consider that to be relevant in the assessment of the treatment effect of the drug.

But let me go back again to the 6-minute walk test and explain why we -- [ what does the ] reason to believe in the data set for the adult patient population with pediatric onset as well as adult onset. I want to remind 4 elements why we believe the drug is actually shows a treatment effect, which we're using also with regulators, of course.

Number one, I go back to the responder analysis, which is a post-hoc analysis, but shows 45% of the patient reach MCID versus 30% in patients on placebo. That's an odd ratio of 2.5 with a nominal P value of 0.036. So the reason why we think the responder analysis is very important, because that's not confounded by extreme values. It only takes into account the true responders or much less confounders, and we clearly see a treatment effect by using this approach.

The second one is the open label extension. Dr. Padidela has already mentioned that, and I want to re-highlight that. Over the course of the OLE, the treatment effect was from 35, [ week ] 25, all the way to 61.9, [ week ] 49, which is a significant improvement over time. And also the placebos, which had additional gain of 43 meters within 24 weeks. So placebo also improved after switch. This additional open-label data and the 6-minute walk test shows treatment effect.

Then the subgroup. I mentioned previously, subgroup analysis in this data set was prespecified and also there was a stratification factor on the subgroups. The strata were part of the primary analysis data set, so it's a meaningful subgroup. And the subgroup also is based obviously on Strensiq label. So that's the reason why it's meaningful.

And what we've seen as a group is that in the pediatric onset subgroup of 60 patients total, we see a 6-minute walk test improvement of 35.6 meters with a nominal P value and above the MCID. We also see treatment effect in other endpoints, including sit-to-stand and pain, which really gives confidence of treatment effect in the adult patients with pediatric onset, patient population for which Strensiq is currently approved globally.

And finally, every single key secondary endpoint favor efzimfotase alfa, including fatigue, pain, which is also very relevant. Now in the adult patient population with adult onset, I mentioned all the reasons why we believe the 6-minute walk test potentially failed, but I also would like to highlight an improvement in fatigue of 7 points, which is highly clinically meaningful, as well as in pain.

So in summary, I would say, we feel very confident on the pediatric data. We feel very confident on the adult patient with pediatric onset. We feel confident also in adult patients with adult onset. We believe that we have a reasonable argument to show treatment effect. And of course, we will discuss all of this with regulators.

So next question is for Steve Scala at Cowen. Steve?

Two questions, probably both for you, Marc. Can you speak to AstraZeneca's expected conversion of Strensiq to efzimfotase both in rate and time? So for instance, do you expect 50% conversion in 3 years or some other target? And secondly, are peak sales of $3 billion to $5 billion achievable if the label is limited to pediatric onset hypophosphatasia?

Yes. Thank you, Steve, for these 2 questions. So for the reason that Dr. Padidela has elaborated upon, we expect the conversion from Strensiq to efzimfotase alfa to be very rapid for -- he has, I think, clearly articulated the strong benefit. And in terms of retention of initiation, but also retention of patient. 40% of patients abandoning due to injection site reaction, I think, should give you a good idea of the speed at which the conversion will take place.

To take on your second question, the range of peak year sales, which we have indicated between $3 billion to $5 billion, we are very confident that we will -- the sales will be within that range regardless of the breadth of the label. Obviously, if the label is more restrictive than we hope, it will be towards the $3 billion. And if it's the wider label, it will be closer to $5 billion. So that's why we have provided in May 2024 this range of $3 billion to $5 billion, which we happy to confirm today.

And the next question is for Colin White at UBS.

Colin White from UBS. I just wanted to ask about the previous comments that you had said about efzimfotase alfa potentially expanding the patient population 4 to 6x above what Strensiq had achieved. Given that the HICKORY study doesn't have a statistically significant benefit, I wondered if you could talk to your expectations of the expansion of the population. And also given that the adult population is often misdiagnosed for something else, I was just wanting to confirm that those previous estimates didn't include the strong data in the adult population driving better diagnosis?

Yes. So let me just -- so yes, I will talk about that. When we were -- when we are comparing and when we comparing the size or potential of efzimfotase alfa, we are comparing the number of patients to a baseline of 2022. And we have said in the past, that we would be between 4 and 6x the number of patients of 2022. And the numbers that we have confirmed in terms of revenues $3 billion to $5 billion are, I would say, consistent with this multiple 4 to 6x, the baseline of 2022.

Now am I -- why am I confident? As we have tried to explain to you today, I think the adoption will be easier for a patient to take a product every other week with very good tolerability. We know that the retention, and this has been discussed several times today, we have mentioned the 40% of abandonment of some patients. And then the regional expansion, today, Strensiq is available in quite a few countries, but certainly not to the whole global territory. So we expect to do a much better job with efzimfotase alfa.

And lastly, we still do hope to gain the adult onset. We are certainly convinced in the company that this is the same disease and the product is -- has efficacy -- has demonstrated efficacy in the population of adult onset. And we take as evidence the great benefit on pain, the great benefit on fatigue, which are, in fact, the symptoms with which a patient consults their physician when they don't understand why they are so tired at the end of the day or why they have pain in their muscle and joints and so on, and that's why they consult their physician. And therefore, these are very important symptoms for -- and some symptom relief for the adult onset.

So that's why we believe that the size of the population would be larger than Strensiq. There will be a better adoption. There will be a greater retention. And finally, the regional expansion that we have demonstrated on the complement products of Alexion, I think we can reproduce that for the treatment of hypophosphatasia.

And then I will go to the next question. Christopher Uhde at SEB.

Uhde at SEB. So, I guess, a question for Dr. Padidela. What factors drive the range of RGI-C and RSS responses with [ efzi alpha ] because the data appear inconsistent with the Gaussian distribution. Obviously, no one worsened, which is in contrast to the untreated population or even with Strensiq. But can that -- I mean, I can imagine 2 reasons for that, and 1 of them would argue that there is maybe a difference between some patient groups. So what are your thoughts there?

With regards to the RGI-C score and the Rickets Severity Score is that your question you're asking about, that you feel the improvement isn't that prominent?

It's not a bell curve in either one, and especially in the RSS has some relatively extreme outliers compared to where most patients sit.

Well, maybe I can...

I can pass this on to Gianluca.

I mean I think this is -- again, I want to go back to the data set, the number of patients within the data set. We're talking about the total of 29 patients within the data set in these pediatric patients. And we do expect distribution, which was not necessarily Gaussian in the effect.

When you look the individual patients, what I can say, we don't definitely don't comment about individual patients, but we saw an improvement for every single patient in the right direction. So where do they land in terms of the Gaussian really depends on where they start in terms of severity of the disease, but individual patient improvement was observed for all the patients in the study. And that's pretty much consistent also on the improvement seen by Strensiq in, I would say, comparable patient population.

We have not done a direct to head-to-head comparables for Strensiq because, obviously, we couldn't do that. But we have looked at Strensiq data sets in comparable patients, and I can confirm that, generally, the treatment effect is quite similar to Strensiq, despite the fact that we provide obviously a much lower dose in terms of in general and much less frequency of injection, which provides all the advantages for injection site reaction we mentioned previously.

In addition to that, we also looked at the switch data in the bone with Strensiq. We see consistency of response over time and no difference in terms of response. So overall, we're pretty confident that the bone data set, it's comparable to Strensiq. And potentially, in the future, we may assess additional dosing regimens as well to further improve this.

Right. But I guess what I'm asking is, are there any differences in patients that say that you can identify that could explain why some have much greater benefit than others?

Well, the -- it is, again, a bit heterogeneous in this population when it comes to severity of skeletal manifestation. We haven't seen anyone deteriorating with regards to skeletal manifestation. In some patients, where the skeletal manifestations are more prominent, it takes much longer for the skeleton to improve. And we are seeing a positive trend both in the open label -- in the randomized period and in the open-label extension period.

And that is true also for Strensiq, by the way. So the same observation is valid for Strensiq.

So next question is for Richard Vosser at JPMorgan.

One, please, just on Strensiq itself at the moment. I thought I'd take the opportunity. The commercialization of Strensiq has gone very well in the last few years and particularly this year. Maybe you could talk about the acceleration that has occurred and what's -- what you've been doing to drive that and how that might apply to the identification of extra patients for efzimfotase as well.

And then second question, just if the adult onset is not granted by the regulators. Would you consider doing a further trial given the benefits that you've seen on other markers other than 6-minute walk test? Is there any, do you think, flexibility with the regulators or anything you could do here given the long patent life?

Yes. Thank you. So Richard, so the first question, Strensiq doing very well. Yes, Strensiq has been doing very well consistently. I think a lot of it is caused by the transformative effect of this medicine. But also another very important factor is the effort in regional expansion that we have put across the network, and we are now -- we are gaining reimbursement as well as approval around the world progressively. And we intend to leverage that for the launching of efzimfotase alfa.

Obviously, as we said, there would be 2 sorts of patients. The first one would be those who are going to convert from Strensiq, but there will be also a source of patient coming from naive patients who have not been treated with an enzyme therapy. So we take this as a confidence for the therapy. There are still great needs around the world in many different geographies, and we will do -- we hope to do a great job on it.

Regarding the adult onset, so I think the question there is speculating again on what the regulators will say or not say, and what will we do if they say this or we say that. So I don't want to speculate today what we -- the purpose of our call today was to explain the data, and Dr. Padidela explained this very well. Gianluca provided some background on this. We will -- we are confident we will have very good interaction with the regulators. But we'll take it from there. And if we need to do more work, anyway in the rare disease, it is very common to continue the development work or post approval. So we will certainly do more work on efzimfotase alfa in the future.

And with this, I would like to ask Graham Parry at Citi to ask his question. Graham, are you on mute? Graham at Citi?

Can you hear me now?

Yes.

One for Dr. Padidela. In the event that regulators didn't give the drug an adult label, how likely would you be -- do you think, to use it off-label in either the pediatric onset or adult onset setting? And do you think that would receive reimbursement? And perhaps how did your international peers would view that as well?

And then secondly, to what extent is Strensiq already used by you and your peers off-label in adults? Is that particularly patients who are in the pediatric diagnosed and then move through into adulthood?

And then actually, 1 question for AstraZeneca, just slightly off topic, but just I'd be interested if you could talk to the positioning differentiation you see for Ultomiris in IgA nephropathy, given you've had positive data there this year.

I think there were 2 elements to your question. I think the second one was how frequently and to what extent we'll be using off-label treatment in adult onset. I think it will be difficult to answer this question in the sense that with rare diseases, with medications which are -- at the cost they are, we don't tend to use off-label medications. We are very strict with using it within the licensed indication. So I don't think we will be able to do that. So we'll be only able to use this if the regulatory authorities approve this.

So that's for the off-label question you had. I've forgotten the first question you asked. If you don't mind repeating that for me, please?

So that was -- it was the extent to which Strensiq is already used off-label. I think you partly answered that with the answer to the first question.

Absolutely. Again, we don't use off-label medications unless -- yes. So we don't.

And regarding the question, Graham, on Ultomiris IgAN, I think the purpose of our call today is to talk at great length on efzimfotase alfa. So we will take note of your question and, at the next potential interaction, we will provide some comments on the differentiating or profiling or positioning of Ultomiris in IgAN, if you if you agree.

And I would like to ask Simon Baker from Rothschild to ask his question.

Two, if I may, please. Firstly, going back to the adult onset group. I was wondering if, in a sense, adult onset was a proxy for disease severity. I just wondered if there was any difference in response based on time from diagnosis within that group.

And then secondly, a question probably for you, Marc. Could you give us an idea of the relative importance of the increased duration of therapy versus the breadth of the label in getting to the $3 billion to $5 billion peak sales indication?

So maybe Gianluca, you can take the first part?

Yes. So we did analyze the data and the details, but we do not see a specific difference in time to response based on the adult subgroup. As I mentioned previously, this is a very fairly small patient population in the study confounded by the effect of 2 patients specifically. Generally, what I would say is the patients above a certain age, over 65, probably tended to respond a little bit less, because most of that is driven by the confounding effect in this patient population and the use of devices, which was one of the elements that potentially could have affected the treatment response. But those are only the 2 -- the only 2 factors that could justify a different response to treatment. So it's more the presence of confounders in older subjects more than a true differential treatment response.

Thank you. So to just talk about the duration of treatment, so we have mentioned several times today this abandonment that -- in the adult population in particular. The abandonment is estimated at 40% due to injection site reaction. So as the disease itself is a chronic therapy, if you could eliminate the cause of abandonment due to the tolerability, this would have a very substantial impact on the average duration of treatment.

Obviously, we do not have the data because the product is not yet launched, but we can simulate to a greater duration of therapy on efzimfotase alfa versus a patient receiving to -- another patient receiving today Strensiq. I think the abandonment of 40% will be helping you model that extended DOT.

And with this, last question from Simon. Thank you very much, Simon. And I would like to close the call. Thank you all for your interest in efzimfotase alfa. And I do hope that we will be able to bring this molecule to patients any day sooner. Thank you very much.

Welcome, ladies and gentlemen, to AstraZeneca's Meet the Management event at the ERS Congress 2026 in Barcelona. 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 statement disclaimer in the slide deck that accompanies this presentation and webinar. [Operator Instructions] And with that, I'll now hand you over to the company.

Thank you so much, operator. Good morning, good afternoon, and good evening, everyone. My name is Ruud Dobber. I'm the Executive Vice President for the Biopharmaceuticals business at AstraZeneca. I would welcome you, and thank you for joining us to hear about the Phase III OBERON and TITANIA data for tozorakimab in COPD presented earlier today here at the 2026 European Respiratory Society Congress in Barcelona. As always, the materials presented today will be published on the AstraZeneca Investor Relations website following this presentation.

Next slide, please. Here are our usual forward-looking statements, which I encourage you to read. Next slide, please. This is our agenda for today's call. We are delighted to be joined by Dr. Frank Sciurba, Professor of Pulmonary and Critical Care Medicine at the University of Pittsburgh, who will walk us through the exciting Phase III OBERON and TITANIA data presented earlier today at the ERS. Next slide, please. Before we go into the data, let's take a step back and look at the role of R&I in delivering our AstraZeneca ambition in 2030 and beyond. Next slide, please.

Many of you will recall that at our Investor Day in May 2024, we set out our $80 billion risk-adjusted total revenue ambition for 2030. Since then, we have delivered strong commercial execution and substantial pipeline progress, further strengthening our confidence in the growth trajectory through 2030 and beyond. Respiratory & Immunology is an important contributor to that growth. Alongside the rapidly growing existing brands in our inhaled and biologics portfolio, tozorakimab is one of the key new medicines we expect to launch this decade, and we look forward to discussing its potential with you today.

In addition to the tozorakimab data, we have a number of upcoming catalysts for high-value assets across biopharma, oncology, and rare disease, which reinforce the breadth and durability of our long-term growth outlook. Next slide, please.

Turning specifically to our respiratory and immunology portfolio, we have key inhaled and biologic medicines across asthma and COPD. 5 recently launched brands have all delivered double-digit growth so far in 2026. We expect further momentum from the recent launch of Breztri in asthma and from the expansion of Tezspire and Fasenra in China and Japan.

We also have ongoing life-cycle management programs for a number of these assets. For example, we recently announced positive high-level results for the CROSSING Phase III trial in eosinophilic esophagitis, where Tezspire demonstrated clinically meaningful and statistically significant improvements across both co-primary and all key secondary endpoints, opening the door for Tezspire to potentially improve the lives of patients with this disease.

Our R&I portfolio also has 5 new NMEs in Phase II that will drive future growth, including our inhaled TSLP in asthma and other assets being studied in COPD, rheumatoid arthritis, Crohn's disease, and idiopathic pulmonary fibrosis. Taken together, this rapidly evolving portfolio and pipeline will fuel future growth for the business to 2030 and beyond.

With that, let me hand over to Sharon to talk about how we are positioned to address the needs across asthma and COPD. Next slide, please. And over to you, Sharon.

Thanks, Ruud. As shown here, our respiratory portfolio spans the full spectrum of asthma and COPD care from primary care-led inhaled therapies through to specialty care-led biologics as patients' treatment needs evolve. In asthma, we already have a strong inhaled presence with Symbicort, Airsupra, and recently approved in the U.S. and Japan, Breztri, which is the first and only triple therapy approved in asthma for patients 12 years of age and older. Today, as patients continue to progress, they can move to our approved biologics, Fasenra and Tezspire. We also have sunakiment, our inhaled TSLP, which recently read out its Phase IIb study. This is the first-ever inhaled biologic in asthma that is being explored to potentially reach a significant number of patients who today are uncontrolled on inhaled standard of care and don't have access to a biologic.

In COPD, we have the potential to extend our inhaled portfolio beyond Breztri and Symbicort with TQC3721, the inhaled PDE3/4 inhibitor for which we announced a licensing agreement in July. Similar to asthma, we are developing multiple therapeutic options to address the high unmet need in COPD. Specifically, in addition to tozorakimab, we also have Tezspire in Phase III and our oral IRAK4 inhibitor, AZD6793 in Phase II, one of the five NMEs that Ruud alluded to earlier. This is a respiratory portfolio purposefully built to meet patients no matter their disease severity or whether they are being treated in a primary or specialty care setting. Next slide, please.

COPD remains one of the greatest areas of unmet need in respiratory disease. Nearly 40 million patients are on inhaled maintenance therapy. Of those maintenance patients who are on optimized standard of care, meaning dual or triple therapy, half still experience exacerbations. And these exacerbations matter enormously. COPD is the third leading cause of death globally. One in two patients die within 3.5 years of their first severe exacerbation. That's a worse survival rate than a heart attack. Beyond the human toll, the cost to global health systems from COPD is expected to reach $4 trillion by 2050, driven in part by the high cost of these severe lung attacks. Preventing exacerbations is, therefore, a critical goal in the treatment of COPD, both to improve patient outcomes and to reduce the burden on healthcare systems.

And with that, I'll hand over to Dr. Sciurba, who will take you through the exciting Phase III OBERON and TITANIA data for tozorakimab.

Thank you, Sharon. So, I'm going to quickly present the data that I presented at the European Respiratory Society today on tozorakimab Phase III studies, OBERON and TITANIA, and the prevention of exacerbations in patients with COPD. Next slide, please. Basically, what Sharon said is that COPD exacerbations are really important events in the life of patients. That first event does predict future ongoing decline and mortality. Repeated exacerbations result in accelerated lung function decline is associated with some of the worst disruptive quality of life, and increase the cost through hospitalization and death.

About 50% of patients remain at high risk despite current guideline-based therapy. And current approved biologics are limited to adults with inadequately controlled COPD and the hypereosinophilic phenotype. And while that's often stated at 30% to 40% in my practice, it is not even that high. Next slide.

So, this unmet need really begets the need for more upstream mediators that impact on more downstream mechanisms than currently available biologics. IL-33 is a very interesting molecule that's released from epithelial cells following multiple stimuli causing damage and death to those cells. It's released in its reduced form. That reduced form binds to the ST2 receptor on inflammatory cells and drives both directly and indirectly pathways of the recently hyped type 2 inflammation, but also the type 1 and type 17, which is the more common inflammatory pathways in COPD, which elicit neutrophils, a different inflammatory cell than eosinophils.

That IL-33 can also be reduced and that are oxidized into the second form. And that second form binds to receptors, EGFR and RAGE on epithelial cells, which drive mucus hypersecretion, another big problem in these patients, and epithelial remodeling, which results in more airway resistance and decline in lung function. So, both of these pathways really appear to be increasingly recognized and important in the downstream effects of IL-33.

Next -- so, tozorakimab is a high-affinity monoclonal directed at IL-33. And first, its binding prevents then attachment to the ST2 receptor and impairs its downstream effects on the broad range of inflammation. But it also prevents conversion of that reduced IL-33 to the oxidized form and thus doesn't create the moieties that can bind to the EGFR and stimulate the mucus cell or the epithelial cell remodeling and mucus hypersecretion. And so, the aim of this clinical trial that is the buzz today is to evaluate efficacy and safety of tozorakimab compared to placebo when added to standard of care, the care that is the maximum in actually most clinics in treating COPD and in those patients with a history of exacerbations. Next slide.

So, the design of this study was a very inclusive study, more inclusive than most of the other biologics in many ways. It included patients on optimized guideline-based therapy who continued to have exacerbations. It included current and former smokers with the current smokers capped at 25%. The reason for that design was that a competitor found that there was some success in one of their Phase II trials only in former smokers, and so that de-risked the product. But the company did not want to lose the possibility of a discovery in current smokers.

And so, you'll see those data.

Post-bronchodilator FEV1s of less than 30% implies the worst stage of COPD and recruitment went down to 20% predicted. So, there were inclusion of GOLD 4 patients, which was not included in some of the competitors. These patients were very symptomatic. And very importantly, eosinophils were not used in deciding who entered the clinical trial.

The study design initially included 2 active arms of tozorakimab, 300 milligrams subcutaneously every 4 hours and every 8 hours versus placebo. The -- I said hours, I meant weeks -- Q4 weeks versus Q8 weeks. The Q8 week was halted because of additional information before unblinding that suggested the pharmacodynamics may not be adequate. And so, the analysis will be just based on the Q4 week versus placebo. The primary endpoint in this experiment related to what I had told you about former and current smokers was a subset of the overall recruited population and the effects in just former smokers as the primary endpoint of annualized rate of moderate to severe exacerbations.

But the first secondary endpoint in a hierarchy was then annualized rate of moderate to severe exacerbations in the overall population of current and former smokers. The company felt confident that they would get it, but did not want to put it as the primary, but they got it as the first secondary. We'll show you some of the results of the other hierarchical secondaries down the line. Next slide, please.

So, the overall population was well balanced between placebo and active arm. Interestingly, the blood eosinophil count included approximately 40% of people in that most unmet need group of less than 150 eosinophils, which is not covered by any of the other biologics. And so, overall, there was -- well, in addition, there was a very severe population of that less than 30% predicted that represented about 20% of the patients. Next slide.

So, these are the big results, the primary results, remembering the primary outcome was in former smokers, and that represented 29% reduction in exacerbation rate and 34% reduction in exacerbation rate in the OBERON and TITANIA studies, respectively, in former smokers. In the overall population of current and former smokers, the overall reduction was 30% and 29%. All of those were very statistically significant and clinically important. Next slide.

These represent a graphic representation of the numbers I just showed you and shows their separation favoring tozorakimab early in the treatment, which continues through 52 weeks. And what's important is to see that really this is balanced across both studies and in both populations that we analyzed. Next slide.

These represent some of the secondary parameters, and we lost the hierarchy because the St. George's Respiratory Questionnaire, which is a quality of life with some symptom emphasis, but really more general effects of the disease on quality of life, it did not reach statistical significance, even though there was a strong trend in one of the studies, less so in the other.

FEV1, an objective measure of lung function, moved approximately 25 ccs in both studies, statistically significant in OBERON and just missing statistical significance in TITANIA, remembering this is a broad population of patients with high and low eosinophils. The E-RS score is a much more symptom-based score, less recognized, less familiar to the FDA. And so, SGRQ was put higher in the hierarchy with their preference, but E-RS did hit. And it was a symptom parameter that moved relatively strongly toward the minimal important difference being statistically significant in both studies.

And it's really -- if you saw the questions, it's a really pragmatic symptom questionnaire -- cough, sputum, dyspnea type questions. And then the annualized rate of another important outcome, severe exacerbations, including ED visits or hospitalization in both trials in the overall population achieved statistical significance with a 36% and 33% reduction in the 2 separate clinical trials. Next slide.

A prespecified pool analysis, looking at the overall demographics and whether there were any -- whether this was a consistent effect across all subgroups showed that, in fact, there was a consistent effect and specifically former and current smokers both had significance. The top row in this represents the effect in the overall study and the green bar represents the 95% confidence interval, which most of the subgroups fell within. Next slide, please.

These represent a similar analysis in COPD-specific parameters. Importantly, patients with both low and high lung function had significant improvement. And most important to clinicians and to increase the potential population of patients treated is that this was effective across all eosinophil levels, unique to any biologic right now in COPD. Next slide, please. Specifically, patients with the greatest unmet need with no therapeutic options at this time with respect to biologics had a 23% reduction in exacerbation rate. That's clinically important. It's along the lines of the overall effect of mepolizumab in a high eosinophil population.

The group that was greater than 150 cells per microliter had a 34% reduction. And the group that had greater than 300 cells per microliter had for COPD really a remarkable reduction of 43%, which on face value exceeded anything we've seen in COPD before with biologics, even in the high eosinophil space. Next slide, please. With regards to adverse events, overall, they were balanced between active and placebo arm, except with regards to site injection reactions, which is expected with biologics. MACE events, cardiovascular events were overall low, although there was a slight imbalance toward tozorakimab, and it was largely related to unexpectedly low rates in the placebo group. Next slide, please. So in summary, tozorakimab significantly reduced the annualized rate of moderate and severe exacerbations by up to 34%. In a prespecified pool analysis, this effect was independent of eosinophil level, airflow obstruction level, and smoking status. It was generally well tolerated. And these findings overall represent a first-in-class biologic with a true valuable therapeutic option now for patients in a broad population with a history of exacerbations despite guideline-based therapy. Next slide.

And that's all I got to say. Thank you.

Okay. Thank you, Dr. Sciurba, for taking us through the results. As you've just heard, tozorakimab was studied in the broadest COPD population of any biologic to date, enrolling patients across the full range of blood eosinophil levels and stages of lung function severity in contrast to approved biologics, which have only been studied in narrower populations. What's especially exciting is the clinically meaningful reduction in exacerbations across eosinophil levels.

We saw a 23% reduction in patients with baseline EOS below 150, where no biologic is currently approved, a 34% reduction in patients with EOS at or above 150, and a 43% reduction in patients with EOS at or above 300. This translates into highly clinically meaningful efficacy across the broad population, including reductions in exacerbations of up to 34% in former smokers and up to 30% in the all-comer population. Given the strength of these data, we were pleased that the FDA has granted tozorakimab priority review with a PDUFA date in the first quarter of 2027.

Next slide. This breadth of efficacy translates into what we believe is a large differentiated opportunity to address the high unmet need in COPD. By 2030, we anticipate that there will be approximately 6 million people with COPD eligible for a biologic. Today, patients with EOS levels below 150, 35% of that population, have no approved biologic at all, and tozorakimab showed a 23% reduction in exacerbations. Patients with EOS between 150 and 300, where tozorakimab demonstrated a 25% reduction in exacerbations, have only 1 biologic option.

And while there are currently 2 approved biologics for patients with EOS greater than 300, we believe that the data from OBERON and TITANIA are highly differentiated in this subgroup of patients. We also see potential beyond COPD. IL-33 is implicated in several respiratory diseases and trials with tozorakimab are already underway in severe lower respiratory tract disease and asthma. We are actively considering additional indications in which IL-33 may play an important role, such as bronchiectasis, chronic rhinosinusitis, and CTD-associated inflammatory interstitial lung disease. Our ambition is to build a leading respiratory franchise with tozorakimab. The broad and compelling efficacy demonstrated by tozorakimab is why we see this as a potential $5 billion-plus asset.

And with that, let's go to the next slide, and I will turn it over to Pascal to discuss how tozorakimab fits into our broader growth ambitions.

Thank you, Sharon. Next slide, please. As you no doubt saw today and heard from Dr. Sciurba and Sharon and Ruud, tozorakimab is a very exciting product. It has delivered exceptional results across the broadest patient population ever studied with a biologic in COPD. And having received priority review with the PDUFA date in Q1 2027, we are, of course, working very hard to bring it to patients as quickly as possible. Given the strength of the data and the significant unmet need, we are confident in our guidance of peak sales exceeding $5 billion for this asset across indications.

Importantly, however, tozorakimab is one of a number of promising medicines that we have in our pipeline. As you can see on this slide, we have 12 programs, each with a peak sales potential exceeding $5 billion, for which we anticipate pivotal data before 2030. Together, they represent a meaningful contribution to our growth in the next decade and support us in our belief that we can continue growing post 2030 through the patent expiries that will affect us.

We've already launched 3 of those important medicines, Datroway, Etcamah, and Baxfendy, and there's more to come. In addition to this, we have also several programs with peak sales between $3 billion and $5 billion that will also support our growth post 2030. So taken together, these products built a strong foundation as part of a diverse pipeline that we believe will more than offset future losses of exclusivity and drive sustainable long-term revenue growth beyond 2030.

And as we have said many times before, of course, our forecasts are all risk-adjusted and account for some setbacks along the way. But so far, this is looking pretty good. So if you look at the next slide, please. Our large pipeline continues to progress. And before I highlight some of the key readouts for next year, I want to briefly mention 2 especially significant catalysts from the past few days.

First of all, on Friday, we were pleased to receive U.S. approval for Etcamah in the first-line setting for hormone receptor-positive patients with emergent ESR1 mutations. This marks the first FDA approval of a cancer therapy guided by the detection of a resistance mutation in circulating tumor DNA, and it validates an entirely new treatment paradigm of ctDNA-guided intervention before radiographic progression. Etcamah is the first oral SERD approved in the first-line setting but is also the first approved for use with all 3 globally approved CDK4/6 inhibitors that sets us on a path to establishing a new endocrine backbone in hormone receptor-positive disease and driving growth both to 2030, but also beyond.

Etcamah SERENA-6 is clearly a blockbuster opportunity, which will, of course, partially be cannibalized by SERENA-4, if SERENA-4 is a positive study. But SERENA-6 will remain quite large in the event SERENA-4 turns out to be negative, which, of course, we all hope will not be the case. The second event is that earlier today, we announced highly positive results from the DeLLphi-305 trial, evaluating Imfinzi plus tarlatamab in extensive-stage small-cell lung cancer.

DeLLphi-305 reinforces Imfinzi as the backbone immunotherapy across stages of small-cell lung cancer. And we see this as an incremental blockbuster opportunity in addition to what we already achieved with CASPIAN, the CASPIAN indication. So this blockbuster additional opportunity is additional to the current CASPIAN revenue, and it further supports our 2030 ambition.

As a reminder, in small-cell extensive stage in the United States, we only have today with CASPIAN 25% share of patients. So this new study, this combination study will enable us to dramatically grow Imfinzi in the small-cell segment, we believe. Now looking towards 2027, we have a number of important pipeline catalysts across the portfolio, including the first Phase III readout for 6 of the NMEs highlighted in the previous slide.

Starting with biopharmaceuticals. We look forward to the first Phase III data for laroprovstat, our oral PCSK9 inhibitor. This once-daily oral small molecule, which has no food effect and is combinable with other small molecules in our portfolio, has enormous potential, we believe. Laroprovstat delivered encouraging Phase II results and our first Phase III readouts are expected in the first half of next year. Despite the broad availability of and usage of high-intensity statins, most patients are not reaching their LDL-C goal.

The need for continued innovation remains, therefore, critical to further reduce the worldwide burden of cardiovascular disease. In addition to this, PCSK9 inhibitors are very great products, but they are injectable. So an oral agent will enable us to go beyond the U.S. marketplace and to some extent, Europe. A large population around the world cannot benefit from PCSK9 inhibitors because they are injectable and more expensive.

We also expect the first Phase III readouts from the dapagliflozin fixed-dose combinations with balcinrenone and zibotentan. These combinations bring together complementary mechanisms of action to address significant unmet needs in clearly defined patient populations, which today have very limited treatment options. In oncology, while we anticipate the SERENA-4 data this year, more importantly, we await Phase III CAMBRIA-1 data in the second half of next year. CAMBRIA-1 will be the first trial of Etcamah to read out in the sizable early breast cancer space.

Here, we are uniquely positioned with the broadest program of any oral SERD. Our trials cover patients at both early and late risk of recurrence and have the option to use Etcamah as a monotherapy in combination or post the CDK4/6 inhibitor. We also expect the first Phase III data for our PARP1-selective inhibitor saruparib from the EvoPAR-Prostate01 trial. This trial looks to build on our established leadership in PARP inhibition with Lynparza and bring saruparib to the earlier hormone-sensitive prostate cancer setting across both patients with and without homologous recombination repair mutations.

Beyond these programs, we also expect more than 10 additional high-value readouts across the portfolio next year, underscoring both the breadth and the diversity of our pipeline. So this catalyst-rich period clearly continues with a steady stream of important data expected over the coming months, and we look forward to updating you on our progress. Next slide, please.

And with that, I will hand back to Sharon to open the line for Q&A. And I apologize for my broken voice today. I hope you could follow me anyway. Thank you.

Okay. So with that, I think it's time to open the lines to Q&A. And our first call is from Richard Vosser at JPM.

One question for me, please, and it's for Dr. Sciurba. Just obviously, very strong data across all patients with COPD. So just your thoughts on how you're going to use tozorakimab. Do you push this as a first-line biologic in COPD and abandon EOS testing? And how are you thinking about switching patients that are potentially on Dupixent or the IL-5s given the stronger data even in high-EOS patients?

Yes. No, I appreciate the question. And honestly, I'm not going to take the, probably the company party line on this. I think it's exclusive in probably less than 300. The competitor in the 150 to 300 space, if you look at the forest plots on those papers, doesn't have really much of a response in that space. And when they just described greater than 150, the real response is above 300. So that's, I mean, I will tell you that is the vast majority of COPD patients.

I'm not willing to give the above 300 space exclusively because trials are not head-to-head. There's differences in inclusion, exclusion -- subtle differences can make a difference. There are certainly big players, and that absolute bottom line in the absence of head-to-head is certainly compelling. So no, I'm not going to switch my patients doing well on dupi over, but I'm certainly not going to exclude considering tozo as first line in above 300 and, but probably not exclusively at this point in my practice. More data will come that could prove that, in fact, it deserves to be there.

And our next question is from Sarita Kapila at Morgan Stanley.

Just on the launch, given that the trial showed efficacy across eosinophil groups, if the label comes without testing requirements, how much could this broaden and accelerate community adoption versus the existing COPD biologics? And perhaps, Ruud, you could indicate your level of comfort or launch readiness upside over consensus first-year sales of $265 million? And then secondly, just a quick follow-up on the MACE and fatal adverse events imbalance. I know you mentioned there was unexpectedly low rates in the placebo group, but how should we think about this imbalance? Are there any potential knock-on label outcomes, so warning or monitoring requirements?

Yes. Let me take the first question, Sarita, and thanks for that. First of all, let's also reiterate that the FDA has granted us priority review. So we are, indeed, we're aiming for a potential launch in the United States in the first quarter of 2027. Let's not forget that this is a highly skewed Part D population. If you look at the clinical trial, you see that the majority of the patients over 65. Now having said that, I truly believe that the data we have shown today are groundbreaking. So we will do everything in order to further increase the diagnosis rate.

At the moment, the current biologics, as Frank said, are limited primarily to eosinophils above 300. There's a bio penetration of roughly 10%. So clearly, the #1 priority is to further extend that bio penetration in a much larger patient population. So that's quite exciting. Of course, we have quite a bit of experience in the biological space, primarily in the asthma space. I'm not going to comment about the, let's say, the first year of launch for the simple reason that we still need to, sorry, there's an alarm here in Barcelona. So that's very unfortunate. I don't know what it is. But I will do my best. It's better now. So I'm not going to speculate about the first year of sales. First of all, we need to get it over the finish line. We will be in active discussion with the payer anytime soon. And hopefully, I can provide a little bit more color in the upcoming months.

Okay. So we'll ignore the floods that we're having in Barcelona. And Dr. Sciurba, if you could speak to Sarita's question about the MACE events in this study, I think that would be helpful.

Yes. So I mean I'm going to just start with a perspective of death versus improved symptoms in this advanced population of patients. I mean the mortality, sorry, we're having these alarms blaring. Let me give you an example of endobronchial valves, which you may or may not know about. It's a different company. When I address patients often with the same level of symptoms and severity, and that's, again, another very precise population. They don't even care about the 5% risk of mortality for the chance to improve because they're really suffering. The other thing I want to tell you about is that most of the patients with COPD don't die of COPD. They die of cardiovascular events and comorbidity.

And cardiovascular disease is disproportionately associated with COPD independent of smoking because of co-inflammatory mechanisms affecting endothelium. So to see no events over a year was really surprising to me. And so I'll give it that perspective. The other thing to recognize is that colleagues who I very much respect reviewed the associations with product and didn't find causal association. So they couldn't find any logical mechanistic link. And so that reassured me somewhat. And then the last thing, and I would urge you to pay attention to because I'm going to, is the extended data set, which will have a much broader safety profile. I'm going to be looking for, and my understanding is that, that's much more reassuring than what we're seeing in the one clinical trial here that seems to have a slight imbalance.

Thank you so much for your clinical perspective. I think that's hugely valuable. If I were just to reemphasize some of those points, I think it's fair to say that the MACE events on this study were rare. They occurred in a highly comorbid population. It's important to note that the events observed in the treatment arm were reviewed by an independent data committee and were not adjudicated to be related to study drug. And our overall data set, together with OBERON and TITANIA, I think, will support what we have seen in the study that tozorakimab is safe and well tolerated. So with that, let's move on to the next question from Sachin Jain, Bank of America.

I've got one follow-on to Sarita's and then maybe since Pascal is on the call, I can ask a few bigger picture questions. So the follow-on question is just from both the Astra and physician perspective, what do you think the main barriers are to biologic penetration? And do you think the tozo data is enough to change that? So just a follow-on, do you think it's EOS testing? Or do you think there are other factors, cost, administration mechanism, and sort of Ruud mentioned driving biologic penetration.

Perhaps you could just give us some color on the factors that you think you can influence -- and then, Pascal, just since you're on the call, it's the first call since the media M&A speculation, and I guess the sort of pipeline midterm perspective is to partly address some of the questions that have been out there with investors. You very kindly, sort of, given your confidence in growth in the post-2030 period, which I guess is the crux of investor debate the pipeline versus patent cliff.

I just wonder if I could push any quantification of what your base case is through that '30 to '33 period? And is that a sales or EBIT comment given what you lose is high margin? And then just any commentary you can give us updated on how you're thinking about large M&A. You did comment that M&A wasn't required for the 2030 targets on the 2Q call, but obviously, this is the first call since the media speculation. And apologies for those last two questions, but I guess it's important.

Okay, Sachin, let me take the first one. First of all, regarding the hurdles, the challenges, I think there are a few which we need to navigate, which is always normal with the new launch. First of all, what I've already mentioned is the diagnosis rate. The diagnosis rate, of course, in some countries, in well-developed countries is high, but we also need to acknowledge that in large countries like China, there's still a lot of work we need to do in order to bring COPD higher on the agenda and as a diagnosis.

So that's one big area of, let's say, attention for our teams across the globe. The other one is what I've already mentioned, the bio penetration. At the moment, we clearly see primarily that biologics are used in a subset of COPD patients, roughly 30% of eosinophils above 300. I think the data today is clearly showing that we have a much broader population. We will discuss that, of course, with the regulator, but equally also with payers moving forward in order to secure a broad label, but also a broad, let's say, reimbursement for those patients.

So I think that those are more or less the 2 big ticket items moving forward for the product. I think last but not least, I think I dare to say that we have been highly successful in the asthma space, both with Fasenra and Tezspire. So we are well equipped in order to detail on the level of the pulmonologists, and we will partly use our current field force for that as well moving forward. And time will tell then how fast we will get traction, especially with the Part D plans, which is always a little bit of a challenge. But all in all, we feel comfortable that we have a very strong product in our hands. We truly believe -- I truly believe that it will set a new bar for any other competitor moving into this space of biologics and COPD. And we are very committed as a company in order to do a very good job here.

And Pascal, to you for Sachin's additional questions and confidence post 2030.

Yes. Thank you, Sachin. It's a great question. We are absolutely confident in our post-2030 forecast and the fact that we can continue to grow post 2030 through the patent expiries. And we believe that for 2 reasons. One is we already have a pipeline of products that are progressing very well. A few minutes ago, I mentioned 12 assets, 12 programs with a potential of about $5 billion each or more. So a simple calculation tells you that in these 12 programs, we have a lot of potential revenue.

Now not everything is going to work. And we keep repeating this to everybody. We don't expect everything to work. We wish everything to work. We pray for everything to work. But reality is we know not everything is going to work. And I've said it before, our average probability of success across our entire Phase III pipeline is about 60%, so slightly less than the industry average. And we have performed higher than the industry average, which is about 65%. We've been at about 75%, 80% success rate over the last few years.

So number one, we have a pipeline of a number of products that if they all worked, we deliver enormous sales, but they will not all work. But that's number one. Number two, we have quite a number of technologies that will drive the future of medicines, we believe. And we started working on those in 2022 already as we were approaching the sort of 2023 goal. You will remember the famous $40 billion sales. We started looking at the next 10-year horizon. And of course, that included the patent expiry of products like Tagrisso or Imfinzi.

So we started working on those new technologies, cell therapy, TCEs, radioligands, weight management, cardiometabolism. So we worked on all of this. And we have invested, as you know, a lot, and we've made a lot of progress. A number of these technologies are now delivering products that are looking pretty exciting. AZD0120, which is not recognized very much these days, I can tell you, is showing early data, but very exciting.

Our cardiometabolism franchise is progressing very well. Our radioligand franchise is progressing well. Our ADC portfolio is progressing very well. So what we have in our hands today in Phase III plus the progress of these new technologies, these new platforms give us confidence that we can grow past 2030 through the patent expiries. Now it doesn't mean we cannot create even more value for patients and for the company by adding BD deals. But as you can see over the last number of years, we've actually prioritized small to midsized deals. That has been our strategy. So that's what I can see about -- I can say, sorry about this question, but I can really tell you we are very confident that we should be able to grow. Of course, we can be incredibly unlucky and everything can fail, but it's very, very unlikely.

And our next question is Steve Scala at Cowen.

First for Dr. Sciurba. Why do you think tozorakimab succeeded when other IL-33s failed? Do you think it's more likely to do with the molecule itself or unique study issues such as patients enrolled? Secondly, only 10% of the people were from the U.S. Does that raise any issues, do you think with the FDA discussions? And lastly, as a follow-up to the question you just answered, Pascal, should we conclude from your response that you do see very large M&A that makes sense for AstraZeneca?

Okay. So Frank, the first question is to you. Steve was asking why you think our tozorakimab trial succeeded where others may have been less successful?

Yes. So, the company has described the reduced and the oxidative form and lack of conversion to the oxidative form, which directly affects the EGFR receptor and epithelial remodeling. I can tell you, IL-33 is a very complex molecule. And those are probably two very important conformational states, the initial reduced state that binds to the inflammatory cell pathways and then the oxidized state, which results directly. And it may be that simple. It may be that by blocking conversion to the oxidized state, it prevents that epithelial remodeling, which on top of the anti-inflammatory puts it over the line.

But what -- this molecule is it actually has many different conformational states and where that antibody binds very plausibly makes a difference in receptor affinities, whether it's EGFR, ST2, and how the molecule behaves. And so there's every plausible reason why a monoclonal that interacts with a cytokine in a different way would have a different result with -- particularly with this cytokine. And so I think it's very likely that, in fact, it is a biological effect.

Overlaid on top of COVID with different times, it could have resulted in some methodologic issues that made it hard with some of the weird results from some of the competitors. But the degree of separation and the results of this study versus the others makes it feel less likely that it's just -- it's a non-biological effect and just a study design issue.

All right. If I could just layer on that. You started off by talking about the differences between tozorakimab as a molecule. And I think I might add one more thing that we were discussing earlier today. We believe that tozorakimab is uniquely differentiated in its ability to bind IL-33, prevent its conversion from the reduced form to the oxidized form and in doing so, to be able to inhibit signaling through both the ST2 arm and the RAGE-EGFR arm. And the reason that we highlight that is because it is the RAGE-EGFR complex that ultimately drives epithelial remodeling and mucus production.

And there were some supportive data presented here at the ERS Congress, although not in Dr. Sciurba's presentation, but in a poster presentation elsewhere in which we demonstrated that with tozorakimab treatment, there was a statistically significant reduction in mucus plugs. This is a key feature of disease. And it is, in fact, the first data that has shown the effect of a therapy on reduction of mucus. And we know that's really important for patients with COPD because mucus production drives exacerbations and exacerbations drive mucus production in a vicious cycle. So this is a clearly differentiated mechanism for tozorakimab, and we think that it may have contributed to the success that we have seen in both OBERON and TITANIA.

You also commented, I think, on the strength in trial execution. And -- and I'll leave that there. Steve, your next question was, do we think that the proportion of patients recruited in the U.S. will raise issues with the FDA. And I will say that the percentage of patients that we recruited from the FDA -- from the U.S. is consistent with many of our other studies, consistent with studies run by competitors for approved therapeutics. So while we can never say for certain, we're going to go through the review process. We are not initially concerned about this in our ongoing submission. And then Pascal, the third question was to you regarding M&A.

Yes. Thank you, Steve, for pushing me because I could have been misunderstood. So I didn't say that at all. I thought I was saying almost the opposite. I was saying our strategy has been to focus on small BD, as you could see over the last number of years because we try to do deals early to build value along the way. The reason I didn't really totally exclude larger BD is that it makes sense. But it depends what you call large. Again, our priority is small ones. But if we found something like, I don't know, Alexion or $10 billion, $20 billion that makes sense, we would certainly consider it.

Not that those opportunities exist everywhere, as you know. But anything we saw -- we would see that would actually make sense for us strategically, financially, scientifically, we would consider. But typically, we would really look at much smaller deal. But again, I don't know what you had in your mind by big, but something in the range of $20 billion, $30 billion, we -- if it made sense, we would certainly consider. Again, those are extremely rare. The last one we did was Alexion almost 6 years ago now.

And our next question is from Michael Leuchten at Jefferies.

If I could just please go back to the secondaries in OBERON and TITANIA. And interested in why a very substantial and consistent reduction in exacerbations doesn't really lead to an improvement in St. George's scores. I guess that's for Dr. Sciurba. And then also, like if the IL-33 oxidized hypothesis is true, why don't we see more of an impact on FEV1? I guess maybe the follow-up is too short. And then maybe for Sharon as a follow-up, where does that then take us as we think forward? Does that mean we need to think about bispecifics to push that hypothesis on remodeling? Or is that just more trials with longer follow-up? Is it a different modality? Any thoughts on portfolio would be great.

Okay. So Frank, the first question was to you about the key secondaries and why we think that there was not a statistically significant readout for St. George's.

Yes. So recalling the ERS, the respiratory symptoms did significantly improve across both studies and both populations. But to your question, in a population that is that severe, often it's harder to move the quality of life metrics. And so I think this population is more severe than another company that did move SGRQ. And that, I think, is at least part of the answer to that. I was reassured that the E-RS moved considerably and that the symptoms improved in these patients because it can be harder to maintain a patient on biologics without symptom improvement. And we did see statistically significant and clinically important symptom improvement, but it was nominally significant because it followed the SGRQ and the hierarchy.

Yes, I think that's very helpful. Is it fair to say in your clinical experience that because this relatively severe patient population with 20% being GOLD level 4, they're already experiencing a significant impact on their quality of life, and therefore, it was more difficult to show an improvement in the quality of life in these relatively infrequent questionnaires.

That's That's what I said, except you said more eloquently.

We're good together then. Okay. So Michael, you also asked about our go-forward plans and our thoughts about the heterogeneity of disease. So I think what we've told you today is a story that we have a very exciting development program in tozorakimab and in fact, an exciting portfolio in our respiratory therapeutic area. And I think we've also made fairly clear in recent weeks that we have 2 powerful franchises in IL-33 and TSLP supported by our recent news of the Tezspire EoE successful CROSSING study.

So we continue to look at a range of platforms. While long-acting antibodies are an exciting area of focus and part of our area of focus, we know that efficacy trumps convenience. Efficacy has to be paramount. And so we have kept that in mind as we build out our portfolio in the early stage, and we continue to explore all the modalities that we think could bring better therapeutics to a broader range of patients.

So most notably, we are in the planning stages for Phase III following our successful Phase II trial for sunakiment. That is the first ever inhaled biologic targeting TSLP, which we have designed to bring efficacy to a broader population earlier in the treatment pathway. We continue to explore oral therapeutics, as I mentioned earlier in the call. Our focus will always be on delivering the best possible efficacy, which brings me back to the story today of tozorakimab and the fact that I think that we have a first-in-class and best-in-class molecule with the data that we demonstrated today in the broadest possible patient population. And our next question is from Graham Parry at Citi.

It's Graham Parry from Citi. Just wanted to query on the current smokers. There was a trend benefit that wasn't statistically significant just specifically in that subgroup, but of course, it was significant across the all-comers population. Just how confident are you that current smokers would be included in the label, reimbursed? And then for Dr. Sciurba, how comfortable would he be using the product in the current smoker population?

And then secondly, in the eosinophil-high population, is there a patient pool that he feels he would choose Dupixent over tozorakimab? And going back to the original question that was asked earlier, does he see the need to test for eosinophils now and to determine which therapy would be best for a patient out of the two?

All right. So why don't we take it this way? Ruud, can you address the potential label and current and former smokers? And then, Frank, can we go to you for your clinical experience, both with smoking status and with EOS?

Yes, of course, and thank you so much, Graham. I'm not going to speculate about the label discussions, but I think the totality of data we are presenting both in the primary endpoint as well as the first secondary, at least that gives me confidence that the FDA will grant us a broad label. But once again, label discussions, or at least the review of the package, will start in the coming months. So I don't want to speculate too much about that.

But of course, our ingoing position is that we will get a broad label from the FDA. Then your second question about the need for eosinophil testing, that's a great question. And if you have a little bit of, let's say, the similarity with Tezspire, which has also a very broad label in the asthma indication, I think it's fair to say that despite the fact that there's no need for a physician in order to test the eosinophil count for Tezspire, most physicians want to know what is the eosinophil count.

So although it will not be -- I think, not a requirement from a reimbursement perspective, I think that most physicians, at least in the Western world, will decide in order to test it so that they have a little bit more confidence at least regarding the phenotype of the patient. But we clearly see it not as a hurdle because it's so well embedded now both in asthma and more and more also in COPD to do an eosinophil test.

And Dr. Sciurba, can we give the rest of that question to you? How would you address smoking status in your practice based on your clinical experience? And then from there, would you use EOS status to assess suitability for tozorakimab? And how are you using EOS in your practice?

Sure. Yes. So I want to start out with one thing. Nobody ever questions the use of cardiac medications in ongoing smokers. Yet for -- it's just an instinctive common question that I have to get, should I treat a patient who still continues to smoke with regards to their COPD. And the answer is I always look for opportunities for smoking cessation. And to the extent that I'll leverage using biologics and be a bit paternalistic, yes, we do that. But we still treat these patients, and they still suffer and they have an addiction often that they just can't overcome. And they feel guilty about it at this point, and they feel bad, and we still help them.

So yes, I will treat smokers. As far as the statistical significance, not significance. Remember, the numbers were very small. It was not powered for ongoing smoking. The mean fell within the 95% confidence interval of the overall population. It's just that the error bars were wider. If the numbers were larger and it followed the same pattern, those error bars will narrow and it would be statistically significant. So I think it worked in ongoing smokers. As far as eosinophils, I mean, my reputation in COPD is phenotyping and endotyping. And so I -- the more -- it's like do an exam, does wheezing matter, does -- we want to know the full range of the patient that we're dealing with.

And so yes, I still want to check it. And I think I'll have other options above 300. I personally will within the 0 to 300 range, consider this product now probably first in that entire range for ongoing exacerbator patients on appropriate maintenance therapy. I really think it's going to own that territory.

Okay. And our next question is Colin White at UBS.

Colin White from UBS here. It was for Dr. Sciurba, taking into consideration everything that's been said about the testing and the penetration rates and use of other biologics, what percentage of the eligible patients would you treat with tozorakimab if it gets approved and has a broad label and it's available next year at the different eosinophil levels, less than 150, 150 to 300, and greater than 300?

What percentage of eligible patients would I treat with tozo who I am treating with biologics? Is that your question?

No. Of the patients that would be eligible -- that would be eligible for treatment in those different eosinophil levels, less than 150 to 300, and greater than 300, what percentage of them do you expect that you will treat with tozorakimab?

Okay. Yes. So in the 0 to -- so let me just tell you, my center is having trouble doing clinical trials because all my people are programmed to use biologics, which is not the case around the world. But we're informed, we've been involved. We see the impact of these on our patients. So now we have the ability to extend that greater than 300 basically is who we look for and treat to patients who continue to exacerbate below 300.

And so yes, I mean, I don't know how the health plans are going to react, but we are going to do our best to fight them. I'm sure we'll get good penetration because these drugs work. And so it would be 100% below 150, the vast majority between 150 and 300. And then we're going to play around with it in the greater than 300 relative to the other products, but we'll definitely be using it over 300. And where I'll be in a year from now, I'm going to be open-minded, but it's definitely going to be used.

Thank you. Okay. Conscious of time, we'll take one more question before we wrap it up. The final question, Luisa Hector at Berenberg.

Sharon, great to see the data. I wanted to follow up on your explanation around the mucus plug and that being a feature of disease. Would you say that these trials were essentially enriched for this? And is CAT score the measure we should look at here? I noticed that CAT score above 30 had a really incredible hazard ratio. And so if that is the thing we should be thinking about, just checking, is that still the majority? And Dr. Sciurba, do you always measure CAT scores in patients? And a very quick one, do you expect an advisory committee meeting on this with the FDA?

Okay. So let me break down those multiple questions. Your first one was about the mucus plug data that was presented at this meeting that I alluded to earlier. What's interesting about those data is the mechanistic support for the hypothesis surrounding tozorakimab's differentiation. The fact that this molecule is able to inhibit signaling through both ST2 to dampen inflammation and through RAGE-EGFR to affect epithelial remodeling and mucus production. That is the important part of the story. And notably, this was the first study that ever tested the effect of a therapeutic on changes in mucus production.

It is the first time that we have been able to demonstrate this, and we were able to demonstrate a statistically significant reduction in mucus plugs. This is valuable because it helps reinforce our understanding of the mechanism of tozorakimab and why it is differentiated. That said, we do not think that CAT score here is the most important metric. I think what's really important in today's data set is that we were able to demonstrate an impact on the most important feature of disease, which is exacerbations.

Exacerbations correlate with disease worsening, and we were pleased to be able to show the impact on both mucus production, which correlates with disease worsening, and exacerbations, which are clearly correlated with disease worsening. You asked about whether or not Dr. Sciurba sees the CAT score and uses that in his clinical practice. Would you like to respond, Frank?

Yes. I mean using it in clinical practice and using it as the priority outcome measure in clinical trials is different things. It's a very quick assessment to make. And yes, actually, we do offer that to patients through the health portal before they come to see me and visit as a quick screen. The SGRQ is a longer questionnaire. Most patients, unless they're part of a clinical trial, don't have a lot of patience to do the entire SGRQ questionnaire.

CAT really correlates closely to the SGRQ as an outcome measure. And -- but it's probably less sensitive to response. So I don't know that, that would have been a good outcome measure, if that's what you're asking. It was used in this trial stratification measure. A CAT of 10 is not really that high. I mean the average score in this population was over 20. And most patients who have frequent exacerbations are going to have CAT scores over 10. So I don't know if I completely answered your question, but that.

Okay. And Luisa, your last question was about a potential AdCom. So as we've signaled, we have submitted our file. We have been granted priority review, which really, I think, signals the interest in the community about bringing forward this molecule to patients as quickly as possible. I think it's very early to speculate what will happen during the review process. But today, we have demonstrated that we have a very compelling data set that has the potential to change the treatment paradigm for patients with COPD, and we look forward to the future conversations with the regulators. Now with that, I will wrap up the questions and hand this back to Pascal for his final remarks.

Thank you, Sharon, and thank you, everyone, for your great questions and your interest. Let me just say that tozorakimab is a good example of what we try to do at AstraZeneca. First of all, we start with great science -- we believe, differentiated science. And then we take a risk if we believe we can make a difference for patients. And it's a good example of this because as you probably remember, most of you thought this agent will not work. So I want to recognize Caterina Brindicci, our Head of Respiratory R&D, who was a champion for this product for many years. So we take a risk and then we work with great clinicians like Frank, who accept to work with us to try to make a difference. And in that instance, it actually worked. And I think this agent will make a big difference to the treatment of COPD. And that's really what we try to do across the board.

And if you go back to the slides that Ruud presented at the beginning, -- we've done -- we are doing this across the portfolio, and our existing portfolio is developing very well. In some -- in many cases, better than we expected back in 2024 when we presented that chart the first time. Tagrisso, we're building the franchise with 2 new deals and the data sets with savolitinib and the Zegfrovy acquisition that will protect Tagrisso, but also extend treatment duration and grow this product. Imfinzi is doing very well. We just announced new data, as I said a bit earlier, that will actually continue to fuel the growth of this product.

Our product is on track. Ultomiris, which many years ago, many people thought the C5 franchise of Alexion was going to disappear, Ultomiris is doing very well, and the IgAN data look extremely good. We had one setback with Wainua in ATTR cardiomyopathy. That's part of life. That's what we try to do, but that's one setback out of many successes.

The key NMEs we presented back in May 2024, many of these products, which were our dreams and hopes then are becoming reality as Etcamah, Datroway, Baxfendy. Now of course, today, we show tozorakimab. We are going to show data next year with laroprovstat, saruparib. We have now data with efzimfotase, with gefurulimab. So these products are progressing very well. And finally, the new technologies that I mentioned a bit earlier are also looking good. So we have absolutely no reason to doubt that we can grow past 2030.

And I must say sometimes I find this question a little bit intriguing. Are you not confident about your post-2030? Because if you continue looking at acquiring new technologies or new products, do you doubt your confidence in your pipeline? No, we don't have any lack of confidence.

But our role is to continue adding value for patients and our shareholders, of course. So we will continue doing this, as I said, mostly with small acquisitions. But if we found something a little bit bigger, $10 billion, $20 billion, why not.

But we should -- people should not think because we acquired products or technologies that we have no confidence. We have all confidence in our post-2030 period. So with this, I want to thank you again and thank the team for the amazing job they are doing and in particular, have done for this agent and tozorakimab, and I want to thank Frank for his great collaboration throughout the program. Thank you.

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 Half 1 and Q2 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 also carefully review the forward-looking statements disclaimer in the slide deck that accompanies this presentation and webinar. [Operator Instructions]

And with that, I'd now like to hand the conference over to the company.

A warm welcome to AstraZeneca's Half Year and Second 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 members of our executive team, I would like to cover some housekeeping items.

Firstly, all of the materials presented today are available on our AstraZeneca Investor Relations website. Please advance 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 and was stated otherwise.

Please advance slide. 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, although 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, I will hand over to you.

Thank you, Joris, and welcome, everyone. I'm really pleased to report that in the first half of '26, we saw strong growth momentum and continued pipeline delivery. Total revenue grew 6%, driven by strong demand for our innovative medicines, excluding the impact of Farxiga and Brilinta, which are affected by generics, as you know, total revenue grew 11%. That is a clear demonstration of the underlying strength of our portfolio and our broad geographical footprint. We also saw strong growth in core EPS increasing 11%.

In the first half, we announced positive results from 6 key Phase III programs including 3 new molecular entities. We secured 30 major market approvals across our diverse portfolio, including the first approval for 2 NMEs, Etcamah in breast cancer and Baxfendy in hypertension, and increasing our number of approved NME to 11 since we outlined our target to achieve 20 by 2030.

Our confidence in reaching our 2030 target is underpinned by the exceptional quality and momentum of our pipeline, together with our proven track record of successful execution and launches. We continue to invest in our pipeline and commercial capabilities to bring innovative medicines to patients around the globe and to support growth through 2030 and beyond.

So please move to the next slide. There you can see the breadth of our company remains a key competitive strength. Oncology and Rare Disease delivered strong double-digit growth in the first half, while within biopharmaceuticals, we see continued momentum in respiratory and immunology that help mitigate the expected impact of loss of exclusivity in severe in particular, Farxiga and Brilinta.

We delivered strong growth in the U.S., in Europe and in the emerging markets outside of China. Growth in China was impacted by continued effects from volume-based procurement, and we expect the recent NRDL additions and new regulatory approval in 2026 to fuel future awards.

Move to the next slide, please. An important message for today is that when we said our $80 billion revenue ambition for 2030, we did so based on the strength of our diversified portfolio, not on a single program. As you know very well, the $80 billion is a risk-adjusted forecast. If everything worked, we would be above the $80 billion. So we have, of course, expected setbacks to happen. Unfortunately, the results of the CARDIO-TTRansform trial were not what we hoped. And they were disappointing for our team and most importantly, for the patients we sought to help. This serves as a reminder, the transformative since carries inherent risk and not every program will succeed.

Our pipeline, however, continued to deliver during the first half with positive results from 6 high-value Phase III programs, including the first pivotal data for 3 new molecular entities to zorakimab in COPD, which we look forward to presenting at [indiscernible] alpha in HPP. And as announced today, our first wholly owned -- including 18.2 positive gastric cancer.

We also received 8 major market approvals across important indications, including 2 additional NMEs. We're very happy to see first approvals for in first-line hormone receptor positive breast cancer with emergent ESR1 mutations in Europe and Japan and a few other countries. This approvals demonstrate the value of this innovative treatment approach, and we continue to have constructive discussions with the U.S. FDA. We also saw U.S. FDA approval for which has the potential to transform outcomes for patients with uncontrolled or resistant hypertension, and we continue our launch activities at pace.

This, together with the more than 20 approvals we have achieved in the first half of this year support our continued growth trajectory and strengthen our confidence in delivering the 2030 ambition. And as you will hear today, we are also working very hard and making great progress on our post 2030 growth.

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 highlighted, we delivered continued top line momentum in the first half of the year. Total revenue increased by 6% with product revenue also growing by 6%. Alliance revenue increased by 29%, reflecting higher profit shares from our partnered medicines and HER2, [indiscernible] in markets where our partners record product sales.

Next slide, please. Turning to our core P&L. Core gross margin was 83% in the first half. While the margin improved in the second quarter compared to the first quarter, we expect lower gross margin in the second half consistent with prior years, reflecting seasonal demand patterns for lower-margin medicines such as flu mist and -- For the full year, we continue to expect a stable to slightly higher core gross margin versus 2025.

Core R&D expense increased by 6% in the first half, reflecting continued investment in our pipeline. Following the positive Phase IIb results for oral GLP-1 molecule, elecoglipron, we have now initiated comprehensive Phase III program in both obesity and type 2 diabetes with first patients dosed earlier this month. Core R&D represented 23% of total revenue in the first half and we continue to expect R&D expenses to be at the upper end of the low 20s percentage range for the full year as we continue to build our pipeline for long-term growth opportunities, including bispecifics, cell therapies, engagers in addition to our CVRM portfolio.

Core SG&A expense also increased by 6% in the first half. During this period, we launched in the U.S. following FDA approval in May, and we continue to make prelaunch investments ahead of anticipated launch of dosiratumab following positive Phase III data. Both medicines are expected to be important growth drivers supporting growth to 2030 and beyond, and we are investing accordingly to maximize their potential.

Other operating income was $341 million in the first 6 months, consisting of royalties and small regional divestitures, and we anticipate a broadly similar level in the second half.

Our tax rate in the second quarter benefited from a onetime adjustment to deferred tax assets following certain internal legal entity changes. Overall, core EPS grew by about 11% in the first half, in line with our guidance for the full year.

[indiscernible] [ 22 ] billion in the first half, and decline versus comparator period. This primarily reflects the Lynparza milestone received in the first quarter of 2025 skewing comparisons as well as working capital impact associated with U.S. loss of exclusivity for Forxiga. We expect these working capital effects to persist through the remainder of the year before normalizing.

Capital expenditure was $1.5 billion in the first half. underscoring our commitment to investing behind our long-term growth ambitions. And as previously communicated, we anticipate CapEx to increase by around 1/3 in 2026. Key investments include our new ADC manufacturing facility in Singapore, along with several other strategic multiyear projects that will enhance our manufacturing network and support sustainable growth well into the next decade.

Deal-related payments totaled $3.3 billion is included in both milestone payments and the $1.2 billion upfront payment for CSPC collaboration, which was during the second quarter. For the full year, we continue to expect milestone payments of approximately $2.5 billion relating to prior business development transactions. We have announced new BD transactions totaling just over USD 2 billion in upfront payments year-to-date, including the most recently announced Dizal transaction. Our lease liabilities also increased as we opened our new Kendall Square R&D center in Cambridge.

Our capital allocation priorities remain unchanged. Net debt increased by around $3.5 billion in the first half primarily reflecting the payment of the second FY 2025 interim dividend in March and the deal payments I just mentioned. We remain comfortable with our level of gross debt. As previously communicated, following refinancing activities earlier in the year, resulting in higher than historic interest rate and lower interest income, we anticipate core finance costs to be higher in the second half compared to the first half.

Turning to guidance. We are reiterating our outlook for the full year. We expect total revenue to increase by a mid- to high single-digit percentage and core EPS to increase by low double-digit percentage at constant exchange rates.

So to summarize, we delivered another period of strong financial performance while continuing to invest significantly in both our pipeline and our commercial capabilities. We remain on track to deliver on our priorities in the near term and support growth in the long term.

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

Thank you, Aradhana. Next slide, please. Oncology total revenues grew 15% in the first half to $14.1 billion, underpinned by double-digit growth in all major regions. Growth in the U.S. and Europe was particularly notable at 18% and 16%, respectively. Focusing in on the quarterly performance of our key medicines.

Tagrisso delivered 6% growth in the second quarter to revenues of $1.9 billion, supported by double-digit growth in the U.S. The share of combination regimens in the first line continues on an upward trajectory in key markets with FLAURA2 remaining the clear preference.

Turning to Calquence, which grew 16% in the quarter generating more than $1 billion in revenue for the first time in a single quarter. Calquence maintains its position as the leading BTK inhibitor in frontline CLL across major markets despite intense competition. Within the finite duration class, AMPLIFY continues to gain share in reimbursed markets with encouraging early signs in the U.S., where it is uniquely positioned as the only BTK inhibitor with both finite and treat to progression options. We continue to see AMPLIFY as a significant growth driver through the remainder of 2026, supported by the clear global trend towards adoption of finite duration treatments.

Imfinzi and Imjudo delivered growth of 25% in aggregate in the second quarter. Imfinzi growth continues to be driven by a combination of new launches and increasing demand for established indications. Meaningful contributions from Matterhorn and gastric cancer reflect its rapid establishment as the standard of care in reimbursed markets and in lung, Adriatic continues to be an important additional source of growth. We continue to see strong global momentum for Imfinzi in muscle invasive bladder cancer. And while the U.S. market is evolving with competitive entrants, VOLGA will continue to expand Imfinzi's reach.

Turning to HER2, we delivered growth of 31% in the quarter and reported revenues of $888 million. Growth continues to be across all regions and reflects sustained market leadership in the HER2-positive and HER2 low breast cancer indications in major markets. This strong position is complemented by increased adoption and additional launches in emerging markets. We are seeing encouraging early signs of adoption and growing awareness in the first-line DESTINY-Breast09 setting in the United States following its approval late last year. Together with the recent simultaneous U.S. approvals of DESTINY-Breast05 and DESTINY-Breast11 in the curative setting, these growth drivers will become increasingly important through the remainder of the year.

Truqap revenues of $233 million in the quarter represent growth of 37% over the prior year. As we've indicated previously, the majority of this growth is from ex U.S. markets, with the U.S. opportunity at peak and the best indication. Beyond breast, we are looking forward to bringing Truqap to patients with P10 deficient metastatic hormone-sensitive prostate cancer following the recent approval of CAPItello-281 in the U.S. and a near-term priority is to establish testing in the setting, which today is not common practice. The actuary revenues of $55 million in the second quarter demonstrate growing demand in later line EGFR mutated lung cancer with signs of increasing utilization in the second-line setting in the U.S. We're excited for the ongoing launch of data in patients with triple-negative breast cancer were not candidates for immunotherapy, following the U.S. approval of TROPION-Breast02 earlier in the quarter. Given its differentiated profile, we see this as a significant opportunity and look forward to additional market launches in the second half.

With strong momentum demonstrated across our portfolio in the first half, we are well positioned for continued growth through the rest of the year as we deliver innovative oncology medicines to more patients. Please advance to the next slide.

Focusing in on EGFR mutated lung cancer, Tagrisso is the #1 prescribed third-generation EGFR TKI globally approved across all stages of disease. This leadership position is underpinned by the breadth of our clinical development plan and our differentiated product portfolio. In the first-line combination setting, we've seen significant global market expansion over the past 12 months with FLAURA2 the clear market leader in the highly competitive U.S. market, FLAURA2 holds around 3/4 of this growing segment.

We were pleased to announce the in-licensing of a novel oral EGFR inhibitor earlier this month. is already approved in the U.S. and China for patients whose tumors carry exon 20 insertion mutations, following progression on or after platinum-based chemotherapy, based on the WUCON28 data presented at ASCO, filings for the first line have been submitted in China and the U.S. This deal complements our existing EGFR leadership and allows us to bring a differentiated treatment to patients with limited treatment options globally. Importantly, it's also a clear signal of our intent to remain the definitive leader in this space.

I'll now hand it over to Susan to discuss some more of the specific near-term pipeline opportunities.

Thank you, Dave. Turning to the right-hand side of this slide. Our near-term pipeline readouts provide the opportunity to further strengthen our position in EGFR-mutated lung cancer with Tagrisso as the backbone TKI with two Phase III trials due to read out later this year, investigating combinations in the sizable post-TKI second-line setting.

TROPION-Lung15 evaluates Datroway alone and in combination with Tagrisso, building on the growing position Datroway already has in later line lung cancer based on TROPION-Lung05.

SAFFRON, then evaluates Tagrisso combined with Orpathys, offering a differentiated combination approach in patients with MET-driven resistance supported by the encouraging data we've already seen from SAVANNAH and Sachi. Looking further ahead, TROPION-Lung14, then aims to bring the combination of Datroway and Tagrisso into the first line, building directly on the success of FLAURA2. This represents significant long-term opportunity to extend our first-line leadership and improve outcomes with the next-generation combination. Taken together, these opportunities represent a comprehensive strategy to maintain leadership in EGFR-mutated lung cancer for years to come.

Next slide, please. I'm also delighted to share with you today the high-level results from two recent Phase III trial readouts. Back in May, we announced positive results from the planned interim analysis of the Phase III VOLGA trial for PMC patients with muscle invasive bladder cancer who are not candidates for cisplatin. VOLGA builds on our existing presence in this setting, where the Niaga regimen has already established Imfinzi as a key treatment option for cisplatin eligible patients.

VOLGA explores whether the combination of important vedotin and Imfinzi plus or minus Imjudo can improve outcomes for the 50% of patients who are not candidates for cisplatin.

Importantly, in this regimen, enfortumab vedotin is only given in the neoadjuvant setting, aiming to optimize outcomes whilst balancing the overall benefit risk profile. Imfinzi in combination with important apedotin demonstrated statistically significant and clinically meaningful improvements in both event-free survival and overall survival, underscoring the potential of this regimen to meaningfully improve outcomes in bladder cancer.

The Imjudo containing arm also demonstrated a statistically significant improvement in event-free survival with a favorable trend in overall survival.

VOLGA broadens our presence in balder cancer, enabling more patients to benefit from an Imfinzi based regimen, complementing in muscle invasive blader cancer, and the recently U.S. approved Patena indication in earlier-stage non-muscle invasive disease.

We also saw positive results this quarter. And whilst the landscape in the first-line setting has evolved significantly since we started this trial, it further reinforces Imfinzi's value across the full spectrum of blood cancer.

Turning now to gastric cancer. We announced today positive results from the Phase III CLARITY-Gastric01 trial, evaluating solicitate vedotin or in previously treated patients with advanced gastric cancer expressing Claudin 18.2. CLARITY-Gastric01 is the first Phase III trial to demonstrate an overall survival benefit with a Claudin 18.2 targeted antibody-drug conjugate in the second-line plus setting. This is a population with a particularly poor prognosis, fewer than 20% of patients with advanced gastric cancer survived beyond 1 year. And at present, there are no targeted options to Claudin 18.2 positive non-HER2 positive tumors in the second-line plus setting.

The trial met its overall survival dual primary end point with Sunny V demonstrating a statistically significant and highly clinically meaningful improvement in overall survival versus investigator's choice of therapy in patients treated with at least 2 prior therapies.

There was also a trend to PFS benefit, we should not meet statistical significance. Critically, the trial also met its key secondary end point, demonstrating a highly clinically meaningful overall survival benefit in patients treated with at least one prior line, potentially extending the benefit to a broader patient population earlier in their treatment journey.

Importantly, the survival data were demonstrated in patients with Claudin 18.2 expression as low as 25% at any staining intensity, a lower threshold than that required by other Claudin 18.2 targeted therapies, meaning that Sunny V could potentially benefit around 50% of patients with second-line plus cancer -- gastric cancer, representing more than 180,000 patients across the U.S., EU5, China and Japan.

CLARITY-Gastric01 represents a landmark milestone for our oncology portfolio. Sunny V is our second ADC to demonstrate an overall survival benefit in gastric cancer following HER2. And our third positive Phase III readout in this tumor type in just 2 years, following Matterhorn for Imfinzi and DESTINY-Gastric04 in HER2. It is also the first Phase III data from our wholly owned ADC portfolio, marking an important step as we establish our independent position in this space. We look forward to presenting the data later this year. Together with VOLGA, these data strengthen our conviction and the opportunity to combine I/O with ADCs, an approach we believe could be transformative across multiple cancers. And specifically, these two readouts reinforce our confidence in CLARITY-Gastric02, our first-line gastric cancer trial, evaluating Sunny V in combination with capecitabine, with or with that, we'll be gusto make on novolumab.

And with that, please advance to the next slide. And I'll pass over to Ruud to cover about our pharmaceutical performance.

Thank you so much, Susan. Next slide, please.

Our biopharmaceutical business is in a transitional period. And in the first half of 2026, total revenue declined by 5% to $11.2 billion. This reflected the loss of exclusivity headwinds for Farxiga, Brilinta and roxadustat, which were largely offset by the growth of our respiratory portfolio. The strong momentum in respiratory was supported by our established biologics for severe asthma, which generated over $2 billion of in-market sales in the first half.

Focusing in on the quarter, respiratory and immunology total revenue grew by 11%. Fasenra grew 13% to $570 million, driven by its continued leadership of the 5 class. In the emerging markets, Fasenra grew 75%, thanks to the ongoing success of its launch in China, where it entered the national reimbursement drug list at the start of the year.

Tezspire grew by 45% to $390 million, with strong performances in the United States and Europe being supplemented by uptake in the emerging markets.

In our inhaled portfolio, Breztri continued on its positive trajectory with 20% growth through $346 million. Breztri received its first approval for asthma this year in the United States. And last week, received a positive recommendation for asthma from the CHMP in Europe. We are excited about this important new indication, which will help us bring this therapy to more patients.

Symbicort revenues of $671 million were down 8% due to the price pressure in the United States, reflecting a new generic competitor entering the market. Saphnelo revenues increased 24% to $209 million, driven by share gains in the intravenous segment for SLE patients. The new subcutaneous formulation is now available in the U.S. and some European markets, which broadens Saphnelo's reach to patients who favor self administration. As expected, generic competition for Farxiga entered the U.S. at the start of the quarter. And this, along with loss of exclusivity in some other markets and VBP in China saw Farxiga declined by 90% overall resulting in $1.8 billion of revenue for the quarter.

Navigating these expected life cycle transitions is a natural part of our business, and we remain confident in the long-term strength of our broader portfolio and pipeline. In May, we secured the approval and launch of Baxfendy in the U.S., and we are now building early market access through affordability programs. We anticipate commercial access for Baxfendy will broaden over the next few quarters in anticipation of Medicare party reimbursement from 2028.

We're also making an early start on our launch preparations for tozorakimab. We are encouraged by the data, which showed highly clinical meaningful benefits in the and titanium trials, representing a broad COPD population, and we are looking forward to bringing this innovation to patients around the world as soon as possible.

I will now hand over to Sharon to take us through the latest developments in the biopharmaceuticals R&D pipeline.

Thank you, Ruud. Next slide, please.

I'd like to start by acknowledging the Phase III CARDIO-TTRansform transform trial for Wainua in transthyretin-meated amyloid cardiomyopathy. This trial was conducted in a contemporary ATTR cardiomyopathy patient population, designed to examine the role of Wainua, a gene silencer treatment on top of today's standard of care in reducing recurrent cardiovascular events and CV mortality.

In this contemporary patient population treated with standard of care, including 57% on a stabilizer, adding Wainua did not provide a statistically significant benefit on the composite outcome of CV mortality and recurrent CV events. However, in a prespecified subgroup analysis of patients treated with Wainua monotherapy as compared to placebo, fewer primary composite events were observed, and this result was nominally significant. In patients who were on stabilizer therapy at baseline, no treatment effect was observed.

Although the trial did not meet its primary endpoint, we believe these results contribute meaningfully to the greater scientific understanding of treatment approaches for the hundreds of thousands of patients worldwide suffering from this progressive and often fatal condition. AstraZeneca and Ionis will analyze the full data set to further understand the results, and we look forward to presenting these data at the European Society of Cardiology Congress in August.

Turning now to elecoglipron where we are building strong momentum into Phase III. At the American Diabetes Association meeting in June, we presented results from our Phase IIb VISTA and SOLSTICE trials, which demonstrated the potential of elecoglipron as a multi-blockbuster asset for AstraZeneca. In VISTA, we observed a clinically meaningful and statistically significant weight loss of up to 11.8% at week 36, importantly, without evidence of a plateau. In SOLSTICE, there was an up to 1.9% reduction in HbA1c at week 26 with the vast majority of patients with type 2 diabetes reaching their glycemic goals. Elecoglipron demonstrated a favorable safety profile with no unexpected safety signals, low discontinuation rates and tolerability consistent with the GLP-1 receptor agonist class.

It is worth emphasizing that elecoglipron is an oral small molecule. This 1 daily treatment requires no fasting or fluid restrictions and critically can be combined with other oral small molecules to treat interconnected chronic diseases.

Based on the strength of these data, we are advancing an ambitious Phase III program. In BOLD is studying elecoglipron monotherapy in patients with obesity or overweight with or without type 2 diabetes. The ILLUMINATE program, which includes 5 Phase III trials, evaluates olecoglipron, both as bonotherapy and in combination with epagliflozin across broad patient populations with type 2 diabetes. I am pleased to say that we achieved first subject in for both the Embold and ILLUMINATE programs.

Beyond these, we also plan to initiate ELEVATE an indication seeking outcomes program designed to demonstrate the value of elecoglipron heart failure with preserved ejection fraction and chronic kidney disease on the background of dapagliflozin and other standard of care.

Finally, I want to highlight a few additional advancements in our biopharmaceuticals pipeline during the second quarter. Staying in weight management, the Phase II APRICUS trial studying AZD6234, our selective amylin receptor agonist read out this quarter, and we are now initiating a Phase III monotherapy trial. We look forward to sharing the Phase II data with the medical community at EASD later this year.

In dyslipidemia, we look forward to the Phase III readout of our oral PCSK9 laraprostat in the first half of 2027 and are advancing our first fixed-dose combination of laraprostat with rosuvastatin into Phase III, bringing together the benefits of a statin and a PCSK9 inhibitor in a single tablet.

Moving to our respiratory portfolio. We are excited to present the highly clinically meaningful results from the Oberon and Titania Phase III studies for doserakimab in COPD at the European Respiratory Society Congress in September, highlighting the compelling profile we have seen for this potential first class asset.

We made exciting progress in other areas of our respiratory portfolio this quarter. Our inhaled TSLP sunacamet, which was formerly referred to as AZD8630 read out its Phase II study, and we are discussing plans for Phase III with our partner, Amgen. Additionally, we entered into an exclusive license agreement with CTTQ, a subsidiary of Sino Biopharmaceuticals, for the development, manufacturing and commercialization of TQC3721, an inhaled small molecule PDE3/4 inhibitor currently in Phase III trials in China for COPD. This licensing agreement strengthens our respiratory portfolio with a novel inhaled option for people living with COPD, a disease with continued patient need, particularly for those who remain symptomatic despite exiting treatment options.

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 total revenues grew by 11% in the first half to $4.9 billion underpinned by double-digit growth access all key medicines. This is driven by increased patient demand and continued global expansion following launches. In the second quarter, Ultomiris grew 12% driven by patient demand across indications, including the competitive MG and PNH markets. Solid risk revenues continued to decline due to successful conversion to as well as biosimilar pressure.

Strensiq grew 36% year-on-year, reflecting strong patient demand. Strategic remain one of AstraZeneca's fastest-growing blockbuster medicines, supported by ongoing investment in commercial capabilities, infrastructure and disease awareness. These investments are driving continued growth today while also laying the foundation for the potential launch of the -- alpha and future franchise growth.

continues to deliver strong global momentum, supported by expansion in adult patients with NF1 PN, an uptake of the granule formulation in recently launched market. Koselugo remained the market leader in patients with PN. Overall, we continue to see great momentum across the Rare Disease portfolio, and please advance to the next slide.

Turning to our Rare Disease pipeline. We have continued to build momentum with Phase III data presentation across rare disease indications, highlighting the breadth of our portfolio and the strength of our late-stage execution. In IgA nephropathy, Phase III data from the ICAN trial for Ultomiris showed a 43% reduction in proteinuria, with significant proteinuria reduction seen as early as 10 weeks. Importantly, treatment effects were consistent across patient groups, including those at higher risk of progression and with more inflammatory disease. Wigan is becoming an increasingly competitive treatment landscape, the eternity of the disease underscore the importance of multiple treatment approaches. And the data we presented at further support the role of complement in disease pathopasiology.

The Higano opportunity represents an important step in the continued expansion and development of our C5 franchise building on Ultomiris established leadership across multiple complement-mediated disease. We are now filed in both the U.S. and

For alpha in repo phosphatase Data from our Phase III pediatric trials, Mulberry and FastNet were presented at the International Conference and Children's born Health in June. Menbery demonstrated clinically meaningful improvement in bond health function and quality of life. In our -- switch safety study, Chesnut, or infiltrates alpha was well tolerated and demonstrated a favorable safety profile in pediatric patients.

In a pooled analysis of the Phase III Mulberry -- trials, including pediatric, adolescent and adult patients, treatment with resulted in a median of 261 days per year free from injection site reactions. And injectite reactions rates were 5x lower than Strensiq. Data from the CORE trial will be presented at the American Society for Bone Mineral Research in October. We are progressing filings across major markets to support a broad SPP patient population.

Also, data from the CALYPSO Phase III trial was presented in May at ECE, demonstrated maintenance of serum calcium within the target range, normalization of urinary calcium and restoration on normal bone turnover in patient with An onselimumab in Kappa light chain amyloidosis patients, results from the CARES program demonstrated a 62% reduction in all-cause mortality and a 71% reduction in cardiovascular spetulization with an overall survival benefit observed even in patients with advanced myostage disease.

Taken together, this program illustrates the strength of our rare disease pipeline with multiple near and midterm catalysts with potential approvals and future launches across several high-value rare disease indication.

And finally, an update on our pace Ultomiris Phase III trial in adults with thrombotic microangiopathy after SCT. High-level results showed that did not achieve statistical significance for the primary endpoint of event-free survival through 26 weeks compared to placebo in adult and adolescents age 12 years old with Ultomiris showed a trend towards treatment benefit and discussion with as authorities are ongoing regarding the interpretation of this data, including in the context of real-world evils.

In pediatric patients, with CT TMA, we're advancing regulatory filings based on data from open-label Phase III trial reported in 2025 and data from an external control study. As pioneers in complement biology, we continue to explore and advance treatment approaches in disease where complement is believed to play a central role in disease pathropatiology with limited treatment option available today. It reflects our ongoing commitment to bringing innovative therapies to patients with severe complement-mediated disease.

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

Thank you, Marc. Next slide, please. As the slide shows you we carried strong momentum into the first half, 6 positive program readouts already delivered and a rich catalyst pass ahead. Over the next 18 months, we have 25 key Phase III trial readouts that are planned, giving us multiple opportunities to add further value and conviction to our trajectory. We expect pivotal data readouts for 6 new molecular entities in 2027 alone across our portfolio. Some of them are really important, as you can see here, and for instance, are pari is a big one, but there are many other very important readouts over the next 18 months or so.

So I move to the next slide. Our growth ambition extends well beyond 2030, and we continue to invest behind the transformative technologies that we believe will redefine how many diseases are treated. If you remember, back in May 2024 we identified platforms that we call -- that we said would drive our growth post 2030, what we called at the time the day after tomorrow. And I'm pleased to say that we have made very good progress across many of these platforms, as you can see here, the slide highlights the momentum we're building in our next wave of innovation. So if we start with rate management and card risk factor. As Sharon mentioned, we expect the first Phase III data for in first half of 2027, and we have now initiated 5 Phase III trials for elicoglipram. So you can see here, our portfolio is building both scale and optionality and focused on not only weight management, but the risk factors that are -- that company excess obesity and particular obesity.

In ADC and conjugates, we continue to make strong progress. As highlighted today, we've just had the first positive Phase III readouts for And we anticipate Phase III data for our second reowned ADC, next year. We also continue to advance our broader program having those patients in our first Phase III trials for Tovisam and also for adage this quarter.

So very good progress across ADCs and radioligand. For next-generation biobaspecifics, we now have 16 Phase III trials across 8 tumor types, including 5 in combination with our ADCs. This supports our ambition to replace the current generation of checkpoint inhibitors. Our cell therapy and T cell engager portfolios are also advancing very rapidly. AZD0120 and both have multiple Phase III trials underway across hematology and importantly, both now have extended into autoimmune diseases, underscoring the broader therapeutic potential of the platforms very exciting program -- progress, sorry, across those two products. Beyond these lead programs, we're also investing behind of the shelf and in vivo cell therapies, which we believe will enable us to reach more patients across more disease areas. These programs continue to advance and are key components of our deep late-stage pipeline of multiple buster opportunities that will not open our next wave of growth.

So move to the next slide. The strength of that opportunity is reflected in this slide. We have three recent launches, [indiscernible] each with speaker revenue potential of more than $5 billion. Beyond these launches, we have a broad portfolio of late-stage assets that are expected to deliver pivotal data before 2030, including multiple programs with multi-blockbuster potential. Together, these assets provide a strong foundation for growth into the next decade.

And really, it's important to remember that our $80 billion is risk adjusted. If everything worked, 100%, we would be much above the EUR 80 billion, of course. But we've also assumed some projects would not work and other projects would work. And a good example of this is the strong data we obtain a -- a product that very few people thought was going to work. We ourselves had a low probability of success for it. We tried because we thought we have a different mechanism of action, and we have a chance, and it actually worked. You will see the data very soon. As a result, we have increased our peak revenue expectation to more than $5 billion.

In addition, with a positive readout for Sunny V today, we estimate that this ADC will reach peak revenue between $3 billion and $5 billion. This is an example of the strength and the diversification in our pipeline. The likelihood that there will be puts and takes is part of how we plan. And we've taken this into account in our growth ambition beyond 2030 as well. We have built what we believe is one of the most exciting pipeline in the industry, one that can now more than offset losses of exclusivity and fewer growth well into the next decade. Including as we move to --

As we move to the next slide, I'd like to say that we delivered strong growth in the first half, again, 11%, excluding Farxiga and Brita showed you the strength of the pipeline and the geographical footprint, 6% growth overall. And so strong growth in the first half. The breadth and depth of our pipeline remain exceptional and our confidence in reaching $80 billion revenue by 2030 is intact. But what excites me most is what comes next.

With multiple waves of blockbuster assets that are progressing through late-stage development and transformative technology platform scaling rapidly, we're building a company that will not just deliver on its 2030 ambition, but continue to grow well into the next decade. We have the science, we have the pipeline, and we have the team to make that happen.

And with that, please advance to the next slide, and we'll move to the Q&A. As Joris mentioned at the start of the call, 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, who actually is from Rajan Sharma of Goldman Sachs.

Firstly, just on the oral PCSK9, which you highlighted. Could you just outline your expectations ahead of the data next year? And how do you expect this to compare relative to Merck And maybe you could just comment on your expectations for pricing in that market given we now have a list price for your competitor?

And then secondly, on CV, you're guiding to $3 billion to $5 billion in peak sales now. Can you just help us understand how much of that is in the first line versus the data that you've disclosed today? And maybe could you just talk about geographical split of patients and potential revenues?

Thank you very much, Rajan. Maybe Ruud could take the first question and Dave, the second one.

Yes, of course, Pascal. Overall, I think we are excited about oral PCSK9. We will see the first data reading out in the first half of 2027. I think we will have -- and hopefully, we will have a competitive profile versus the compound of Merck. But I think the breadth of our portfolio for cholesterol-lowering medicines is broader than only the oral PCSK9 as Sharon has mentioned, we have started the first combination with Rosevestin. I think we have a unique opportunity because it's a true oral medicine in order to combine that with other products in our portfolio, and hence, that will increase the level of competitiveness.

Regarding the pricing, of course, we have seen the official list price of our competitor in the United States. It will not change dramatically our own outlook. Of course, I'm not going to disclose our pricing strategy moving forward. It also depends on what we are going to see in our clinical trials. But overall, I think we are well on track in order to develop a very competitive oral PCSK9 moving forward.

So just picking up on the question about EV and CLARITY-Gastric. After I'm going turn it over to Susan, who can talk a bit more about the life cycle plan beyond CG01, but we're very excited about these results. and look forward to getting an opportunity to presenting them soon. Specifically, the CG01 opportunity has potential to be a blockbuster indication. Now some of that will depend, obviously, on indications that we are able to achieve, but the data set looks good. We look forward to sharing it. I think a couple of important points. First, we will pursue discussions across all major markets, U.S., Europe, China, Japan, and throughout the emerging markets. This data set, we think, supports those discussions.

Secondly, as you saw, overall survival being an absolute gold standard within this setting, we think, well positioned Sunny V for uptake upon approval. And we expand the definition of Claudin 18.2 positivity with the cutoff that we're using in this study and that cutoff is greater than 25%. And that represents about half of the patients with gastric GEJ So it's a great opportunity and one that we're really looking forward to getting an opportunity to launch as quickly as possible. Susan, do you want to talk a little bit about the life cycle plan beyond CG01?

Yes. So obviously, in the first line, there's an opportunity to combine with IO agents, as I've discussed with both plus backbone of Cape sites been. And the CLARITY-Gastric02 study has two cohorts, one in the PD-L1 greater than 1% but also has a cohort in the less than 1% where we're looking at further fee-based regimen versus a standard of curve as well. So I think that gives us an opportunity to have a broad first-line opportunity to have a IandADC combination in the relevant patient population, and it is a big segment in gastric cancer. And then again, I think there are opportunities to consider based on the data that we've got with whether there's an opportunity to go into the earlier-stage setting.

Plus point is not just expressed on gastric cancer but also on some pancreatic cancers and block cancers, and we're exploring those in our ongoing Phase I, and I'm encouraged by the data that we've seen to date. So I think there's going to be a broad program for Sunny V across all of these GI-based cancers.

Thank you, Susan, Dave. Maybe one thing I could add to the PCSK9 is that another fixed dose combo we are developing is with together with -- oral because if you have elevated cholesterol, typically, you also need to lose a bit of weight. This is a good example of how we can differentiate our we also differentiate our by providing convenient formulations to patients who are typically polymedicated in these circumstances. .

So next question is, I think, Richard yes, Richard from JPMorgan?

One question, please, on Just now we've seen the persevere data in detail ASCO, I don't think when we last spoke, we'd seen it. Could you give us your latest thoughts around how SERENA-4 could differ in terms of patients enrolled and how that impacts your thinking around potential benefit of CAMI what it could deliver in the trial? And does the data you've seen change your view of the importance of endocrine sensitivity for generating a benefit? And how endocrine-sensitive do you think you have in the trial?

Susan, do you want to...

I'll take that. Yes. Okay. So thanks for the question. So as you said, the goal for SERENA-4 is to enrich for endocrine sensitivity. Again, as a reminder, we have a larger sample size, 1,370 patients enrolled compared to And I think what you've seen with the placebo data is evidence of activity, which varies across the different subgroups there. I can't comment on the exact today. Obviously, we're anticipating the trial readout in the second half of this year. And obviously, we have to wait for that readout to But again, we have striven to enrich for that endocrine sensitive population with the design of those subgroups. And again, I think what we're happy with the SERENA-6 data is the overall tolerability profile that we've seen with low rates of GI, side effects that are seen and a very low discontinuation rate with good tolerability overall in that trial. So I think we have to wait and see at this point, that's why we run Phase III trials, and we're very happy to share the data with you as soon as we have them.

Thanks, Susan. Next question is from Simon Baker at Rothchild.

One, if I may, on simvazertinib. The profile based on the data we've seen so far looks very impressive indeed, against the competition. But I just wanted to get your perspective on how you see the profile of sumbazertinib in that setting. And also the significance or otherwise, the versus near loop mutation performance, it appears to be particularly differentiated on Is that a significant factor? Or is that less important than perhaps you might see?

Okay. So you're talking about -- Pascal, do you want me to take this one?

Yes, please. Yes, if you don't mind. Please go ahead.

Okay. So -- obviously the asset that we've licensed from for exon 20 mutations, but also has activity in a group of mutations that are nonclassical as well, which is about a similar size patient population. So I think one of the profiles that we see overall, first of all, is potent against the exon 20. It's delivering this high and durable response rate there, and really has differentiated activity in that second line setting, which has already provided the label that we've got in the U.S. and China. In the first-line setting, the data were presented at ASCO, so there was an oral presentation at people want to have a look at that. And that will form the basis of the filing in the first-line setting. So we've -- we look forward to having discussions with the regulatory authorities, given the high response rate that we've seen and really good progression-free survival, which was obviously the primary endpoint in that randomized trial. .

So yes, I think if you look at that compared with the other competitors in this space, it's oral, easy to administer at home the tolerability profile, I think, is competitive with other agents and the potency is also competitive. So again, we're excited to have this as another agent to build on our legacy in each of our mutant lung cancer.

Thanks, Susan. Maybe go to hear also from Dave telling you about what we're trying to do to solidify the Tagrisso franchise because we are under -- of course, two major competitive on in China, which is the multiple -- the multiplicity of EGFR in a market and very, very competitive market. We're doing well, but it's competitive. And the second is, of course, the Mariposa regimen, which again, we are still doing well. As Dave mentioned before, market share is still very strong for Tagrisso. But beyond that, we are actually trying to build a variety of ways to differentiate Tagrisso. So maybe, David, if you can give us the whole picture again, that would be useful.

Yes, it'd be my pleasure. And let me use this as just an opportunity also to comment that the strength of FLAURA2 is really laying the foundation right now for the expansion of the clinical development plan to build off of the combination approach to a Tagrisso backbone in order to improve outcomes in EGFR-mutated lung cancer. And as Susan quite nicely articulates Zefrovi adds to the group of patients that we now have an opportunity to be able to engage physicians about and offer a new therapy.

I think just very, very importantly, we're seeing double-digit volume growth and, in fact, double-digit revenue growth in the U.S. in the face of the competition with Tagrisso right now. What that's allowing us also then to do is get ready for both the data and the Orpathys combinations, which we're looking forward to. I think that with data, obviously, we've got -- in the later lines and also Tropin 114 in the frontline setting. I think relative to what we see with the other TROP2 class players, this is a very differentiated position of having the Tagrisso combination as a way of bringing this set of therapies into these settings. We've got SAFFRON on the horizon, and that's with the Orpathys combination. And we are very enthusiastic about Tagrisso continuing to be an important driver of growth and contributing meaningfully to the 2030 ambition that we've laid out.

Thank you, Dave. So this is a very good example of what we've told you before. The ability we have to combine products through our portfolio to defend our various franchises and build beyond where we are. And then with the addition of -- we are also addressing a gap in our coverage of this the market. So you can see we are really reducing the space where the competition could actually have an impact over time.

So the next question will be from Sarita Kapila at Morgan Stanley.

On AVANZAR, we notice as the PFS and OS endpoints in both troupositive and ITT populations. Could you give us any more color on the testing hierarchy? For example, are you looking at PFS and then OS in TROP2 followed by PFS and OS and ITT? And what is the minimum outcome that would be filing enabling? So for example, with a PFS win in TROP2 positive patients, be sufficient without a clear OS benefit. And just a quick one, taking a step back, how should we think about profile versus that TMT particularly post the positive OPTITRUPLUNG-06 data and ahead of the PD-L1/GFdata in 2027?

Thanks, Sarita, good question. Two good questions for you, Susan.

Okay. Thanks, Pascal. Thanks for the question. So as a reminder, what we previously said about AVANZAR is that we have both the ITT and the biomarker-positive patient populations at the top of the multiple testing procedure. So it is possible to get a positive study with success in either the ITT or in the biomarker-positive group. So that answers your first question. Obviously, regulators will be interested in the effect size, the meaningfulness and the differentiation between those groups in discussions.

In terms of differentiation from the competitors, I think we have a best-in-class TROP2-based ADC based on the design, which is based on the stable linker. And you can see that based on the half-life of the molecule and also the lower rate of bone marrow toxicity because you see higher rates of bema toxicity with ADCs that have less stable linkers and so more exposure to the free payload. That, I think, underpins the data that we've seen in the triple-negative breast cancer where we saw a differentiated activity with high response rate, progression-free survival and leading to overall survival in that first-line triple-negative breast cancer. So that underpins our confidence in the design of this ADC.

I do think that the data that's been seen from the Opto trials in lung cancer the potential for TROP2-based ADCs in this first-line setting in combination with IO. But I think given the design that we have of the molecule and the design that we have at the AVANZAR study with the ability to look at the ITT and the biomarker, we have the ability to be first into first line and to be best based on those combinations and that differentiation. So we look forward to seeing the results. And again, I should just caveat as we do with all of our whilst we're confident in the hypothesis that we got, we obviously have to wait for the Phase III trial. And nobody is keener than I am to see the data. And as soon as we got it, we will share it with you.

Thank you, Susan. Next question is from Gonzalo Artiach with Danske.

Gosalia from Danske Bank. I have one for Sharon, one for Marc. For Sharon, on your TTR depleter. And I know the first three study with ceramic monotherapy, keeps moving as planned. But could you give us some color on how you are seeing this drug moving forward in case the Phase III hits the line? Is it something that you could put out a monotherapy or the -- case would be to get in combination with now, for example, Ambutra given the failed carditis study? I'm just trying to figure out what you're thinking on this molecule phone today?

And the second question on Strensiq, and for Marc, you guys are confident on this $3 billion to $5 billion big sales for pivotal based on the results presented so far. But I was wondering if you could give us some color on the dynamics across commercial regions expected between Strensiq and alpha. How should we expect those to playing out in the market?

Thanks, Gonzala. There's probably two questions from Marc actually cause is developed by Alexion. Over to you, Marc.

Gonzalo, thank you for the two questions. So let me take the first one. So to your question on the add-on design, so is -- the trial we are doing on ceramic is as an add-on to either stabilize FMD so [indiscernible] So the trial is not done as a monotherapy. What is very important to understand is the difference of mechanism as the class indicates, is a depleter and therefore, deplete the amyloid burden in the tissues -- amyloid plaque in the tissues. This has been confirmed during our Phase Ib studies over 1 year We have also read across from another product that another depleter that we are developing in another disease [Technical Difficulty]

We have seen on this product a very clear outcome benefit both on mortality as well as cardiovascular event following cardiac remodeling as well as improvements of many, many cardiac functions. So it's not the same disease exactly, but we have a reasonably good read across of the depleter mechanism in the treatment of amyloidosis. So for we are expecting the results in the future, and we look forward to demonstrating again the same benefit improvement of cardiac model improvement and outcome benefit in both post mortality and cardiovascular spitalization, and we look forward to these results.

To the second question on Strensiq. So Strensiq today is -- has been on the market since 2015. We do not have a very wide coverage. And I think this is what -- is what going to bring us is going to have a much wider coverage in terms of countries, possibly we would have a wider label than Strensiq, but this remains to be discussed with regulatory authorities.

What -- the big difference between those two products is the greater tolerability of which is remind you, administered every 2 weeks instead of administered either daily or every other day for Strensiq. So there are a big difference in the patient's utilization. And in terms of tolerability, just to give you some numbers, the patients who are on notes alpha, basically have 5 days of injection site reaction on average in a given year. And this is many times low -- many times lower than what is experienced with Strensiq. We also know that the retention of Strensiq is often impacted by this issue tolerability. So that's why we are -- we remain confident that in since will grow in terms of number of countries in the brands of patients and also in the retention of patients on the

Thank you, Marc. And maybe going back to Gonzalo see from a -- Marc's response that can be used as monotherapy, but it can be used on top of -- can be used on top of have stabilized. Of course, we'll have to show that it had something, but that's potentially a broad use for this agent.

Next question is Sachin Jain at Bank of America.

One financial -- one is financial. Could you talk about balancing the investment in pipe and launches that are Aradhana talked to versus delivering margin expansion. So as we think about 2H '26 and '27 cost growth, is the 1H R&D SG&A cost growth of 6%, a good proxy? Or should we think about acceleration into second half of this year and into next year?

And then quick hits on one -- biopharma '27 pipe. So Cambria on the switch study due next year, perhaps us and you could just talk to how you think about the probability of success in that study relative to 4 and where it sits on the endocrine sensitivity continuum. And then one for Ruud, Farxiga life cycle management, just a simple question. You've got substantial peak sales of almost $10 billion across the various fixed those combos, concerns us basically, has nothing. Where do you think consensus is missing on these assets?

So that's great. And Sachin, thank you. You have -- you are very ambitious with many questions, but we lack ambition. So maybe Aradhana could cover the first one, then Susan and then Ruud -- Is that okay, Aradhana, will you start?

Great. Thank you, Sachin. So for 2026, we have given, obviously, our revenue and EPS, and we give, I think, enough detail on other line items as you've seen, whether it's on R&D or some of the other moving parts on gross margin and other income, et cetera. So I think for 2027, we will obviously give guidance for 2027 at the beginning of 2027. We will start our sort of annual budgeting process later this year. So we started that in a few months. And as you know, there's a lot more readouts still to come and investments still to make, whether it's on too or we'll see how some of the other events read out. So all of that is going to be part of our planning. And we base our guidance for 2027 or any year, we base our guidance on our budget and on our planning process. So we'll give more view on that when we do that early next year. Susan?

Okay. Thank you. So thanks for the question about CAMBRIA-1. Just as a reminder, CAMBRIA-1 is an extended adjuvant trial in patients with intermediate to high-risk hormone receptor positive and HER2 negative breast cancer. So it's already been well established that extension of duration of endocrine therapy in this adjuvant setting improves outcomes.

By taking patients who've completed 2 to 5 years of adjuvant endocrine therapy with or without a CDK4/6 inhibitor, which is this switch design and randomizing them to continuation of AI or tomoxfone -- We're actually taking what is an endocrine-sensitive patient population. The patients that have got higher risk factors will likely have progressed through the initial period of adjuvant treatment. And by focusing on the intermediate or high risk, we're taking out those patients with lower-risk disease were likely ordered with current standard of care. So I think it does select for an endocrine-sensitive patient population in a setting where endocrine intensification has already been proven with other trials. So I think from that perspective, and given the profile that we've seen with of tolerability and efficacy within the Sun study, I think it has a good probability of success together with data that we've seen from a competitor in the adjuvant setting.

Okay. Thanks, Susan. let me quickly address the question of Sachin regarding the combinations. We have currently three combinations in development. All those combinations are addressing patient populations where there's a high risk and where there is almost no current treatment. So if I take Zebedepa as one example, it's a Phase III. It has recruited very fast, clearly showing the high-medical needs in proteinuric CKD. Those patients are very ill. The kidney function is declining, and we know the beneficial effects of dapagliflozin. And on top of that, we hope to see a beneficial effect of endothelium receptor antagonist.

The other one is in heart failure patients with a low eGFR, where mortality is very high, normally twice, as you see normally in a heart failure patient, and there's no data available. So again, it's a highly, highly risky patient population the estimates of the Epi data has shown that more than 12 million patients in the top 8 markets are eligible for treatment like this. So it clearly shows the potential if the study is reading out. Both of those fixed those combinations, we're expecting to see data in the first half of 2027.

And then last but not least, Paxostatand the combination with -- also that is in a high-risk population in chronic kidney disease and hypertension. We know that hypertension is a very important risk factor for the development of chronic kidney disease. And we hope to see a slowdown of the progression of kidney disease. So again, a high-risk patient. And I think not everyone is, let's say, addressing and seeing the potential of those new combinations. Those are really new molecular entities if they are successful. So I think building on the massive experience we are having is definitely 60 million patients are currently treated with detcleflozin. I think it's the backbone of heart failure and chronic kidney disease patients. And adding those new mechanisms hopefully will lead to a much more beneficial effect, both from a mortality perspective, but also from a kidney disease progression perspective.

Thank you. I had not realized we had many more questions in the line. So if we can stick to one question per person, it would be great. .

Graham Parry at Citi.

So I had one on simpatico you said your filing for a broad label. Can you confirm that, that does include adults? And was that based on any discussion with regulators to date is the acceptability of the HIRI trial and the trend benefit in the pediatric on cell adult population. And does the $3 billion to $5 billion sales outlook include the adult population? Or is that just in pediatrics?

Marc?

Thank you very much for the question. So the broad population, so the filings will be above 2 years of age for a broad population, as I said in my prepared remarks, this has been done in discussion with regulatory authorities. But obviously, they will need to look at the detail of the three studies that we have completed and submitted.

To your second question on the -- so the adult population is segmented into two parts, adult with pediatric onset, which is in several countries already obtained with Strensiq in adult with adult onset where Strensiq is not approved today.

Your second question on the $3 billion to $5 billion, even if we get less than the totality of available that we have filed for, we expect to be within the range of $3 billion to $5 billion.

Thank you, Marc. Next is James Gordon, Barclays.

Can you hear me?

Yes.

Pascal called out Saruparib, so the selective PARP in prostate cancer where we're getting data next year, and this has been described as a $5 billion-plus product. There was some excitement about the asset a few years ago than it wasn't pine with Merck and maybe there was a thinking that Lynparza is a pretty high bar to beat. So how big could it be if it works next year? Is the $5 billion, a lot of that is derisked by the date of next year? Or does that need a lot of other trials to work? And how excited are you by that readout?

And then if I could just squeeze in a quick clarification. So other operating income or OOI. So the updated 2026 guidance implies higher OI and higher OpEx and then you're reiterating the guide because you're reinvesting in higher ROI. But how much of this year's ROI is ongoing versus one-off? So is that going to create a headwind next year when you don't have the ROI? Or is most of this year is going to repeat again next year from an ongoing source?

Thank you, James. Susan, do you want to cover the Seraparib question. I mentioned it, James, just as an example of many projects in our pipeline that nobody talks about. We seem to be facing from most an obsessive focus on 2 readouts that are important, of course, I don't want to underestimate the but I just wanted to highlight the fact that we have many, many more projects. And what we showed you today are only the most important ones, and Seroparib is certainly one of the most important ones as well. Susan, over to you.

So as you have seen from the clinical trials appendix, there's a significant effort that we've got with sorafrub in prostate cancer. One of the key trials is the Evapostate01, which is a metastatic common sensitive prostate cancer, including both the HRM and non-HRM cohorts. So -- we already have seen from the PROPEL study in a later line that we do have activity for PARP inhibition in combination with anti receptor inhibitors. And what we've done is taken the learnings from the PROPEL study and move this into an earlier line setting and power the study for both our HRM and non-HRM. And of course, having seen the data for the talazoparib and enzalutamide data sets coming out. I think there's significant opportunity in this setting to improve the tolerability profile, increase the potency of inhibition on PARP and see benefits in both those subgroups. You will recall that we did see a positive effect on PFS in the non-HRM in the PROPEL data set. But there was a lot of discussion at the time of the We've addressed those concerns with the design of this study, and I think that's a significant opportunity. But it's also backed up by other studies in other segments in prostate cancer and also in the Evaparbreast opportunity as well. So when you look at the totality of the sort of prove opportunity, it is significant and definitely in the $5 billion range, and we're excited to see these data read out.

Just to address...

Let's park this one and revisit it at the end. So we give everybody a chance to ask one question, and we may have a chance to cover it as part of another financial question. And next is Christopher Uhde.

I guess this one would be on Bexendi, noting that you have the primary aldosteronism trial reading out next year now. So today, screening for aldosteronism is not really or active. So what are you doing to try to ensure as rapid a rollout that would not be a break on your launch?

Sharon, do you want to cover this?

Sure. So first, I'll say thank you for noticing the potential for Baxter stat in primary aldosteronism. This is a really important and unmet medical need. It's really a group of disorders in which aldosterone production is unusually high for sodium status, and it is relatively autonomous of the normal regulators. So this is a major unmet medical need and a key driver of cardiovascular damage and is the leading cause of secondary hypertension. We think it could affect as many as 5% to 10% of all hypertensives and up to 20% of resistant hypertension.

And you're right, relatively few of those patients today are being streamed because there hasn't been a therapy to give them. Now we have the first approved aldosterone synthase inhibitor with an excellent treatment profile, our target product profile. And we think that this is going to be pivotal in helping to drive uptake now that there is a recognized therapy that addresses aldosteronism. So we're running that study. And as we have disclosed, it is -- it has accrued very rapidly. So we're accelerating that time line for primary aldosteronism, and excited to see the interest around as a leading molecule. So increasing uptake will, I think, follow through naturally from what we hope will be a positive data set. And the rapid recruitment that we're seeing for our studies really speaks to the major unmet medical need and the general enthusiasm of the clinical community for this mechanism.

Thank you, Sharon. Peter Verdult, BNP.

Peter, BNP. Two quick ones, Pascal, one for Ruud on IL Phase III and $5 billion target for Tazo. Are you anticipating any competition here? And the reason for the question is we're hearing Sanofi and the part of Regeneron might not undertake the third Phase III study for itepekimab that will be required for approval in light of your data and probably the fact you now enjoy a 3-year head start. So first, a quick question on Tazo. And then secondly, the obligatory sort of MF pricing question. When you think about approved in Europe, hopefully will get approved in the U.S. How have your thoughts on pricing strategy evolve if we compare it to historical presents like Calquence and Tagrisso?

Thanks. Ruud, do you want to cover the question, and I'll return to the pricing at the end?

Yes, for sure. Now I think, Peter, it's a fair question, but it's so difficult for me to answer this one because I simply don't know what Roche or Sanofi are planning to do. What I can tell you is that the data set, hopefully, you will see at the year is very convincing. And we get many questions about why do we think that our IL-33 was successful in those pivotal trials. And we truly believe that the mechanism of action is very specific to our anti-IL-33. It's inhibiting the anti-inflammatory pathway, but equally the mucus pathway. And I think that combination makes this a quite unique molecule. So let's see how the competition is going to react to the data. But of course, we keep a close eye on it.

Thank you, Ruud. Stephen Scala, TD Cowen.

Pascal, you have been bullish on China for years, although headwinds were clear in the quarter. All things considered, are you as confident as you have been in the past? And how threatening are the local companies on the global stage? And just a very brief question. Should we view it as possible that SERENA-4 and Avanza are presented at ESMO?

Thank you, Stephen. So I'll cover the first question, and we'll return to the S-4 question at the end. China, still very bullish for reasons that have evolved, I must say. I mean the potential in China is still large. But on top of it, the innovation potential is also enormous, as you've seen from the various deals we have made but also other companies have made. Today, Chinese companies are innovating at great speed and tend to partner with global companies like Harvest to globalize the development and the commercialization. But it's reasonable to expect that over time, they will expand globally.

Expanding globally is not that simple, right? I mean, because the profitability in China is not that high. Prices are low. So if you don't have a very strong domestic business from a profit viewpoint, it's not that simple to globalize, but you have to assume they will at some point. So what we're doing is collaborating, but we're also competing. You saw the competition in the Tagrisso market. It's very, very intense. And in the ADC market, very intense too. So we learned to compete with them and something we'll take those learnings globally when they become global companies, if they do.

We're also learning from them in terms of how they develop products and how fast they operate. And we've made some changes in the way we operate. And for instance, that we announced this morning is a good example of the role our Chinese team has played in the speedy development of this product. So I think being present in China very present and strong enables us to collaborate with companies, learn from them and plan to compete as well.

So the next one is Colin White at UBS.

I had a quick question on the C5 franchise. I was wondering if you could talk about how much you expect to may be impacted by longer-acting C5 inhibitors like Regeneron cemdisiran? And then just quickly, if you could comment on the Fortis arbitration in the U.S., the time lines possible outcomes of that, that would be helpful.

Thank you. Marc, do you want to cover the C5 question, and we'll cover a little later.

Yes. So obviously, there have been a number of competitors against the C5 franchise, we continue to grow. But obviously, other mechanism or similar products on the C5, complement biology also will compete with us. What we have been doing with Temeris since the acquisition of Alexion was also to explore and pioneer in new indications, and we are going to continue doing that. I mentioned today, IgAN. We saw the results in We have other trials such as the delayed graft function. And then we will be developing several other areas in the renal rare disease, but also in -- with other modules of the nodes of the of the complement biology to propose answers to disease that have no response today. So we are continuing to compete in the C5, but also outside of the C5 from within the complement biology.

Thank you, Marc. And as you can see, I mean nonacting could have a place, of course, but you have to develop every single one of those indications. So takes time and it takes money.

Next question is Michael Leuchten at Jefferies.

Pascal, maybe if I could just go back to rate on the other operating income question that we have to covered. How much of that is sustainable going forward? How much does the higher run rate cost and a higher base that makes 27 a little bit more challenging?

That's great. Aradhana, you got your question.

So again, we don't provide the split of other income, but there is a portion of that. Obviously, that is relating to royalties and some milestones that we get. And then there's a portion for this year that also relates to, like I said, smaller regional divestitures we've done, again, as we clean up the portfolio, again, all of these are small legacy products that we continue to sell and monetize those. But there is a portion of that, that is consistent and will likely continue into 2027.

Thank you, Aradhana. So if we return to the -- sorry, there is a question from Seamus.

This is Zach Dunn on for Seamus Fernandez. I just want to touch on BD. More specifically, is the current Phase III pipeline sufficient to deliver a stable profile during the main patent expiration period in 2032 plus? It seems to us that the current pressure on the multiple has much less to do with 2030 and much more to do with 2032 and beyond and the larger BD may be necessary to drive growth in that time frame?

Well, I think on this one, I can be very clear. The answer is no, we don't need mobility to deliver. But of course, to deliver this growth post 2030. But again, it assumes that the aggregate probability of success across our pipeline of new products will be at least as we plan it. because again, there's no 1 or 2 projects. It's the aggregate view of the pipeline.

And then if you look at that, -- the average probability of success across Phase III for the industry, 60%, 65%. I think Aradhana mentioned it earlier. The probity -- the aggregate probability of success that we use across our pipeline, and we looked at it again recently, it's around 60%. So we are more or less planning as if we were going to develop the industry average, in fact, a little bit lower. But we have consistently developed higher now mentioned 75% plus has been our record. So if we deliver what we have in our plan is a profitive success -- And then we have -- actually, we don't need more BD. So the reason we don't -- we need is really to continue planning long term and continuously strengthen our franchises. The most recent one we just talked about is how do we strengthen the -- sorry, the Tagrisso franchise? So net-net is, no, we don't need new bid to achieve this goal. I don't know where this side it comes from probably from people who haven't analyzed the pipeline in detail, I have to say.

Luisa, Berenberg, do you want to go ahead?

Pascal, so at the start of the year, you highlighted over $10 billion combined and risk-adjusted peak sales from the 2026 readouts. And today, we see a couple of increases in too and then the and also hearing consistent messages from Susan on Serena and Avanza are kind of balanced and consistent. So does that guidance still stand? Or have there been some risk adjustment changes maybe that were negative for the cohort?

No, the -- when you're talking about the 2030 targets, right?

No, the $10 billion peak sales potential from the readout this year 2026 was a slide you had at the full year '25 results. Yes.

Okay. Aradhana, do you want to cover this one?

Sorry. So the $10 billion was the peak year estimates with the risk unwind. So what that means is as risk unwinds for the 2026 cohort, we were still -- we would say $10 billion. Now some of them have unwound in a positive manner like a too. Some of them have unwound in not so positive manner like But I think, again, all of those being probability adjusted, I still think we'll unwind close to $10 billion. Now that $10 billion is not a 2030 number, that's a peak year sales number and the peak for some of these products may hit beyond 2030.

Maybe the one thing I would add to this is that our probability of success in our risk-adjusted overall forecast, the probity of success we gave to Toso was on the low side, and I'm sure you would agree with that nobody thought it was going to work. We thought it had a good chance, but we still give it a low And then we had a higher sort of a good PTS for and more industry standard because we had good reasons to believe based on what the entire cardiology community was saying, a good the reason it was going to work. So the net result is we've unlocked Toso, and so the uplift in sales is much higher than the downlift in sales from If you consider the low PTS we had for Toso. That's one. And two is the profitability of Toso is higher. We own this product 100%, whereas with we were going to share it with our partners at Ionis. So clearly, we gained more with Toso than we lost with

I think maybe we'll take -- that was the last question. So we'll take the questions we left sideways. And maybe, Dave, you could cover both the MFN impact on the pricing of and also the question about S4

Thanks, Pascal. Well, on the second question, we will present it when we have our high-level results at whatever Congress we can make it to. So we're not going to be able to comment any more specifically than that in terms of where we'll see the presentation of that.

On MFN, we don't give brand-specific pricing commentary on MFN and don't plan to. That said, our pricing approach across all of launches now has really evolved in response to MFN. And with the U.S. now referencing a basket of countries and setting its price, we are seeing productive engagement with payers and the wealthy nations within that context. With it Cama specifically, we're still early in the commercial life cycle in the markets where we have approvals, but the early negotiations are reflecting this new reality that funding for innovation needs to rise in line with a country's GDP per capita. We do anticipate that these will be discussions that are going to take more time than perhaps sometimes in the past. But we do think that -- so far, the objective that was set by the U.S. for prices in wealthy nations to come up and U.S. prices to come down a bit, we think is the direction of travel.

And S4 at ESMO?

Yes, I commented on that at the beginning and said we will share when we have the data, what the timing of the Congress will be.

Okay. And the last question for Ruud

Yes. Pascal, there's not so much I can comment on this one. As we mentioned in our legal disclosures, we started an arbitration process regarding be Fortis in the United States. And as we normally do, we are not commenting on either an arbitration or legal procedure.

Thank you, Ruud. So we'll close the Q&A here. Thank you so much for all your great questions. And being closing or thank you for joining us, for your interest in our company and also restate that we are firmly on track for our 2030 goal, but also on track with our post 2030 goal ambition. And again, we don't need additional bid. It doesn't mean we will not do additional bidding, but we don't need additional bid if we continue delivering as we expect to across the pipeline.

Again, thank you, and have a good day.

Welcome, everyone, to AstraZeneca's 2026 Sustainability Update for Investors and Analysts. I'm Philip Sparks, Director of Investor Relations. And before we hear from Pam and members of our sustainability team, I'd like to remind you of our forward-looking statements, including our safe harbor provisions.

And now I will hand over to our EVP, Global Operations and Chief Sustainability Officer, Pam Cheng, who will run through the latest progress in our sustainability strategy before we move on to Q&A. Pam, over to you.

Thanks, Phil, and welcome, everyone. It's a pleasure to be here today. In addition to leading our global operations, which includes manufacturing and supply and global IT, I have had the pleasure of being AstraZeneca's Chief Sustainability Officer since 2023. I'm pleased to share an update on our sustainability performance today and welcome any questions at the end. In addition to Phil, I'm joined today by Liz Chatwin, who leads our sustainability strategy and safety, health and environment as well as Stefan Weber, who leads policy, advocacy and health equity.

Next slide, please. Let's first start by considering the context we are operating in and why as a pharmaceutical business, we place a significant focus on sustainability. At AstraZeneca, we are focused on improving health. We understand that the health of people, society and the planet are deeply interconnected, and we believe we have a role to play in taking action here.

Climate change and nature loss are worsening and changing the burden of disease with a rise in noncommunicable diseases and impacts on human health. The delivery of health care carries a significant environmental footprint, so we are focused on delivering more sustainable care. At the same time, health systems are under increasing strain with aging populations, the rising burden of chronic diseases and continued pressure on health care funding.

We know that by acting early on disease improves health outcomes and reduces pressure on health systems as well as minimizing carbon and resource-intensive hospital care. And health disparities are widening within and between countries, worsening health equity and pressures on health systems. I will speak more to this shortly.

Ultimately, governments and health care providers recognize the need to improve health outcomes through more effective, sustainable care. We believe we can play a key role to help achieve this through collaboration.

Next slide, please. Central to improve health care is the delivery of the remarkable science and innovation before us. Today's medical breakthroughs can truly transform outcomes for patients. And AI is helping us bring these medicines to patients faster and with a greater probability of success. In R&D, AI is helping to accelerate drug discovery, improve decision-making and support the design and execution of clinical trials.

Across our operations and manufacturing, AI is helping us improve productivity and efficiency, thereby reducing energy use. And digital and AI-enabled tools can support earlier diagnosis, more targeted care and better patient follow-ups. We are deploying the latest technology to develop medicines and treatment pathways that can help keep patients healthier for longer. This is good for the health of people as well as society and the planet. Next slide, please.

At AstraZeneca, sustainability is embedded in our business strategy. Operating sustainably is good for business and core to operating a responsible, efficient and resilient business for the long term. Our sustainability strategy focuses on how we make a positive impact through actions on climate and nature, health equity and health systems resilience and how we run a sustainable business through a focus on good governance, our people and values. All of this is underpinned by science. Next slide, please.

When it comes to our climate and nature action, over the past decade, we have shown that business growth and decarbonization can go hand-in-hand. As of December 2025, we have reduced Scope 1 and 2 emissions by 88%, while more than doubling our revenue compared to 2015. Our bold ambition is to reduce Scopes 1 and 2 by 98% by December 2026 where addressable. As a matter of fact, 11 of our sites have already met that goal.

We've also made progress on our value chain or Scope 3 emissions. More than 80% of our supplier spend is with companies with science-based targets. We are making a $500 million investment to transition our pressurized metered dose inhalers to a next-generation propellant with near zero global warming potential for respiratory medicines. More on this shortly.

We've also transitioned our car fleet to electric vehicles. 81% of our global fleet is now electric. We've also reduced our water and waste by 23% since 2015. These are strong results, which we are proud of and continue to double down on. Next slide, please.

Now turning to health equity. Our work spans 3 areas: science, health care delivery and community investment. We aim to improve equitable health outcomes in low middle-income and higher-income countries. By the end of 2025, more than 40% of our genomic data came from people in underrepresented populations, an industry-leading achievement. This is key as it will help us develop medicines that will benefit a broader range of patients. Through our Young Health Programme, we have partnered with more than 60 NGOs, including UNICEF and Plan International. We've reached more than 23 million young people in 56 countries over 15 years. Since 2024, AstraZeneca's health education, screening and early detection programs have reached more than 49 million people. And 156 million people from underserved communities have been positively impacted by our health equity programs since 2024. Next slide, please.

Now turning to health system resilience. Many health systems remain structurally oriented towards managing disease at later stages without enough emphasis on prevention and early intervention. Building resilience requires a better balance across the care pathway with greater focus on acting early to improve outcomes and reduce long-term system pressure. We are co-creating solutions that slow disease progression, reduce hospital admissions and prevent premature deaths while helping health care professionals to deliver more sustainable care.

This includes earlier detection, access to guideline-directed care and the use of digital technology to identify risk sooner and respond more effectively to patient needs. And we are advocating for evidence-based policy change as a founding member of PHSSR, the Partnership for Health System Sustainability and Resilience, I apologize. We have been driving systemic changes since 2020 alongside our partners across the health care sector. The PHSSR is now active in more than 37 countries, has published over 30 reports and engaged more than 200 policymakers on health system strengthening, translating insights into policy change that is improving care for millions of patients. Next slide, please.

Examples of action and impact, as I will just outlined, are included in our 2026 sustainability impact publication released in April. Here, we also included our sustainability targets to 2030. Our targets focus on areas of greatest materiality to our business and where we believe we can make the greatest impact. For climate action, we have updated 2 of our 2030 targets.

Firstly, Scope 3 emissions, which I will discuss shortly; and secondly, the target for AZ Forest, which we have adjusted to planting 100 million trees by 2030. The original target was 200 million. The change is based on our learnings since we've launched the initiative and a more focus on high-quality projects over volume. Our health equity and health systems resilient targets outlined here have not changed over the past few years [indiscernible] target areas, Scope 3 emissions and health equity. Next slide, please.

With great progress having been made in reducing our sites and fleet emissions, we are now increasingly focused on reducing the emissions from across our value chain. As we grow to deliver more medicines to more patients, our Scope 3 emissions have increased alongside our business growth with expanded product portfolio, capital investments and geographically diverse supply chains. Our commitment to our science-based net zero target for 2045 remains steadfast. However, we have recently updated our near-term Scope 3 target to reflect our business growth and aligned it with our ambition to deliver $80 billion in total revenue and 20 new medicines by 2030.

Our updated target for 2030 aims to reduce Scope 3 emissions by 35% versus 2019. The original target was 50% reduction off a smaller base given our business growth. It is worth noting that the absolute amount of emission reduction with the new target is the same as the original target. Our action on Scope 3 remains very focused with key areas outlined on this slide. We are prioritizing supplier engagement. We've engaged our suppliers to adopt science-based targets for several years now and sustainability requirements are included in supplier contracts. We are expanding supplier access to renewable energy through group initiatives like Energize and the Sustainable Market Initiative, Health Systems Task Force, a CEO group to advance the decarbonization of health care systems chaired by AstraZeneca's CEO, Pascal Soriot.

As mentioned, we are focused on sustainable product innovation, including our inhaled respiratory portfolios transitioning to our next-generation propellant. We are reducing the environmental footprint of our products by driving improvements throughout the product life cycle. We are delivering sustainable [indiscernible] mines across our sites, utilizing low-carbon material and energy-efficient architecture from the U.K., Ireland, France, Puerto Rico, China to Singapore. Our sites are sustainable by design. We are also reducing our transport footprint by shifting from air to sea freight where possible. And we are optimizing business travels, having cut business air travel by 58% versus 2019. Next slide, please.

Turning now to the transition to our next-generation propellant, which is core to our Scope 3 progress. The transition of our pressurized metered dose inhalers to a next-generation propellant is a landmark innovation in sustainable health care. We are making a $500 million investment in this propellant with near zero global warming potential. Our goal is simple: support patients with asthma and COPD, support health care systems and reduce the environmental footprint of respiratory care so that no one has to choose between the most appropriate treatment and a healthier planet.

In a world and industry first, last year, the U.K. approved this new generation propellant for one of our respiratory medicines, and it is now in use across the country. The transition is also complete in Europe and other regions to follow very soon. We aim to transition our wider product portfolio by 2030 as part of our Ambition Zero Carbon strategy. Next slide, please.

Next, we turn to our work in advancing health equity. Health outcomes are [indiscernible] environmental and genetic factors that amplify inequities in every region of the world. Quality, timely health care remains out of reach for so many, and those at highest risk of disease often face the greatest barriers to screening, early detection, diagnosis and treatment. By closing these care gaps, we can improve health outcomes across our therapeutic areas from cancer to cardiovascular to rare diseases. As our company grows, so does our opportunity to improve access to diagnosis, care and treatment for underserved patients.

We see health equity as an area where sustainability, patient impact and long-term economic impact comes together. Diagnosing and treating patients earlier can add years of quality life expectancy to individuals and improve the resilience of health systems. Of the 1 billion people we aim to benefit through our health equity programs, we aim to reach 400 million people from underserved groups as classified by 2 principles.

First, we include all patients from low income, low middle income and upper middle-income countries due to the significant challenges assessing quality care in these regions. Second, we include all patients with rare disease due to inherent challenges posed by the rarity of their conditions. We recognize there are limitations with this definition. For example, there are also underserved populations within high-income countries. As our understanding of care gaps both between and within countries deepens, we are committed to refining our classification of underserved groups so that our definition accurately reflects the reality on the ground. Next slide, please.

So how will we reach 1 billion people? Most of our patient reach is driven by medicines given the prevalence of chronic diseases and that reach will continue to grow. As we bring new medicines to markets, expand our geographic footprint and work with governments and health systems to improve affordability and access, we are reaching more patients in more places. Beyond medicines, we reach patients through clinical trials, awareness and education and screening and detection programs.

Today, multiple programs across our business units are enabling earlier impact by connecting people to care before disease progression, relieving the burden of late-stage disease for individuals and health systems alike. Healthy Heart Africa is a strong example. The program is now active in 9 countries, including recent expansion into Egypt and Morocco and has screened more than 80 million patients for elevated blood pressure and chronic kidney disease.

In rare disease, we are partnering to expand access to newborn screening and next-generation sequencing with the aim of identifying serious genetic conditions earlier and connecting children to appropriate intervention sooner. We continue to invest, evolve and expand, including new programs and lung health equity to reach more underserved patients. Next slide, please.

Let me close with 3 points. First, AstraZeneca has made considerable sustainability progress to date, all while our business has grown. We continue to value sustainability and embed it across the company. Second, our few updated targets aim to ensure we are realistic and transparent as we focus on and measure the next phase of our impact. Third, Scope 3 and health equity are 2 complex areas where the balance between setting bold ambition, driving real action and bringing others along with us truly matters.

I hope this has been a useful update and gives you a clear sense of our progress and our priorities as we continue to play our part in improving the health of people, society and the planet. I will stop here so we have time to answer questions. Thank you.

Thank you, Pam. And thanks also to those of you on the call who have sent in some questions for Pam, Liz and Stefan in advance. [Operator Instructions]

Let's kick off with a question on a hot topic for investors at the moment. And this one comes in from Ben Yeoh at RBC. Are AI tools helping reduce waste or energy or supply chain inefficiencies? Can you quantify or make any comments on AI and its impact on sustainability and operations?

Thank you, Ben, for the question. It's very timely indeed. AI is driving measurable efficiencies across our R&D and operations. It can actually help shorten drug development lead times, automate manufacturing processes and deliver earlier and more precise health care, all of which support sustainability and equitable care outcomes. So let me give a few examples.

We are leveraging AI to enhance how we digitally model drug candidates, which means that we can now reduce the amount of physical screening required to assess new molecular designs. In development, our AI development agent accelerates pharmaceutical development of our late-stage medicine through digital twins and advanced modeling and generating roughly 35% productivity by 2030 is our ambition and at the same time, reducing the lead time by 50%.

So in manufacturing, we are using AI to drive efficiencies and productivity, reducing manual tasks and driving right first time and AI is also helping us save energy through AI monitoring and control. In early diagnosis and early intervention, a good example is our AI tool called MILTON. It is trained to identify a patient's risk of developing a disease using data from the U.K. Biobank in this case, MILTON combines the identify health records with genetic and proteomic data to predict the risk of more than 1,000 diseases, in some cases, 10 to 15 years before clinical diagnosis. It's published in nature genetics and recognized by the World Economic Forum. MILTON accelerates target identification and reduces the time and resources needed in early discovery.

A couple of more just to showcase what AI can do in this case. In patient care delivery, AI-enabled biomarkers is helping us get the right medicines to the right patient. This increases the probability of success in our trials and reduces the waste that occurs when patients do not respond to their treatment. AI can also turn low-cost imaging and listening devices into very sophisticated diagnostic tools, which can help the LMICs to make the most of their limited screening resources. And AI also has the potential to identify diseases early in its progression, enabling more efficient treatment than when diseases are diagnosed at a less -- at a late stage.

And lastly, we recognize that AI computing has an environmental impact, and we are embedding sustainability into our AI strategy in a few key ways. First, we are shifting our data centers and compute needs towards more energy-efficient infrastructure powered by renewable energy. Then we ensure suppliers have climate change -- climate transition plans as part of our Ambition Zero Carbon strategy. And then lastly, prioritizing suppliers who are investing in water and energy efficiencies at scale. So as you can see, we have quite a few examples how we are embedding AI into R&D, into our operations to ensure that we -- to help us drive sustainability and more efficiency.

That's great. Thanks, Pam. And as a follow-up to that question, this one comes a lot in the calls I have with investors. Can you tell us a little bit about AZ's approach to AI governance?

Absolutely. This is a very important topic. We govern AI with a focus on human accountability, patient safety, privacy, security and legal and compliance and scientific integrity. These are all very important elements. Public AI tools are not permitted for AstraZeneca work unless they have been formally approved. AI use cases are assessed before deployment and systems that we deem to be higher risk are subject to ongoing validation and monitoring. An AI use case might be deemed high risk because of the scale of the rollout and the consequences of inaccuracy or the sensitivity of the data.

So for example, an AI system that determined whether or not a patient would -- could participate in a clinical trial will be treated as a high risk. We apply clear legal boundaries if an AI use case is prohibited by applicable regulation, we do not allow it. Uses prohibited under the EU AI Act are treated as prohibited globally. Our employees are trained to identify risks and understand the ethical and legal issues around AI. And over 50,000 AZ employees have participated in our in-house training program on thriving in the age of AI that focus quite a bit on AI governance and ethical use of AI.

Thank you. And this is another one from Ben. Can you give any examples of where sustainability investments and thinking have created shareholder value either through lower costs, better access or stronger stakeholder relations?

Absolutely. Let me start with by saying we really believe sustainability is good for business. Embedding sustainability in our business strategy creates shareholder value by reducing costs, driving operational resilience and efficiency and reducing pressure on health care systems and at the same time, ensuring we can serve patients for the long term. Perhaps I can turn to Liz for -- to share some specific examples. Liz, over to you.

Sure. And thanks, Pam, and good afternoon, good morning, everyone. Thanks so much for joining the call and for this question. We see numerous examples across our business where sustainability is good for business and good for health care systems, good for now and for the long term.

A few examples for you. So with our renewables investments, so we've made investments in sustainable energy, for example, renewable electricity and clean heat, including in the U.S., in China, the U.K. and Sweden. And through that, we've seen enhanced operational resilience and reduced risk and costs. For example, in particular, we've had reduced exposure to energy price volatility that we've seen this year.

Also, I can talk to investments which lower energy and reduce water use and waste across our sites, support long-term operational continuity and also, in some cases, reduce our costs. Pam talked extensively about our investment in the next-generation propellant, where we're reducing our own footprint and the environmental footprint of respiratory care through the transition of our pMDI or our pressurized metered dose inhaler to a next-generation propellant. This was $0.5 billion investment back in 2020, and we're already starting to see the transition in the U.K. and Europe with other markets to follow.

We chose to be proactive here in taking action and leading by doing because we really believed it was the right thing to do. And we see this as really important now given the increasing nature of environmental regulations. And I can say the launch has been greeted extremely positively by the respiratory community. An example in health care in the United Arab Emirates, they've adopted a guidelines-based care approach to the treatment of CKD, which involves early detection and appropriate treatment, which they found has reduced costs and the environmental impact of care and improved outcomes for patients.

An example in our science portfolio with one of our new cardiovascular medicines being developed, our scientists have been working extensively on improving the process design to reduce the environmental impact of its manufacturing process when it finally moves to commercial manufacture. So from first in-license to the first commercial stage manufacturing, the environmental impact has reduced by more than 90% and 40 complicated process steps have reduced by 1/4. So these sustainable design improvements also have the added benefit of lower overall cost of manufacture once the product is launched.

As probably a final example, and we have many is we find that innovations in our manufacturing process that enhance productivity often also have a sustainability benefit. So one example is a new process called continuous direct compression. And this is a capability which has reduced the production time for one of our new hypertension medicines from 20 days to 20 minutes for the production of tablets. This lowers energy use, reduces waste and supports efficient inventory management and ultimately helps getting medicines to patients more quickly. So as Pam said, sustainability, we truly believe is good for patients. It's good for health care systems and is also good for our business.

Thanks, Liz. Moving on then to the topic of health systems resilience. This question came in from Richard [indiscernible] at Northern Trust. Regarding the health systems resilience target, what does AZ need to achieve in order to strengthen the health system of an individual country and then count that country towards the target of 45%?

Thank you for the question. Let me start and then hand over to Stefan to give more specifics. In terms of our metrics for health system resilience, a country counts towards the health system resilient target when we can demonstrate that AZ is helping strengthen health systems through evidence-based advocacy and partnership with governments. Perhaps, Stefan, you can go into more specifics. Over to you.

Absolutely. Thank you, Pam, and hello, everyone. So as Pam mentioned in the presentation, our main platform through which we do that is the Partnership for Health System Sustainability and Resilience, PHSSR, which we cofounded in 2020. So through the PHSSR, we commission research with leading local health system and policy researchers, and we use these findings to engage and advocate for evidence-based policies. So it's really research and action, if you want, and then we can count a country towards our target. As you've heard before, PHSSR is currently active in 37 countries. We have over 30 research reports published already, and we're expanding the scope of PHSSR geographically and also across different health system problems.

But this year, we expect to launch engagements and reports in Mexico, Indonesia, Finland, and Turkey, bringing the total number of PHSSR countries to over 40 by the end of 2026. So close to our target of 45 in our 2030 ambition. An example of that is Greece, for example, where we recently concluded research on what the health system would need to do to promote earlier action on noncommunicable diseases together with the University of West Africa. And with the research findings, then the PHSSR partners and AstraZeneca included, we engaged with the government on the importance of expanding access to early detection of chronic kidney disease, one of the main diseases that causes an immense burden on the Greek health system, on population health outcomes and cost to the economy.

So informed by this work, the Greek Ministry of Health then strengthened early detection programs on CKD and introduced a screening program using the national electronic prescription platform to send SMS invitations to high-risk citizens for free diagnostic tests. So as you can see, a really proactive approach of the health system to engage people at risk with a free test, which is obviously important because we know through the research how little people engage and pay for tests for a disease that they don't know they even have or at risk of having. So the aim of this work is obviously to close the diagnostic gap, enable timely referral to care and ultimately strengthen the Greek health system resilience while also advancing health equity. So a great example of how we've connected research and policy action.

Thanks, Stefan. Now we're staying on the topic of health equity. We've actually a couple of questions on the overlap between health equity and AI. One from Francis [indiscernible], who's asked, given increasing reliance on AI-enabled screening and diagnostics, how does AstraZeneca ensure equitable deployment and mitigate potential biases in underserved populations? And then this one was from Lucy [indiscernible]. How is your collaboration going with Qure.ai to screen 5 million patients? And what is the impact that is having on low- to middle-income countries?

Great. Thank you for the question. Indeed, Qure.ai has some great examples that we have actually accomplished. So maybe, Stefan, could you please share the specifics?

Absolutely. Thank you, Pam, and Lucy and Francis for these important questions. So last year, AstraZeneca and Qure.ai announced the successful completion of 5 million artificial intelligence-enabled chest X-rays across more than 20 countries in Asia, the Middle East, Africa and Latin America. It's really a remarkable achievement if you think about it, and it's demonstrating the transformative potential and reach of AI to improve early lung cancer detection in low and middle-income countries.

But I would also add in other resource limited health care settings, including in high-income countries where screening uptake can also be very low. So really to the point that you asked, Francis, on the chat, by design, these programs are made with underserved populations in mind. And a recent study showed that over half of the suspicious lung nodules flagged as high risk by AI on the chest X-rays were confirmed as high risk on computer tomography scans. This is really important because it suggests the approach can help identify more patients, more high-risk patients and earlier, prioritizing them for follow-up CT scans and supporting more targeted and efficient use of CT-based early detection pathways.

We are already seeing strong signals that this approach is working and supporting a stage shift in lung cancer diagnosis. And that's really crucial. As you know, our ultimate goal is to reduce the mortality of lung cancer. And by finding and treating cancer early, it's really the best way to do it.

In addition to the partnership with Qure.ai that we've spoken about now, we also support other programs that drive early detection, and we work closely with governments, health systems and patient advocates to scale pilots, but also advance policies for broader patient reach and impact, including, as I mentioned, particularly underserved groups.

Thanks, Stefan. Now moving on to climate and nature. This is a question that came in from Anna [indiscernible] from Handelsbanken. Nina Meiniche from PFA and also [indiscernible] and [indiscernible] from Rathbones, all members of the Nature Action 100 investor group. And the question was, could you help investors understand how your nature materiality assessment informs target setting and whether you plan to disclose this linkage more explicitly going forward?

Thank you for the question. Our sustainability targets were developed following a double materiality assessment and an in-depth business review. We focus on areas where we can have the most material impact and targets that I have presented today, specifically for climate and nature and value chain emissions, water stewardship, waste circularity and of course, our commitment to product sustainability such as the next-generation propellant.

Our targets are grounded in high-quality data, and they are scrutinized and approved by the Sustainability Committee. and remains externally verified and publicly disclosed and are reported annually. Sustainability reporting is now fully integrated into our annual report, which mirrors the integration of sustainability matters into our company's risk management process.

In 2024, we published a TNFD statement, which describes our assessment of nature-related dependencies, impacts, risks and opportunities. In our 2025 annual report, we outlined that our latest double materiality assessment use the same methodology as in 2024. So for further details on the linkage between our materiality assessment and targets, you can continue to refer to our TNFD statement on our website. Some of the examples of our nature strategy in action are practically eliminating the use of horseshoe crab blood derived materials in our water testing, for example, also building the use of a synthetic alternatives into our quality protocols for new products is another example, all of which we continue to drive sustainable sourcing of priority natural commodities.

With AZ Forest, we've planted over 66 million trees of 80 different species to restore land, support biodiverse habitats and strengthen ecosystems while supporting community investments. Thank you.

Great. And sticking with climate and nature, this one came in from Tessa Younger at CCLA. Given the progress already made on operational emissions, could you provide a visual decarbonization pathway chart that quantifies expected absolute emission reductions across the main levers of energy, manufacturing, suppliers and product design?

Thank you. As I've mentioned, we've achieved an 88% reduction in our Scopes 1 and 2 emissions versus 2015, demonstrating that business growth and decarbonization can actually go hand-in-hand. We aim to achieve a 98% reduction by year-end 2026, where addressable. We've achieved this progress by focusing on energy efficiency and switching to renewables across our sites and transitioning our global fleet to electric vehicles.

As we are committed to net zero by 2045, the majority of our remaining emissions are generated across our value chain. We transparently report Scope 3 emissions annually with third-party assurance. We don't publish a year-by-year waterfall because Scope 3 emission reductions are inherently non -- it's nonlinear and will evolve further with data quality improvements, portfolio evolution and supplier decarbonization rates.

What we are very clear about is focusing our decarbonization efforts on our most material areas. In the near term, a critical lever for us is the transition of our pMDI portfolio, as mentioned, to the next-generation propellant with near zero global warming potential because these emissions represent 26% of our total Scope 3 footprint is a good example of this nonlinearity. Respiratory sales have outperformed analyst projections, which is positive for patients and for business, but it also has increased Scope 3 emissions recently since most of today's portfolio still use our original propellant.

However, our aim is clear, which is to reduce these emissions by transitioning our pMDI portfolio to the new propellant by 2030. So we have also reduced our business travel by half since 2019 and reduce emissions from the distribution of our products. This is quite significant and impressive given our business growth. We have doubled our revenue over the past 10-plus years and we continue to grow our top line revenue and our portfolio. But at the same time, we've reduced our business travel by half and also reduce our distribution and freight emissions.

We are also focusing on our suppliers as the goods and services we purchase are a large proportion of our Scope 3 emissions. To date, more than 80% of our suppliers have committed to science-based targets, and we've now are working with our top suppliers on specific decarbonization actions.

So overall, our approach is to focus on credible disclosure of baseline of the baseline, clarity on the main decarbonization levers and transparent update on an annual progress. We believe that this is the more transparent way to go and to show how growth and decarbonization can coexist across the value chain. Thank you.

Thanks, Pam. And here's another one we've had in from Francis [indiscernible] on the topic of Scope 3. So while over 80% of supplier spend is aligned with science-based targets, how does AstraZeneca track supply performance against these targets? And what escalation mechanisms exist for noncompliance?

That's a great question. Perhaps, Liz, hand it over to you.

Sure. Thanks for the question, Francis. So as Pam mentioned, we've been working for several years now on ensuring that the vast majority of our spend is signed up to science-based target, and we've achieved a more than 80% result, as Pam said. We now build sustainability expectations into supplier contracts. And we've been facilitating support and access to PPAs. So that's power purchase agreement for renewables across several markets. For example, in China, we have included many of our suppliers into our joint PPA with the Sustainable Markets Initiative Task Force. And we've also worked with Energize to help our suppliers.

Many of our emissions with our suppliers are multifactorial. They're from many different areas of our business. So we're now working with our top suppliers, as Pam said, on decarbonization actions. So that is the work that they're doing with us, for example, whether they're manufacturing our products, whether they're helping us with particular clinical trials on what specific actions we can take together to reduce those emissions. So that's where we're up to right now, very active with our suppliers on our emissions reduction plans.

Thank you, Liz. Okay. So I think we've got time for one more before we have to wrap up. And it's another one from Ben Yeoh from RBC. And he's asked how early on in the R&D and commercialization process are sustainability matters taken into account in, for example, device design, packaging or even molecule development?

This is actually a really excellent question because the best way to be sustainable is we start from the beginning. So we don't have to decarbonize. So we know that early-stage scientific decisions long before a potential medicine reaches the patient can actually, as I say, play a huge role in their long-term sustainability impact. And that's why we embed sustainability across our R&D and treat it as foundational to innovation. We call it sustainability by design. In development, for example, we want to start with green chemistry from day 1, for example, as we develop commercial processes that we can scale up and commercially manufacture at a much larger scale for years to come. So perhaps, Liz, let me hand it over to you for more examples.

Great. I mean you've already shared one example, Pam, that we made the decision back in 2020 to invest in the next-generation repellant, and we see the first approvals in 2025. So we really needed to start that early. As I mentioned before, with one of our new cardiovascular medicines that we started to work on immediately from in-licensing that medicine, to reduce the complicated process steps, take out solvents and take out carbon in the manufacturing process so that eventually, when it gets to market, it will be a much lower emission product and also a lower cost to manufacture.

In our labs, we adopt a circular approach to solvent use. We collect, purify and reuse these materials, and we know that, that reduces significantly the CO2 impact. In fact, just with recycling our solvents in our labs, we've removed a similar amount of carbon to removing 169 cars from the road. Early on, we use flow chemistry rather than making drugs in large batches, chemicals move through a continuous process that's more energy efficient and enables actually more precise processing. We use a technique called biocatalysis, which uses natural and biodegradable enzymes to speed up chemical reactions, which allows for a single step route to a desired molecule that might normally require multiple synthesis steps. So our scientists are extremely engaged to look at these efficiencies and minimize resource use and result in carbon impact.

I spoke to you earlier about the new technology, the CDC or the continuous direct compression. I mean this was something that was started to be developed several years ago, and we know that these enhancements in manufacturing process need to be worked through several years in advance. As a final example, in terms of packaging types, we need to start very early here with developing new packaging types as our medicines often have long development and regulatory lead times. And we often need to invest in new line structure and line tooling.

So for example, we're now working on a non-PVC recyclable polypropylene blister material for several upcoming launches, which will allow future blister materials to be safely recycled when eventually they are available to patients. So you can see that we think about this very early in the development process and our scientists across the company are engaged very actively in how we can make our future portfolio more sustainable. Hand back to you...

Yes. So thank you so much, Liz. It looks like we're running out of time. We can talk about this for a lot longer. But let me close by saying that we really, really believe that sustainability is good for business. And hopefully, you have seen from the many examples that we've talked about over the past 45 minutes that embedding sustainability in our business strategy really creates shareholder value. And at the same time, it's good for the people, the society and the planet. Thank you very much. Phil, over to you.

That's great. Thank you so much to Pam, Liz and Stefan for your time today. And thanks to everyone who's joined the call. And to those -- a few of you who've got questions that we didn't have time to get around to, I will follow up with you afterwards. And for anyone who has any further questions on our sustainability strategy and goals, then you can reach out to the Investor Relations team here at AstraZeneca. Goodbye.

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.