Thank you, operator. I'm Andy Barnett, Head of Investor Relations at AstraZeneca and I'm very pleased to welcome you to AstraZeneca's nine months and third quarter of 2023 conference call.

As usual, all materials presented are available on our website. This slide contains our usual Safe Harbor statement, we will be making comments on our performance using constant exchange rates or CER, core financial numbers and other non-GAAP measures.

And non-GAAP to GAAP reconciliation is contained within the results announcement, numbers used today are in millions of U.S. dollars unless otherwise stated.

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 and address as many questions as we can during the allotted time. Although I'd asked participants to limit the number of questions you asked to allow others a fair chance to participate in the Q&A.

As a reminder to ask a question use that raise a hand function in Zoom. Alternatively, you can use the Q&A button and write your answers.

And with that, Pascal, I will hand it over to you.

Thank you, Andy. Hello, everyone.

Please advance to the next slide. Total revenue in the first nine months of the year increased 5% to $33.8 billion with 15% growth from non-COVID-19 medicines offsetting a $2.9 billion decline in revenue from our COVID-19 medicines.

Core earnings per share increased 17% to $5.80. This increase is reflective of our robust company performance, our financial discipline, as well as again in other operating income that we announced with our half-year results.

We continue to benefit from our diverse commercial portfolio in our broad global footprint. Given our confidence in the remainder of the year, we have upgraded our 2023 guidance.

We now anticipate total revenue ex COVID to increase by low teens percentage and core EPS to increase by low double-digit to low teens percentage. Aradhana will provide more details on our financials shortly.

Next slide please. Taking a closer look at the performance of our non-COVID revenue across our regions and disease areas, we saw double digit growth in the U.S.

and Europe in the period, reflecting strong demand for medicines and continued commercial execution. Our growth in the emerging market continues to impress, particularly outside of China, which was up 37% in the year-to-date.

This sustained growth underscores our confidence that these markets will become increasingly important for our company. On the right-hand side of this slide, you will see that we delivered a robust double-digit growth across oncology, CVRM and rare disease.

And as expected, we saw declines in V&I. R&I medicines grow more than compensated for the impact of January competition to Symbicort, launched in the U.S.

during the third quarter. We saw a reduction in promotional activities in China in Q3, which created some demand softness for certain medicines in the quarter, but have already seen recovery beginning in October.

We remain confident in delivering our total revenue guidance for China for the full year, which we have graded with our half year results. Please move to the next slide.

And like many of our peers, we have a relatively low exposure to patent expiries. We have a broad diverse portfolio of commercialized medicines.

And we have an industry leading late-stage pipeline which includes several high potential assets. However, our vision is not short-term, we also striving to deliver sustainable industry-leading goals for many years to come.

And while we are maintaining a focus on discovering new small and large molecules, we have taken a strategic decision to increase investment behind new modalities that we believe have the potential to revolutionize outcomes for patients. With IDC portfolio, we are aiming to replace the use of traditional chemotherapy across the board.

Combinations of our ADCs with our next generation IO BISPECIFICS portfolio offers the promise of more durable benefits for patients with improved tolerability. We are pioneering new modalities such as epigenetics, oligonucleotides and RNA therapies to unlock entirely new treatment approaches.

And we are excited by the curative potential of cell engine therapies. I'm pleased with the progress we're making in each of these areas, and I look forward to sharing updates with you over the coming years.

With that, please advance to the next slide and I will hand over to Aradhana who will take you through our financials and also provide a closer look at how we're leveraging AI in the commercial part of our company.

Thank you, Pascal. Please advance to the next slide.

As usual, I will start with our reported P&L. As Pascal highlighted, total revenue increased by 5% in the first nine months, and product sales increased by 4% at constant exchange rates.

Excluding COVID-19 medicines, total revenue and product sales increased by 15%. Alliance revenue of $1 billion was driven by increased and HER2 profit sharing from geographies where : Daiichi Sanky books product sales.

As a reminder, Daiichi will book product sales in the U.S. and many European countries.

Please advance to the next slide. Looking at our core P&L, we saw the product sales gross margin increase by two percentage points to 82.4% driven by lower COVID sales compared to the prior year.

We anticipate a lower gross margin in the fourth quarter driven by higher FluMist sales, which has a very low gross margin. Beyfortus which we supplied to Sanofi also has a dilutive impact on our product sales gross margins.

Over time, the gross margin percentage will be diluted by both increased profit sharing for partner products such Tezspire and Enhertu in territories where we book revenue and higher emerging market revenue, partly offset by favorable product sales mix. Our core operating expenses increased 7% over the period.

Similar to previous years, we expect a step-up in absolute cost in the fourth quarter driven by SG&A spend phasing and the number of new Phase III starts. For the full year, we anticipate operating expenses around the upper end of our previous indication of low to mid-single digit increase, driven by continued investment in our business to support the strong top-line growth seen into year end.

Core EPS of $5.80 represents a CER growth of 17%. Next slide please.

Our cash flow continues to improve and net debt decrease in the quarter to $23.4 billion despite an interim dividend payment of $1.5 billion. Our net debt to EBITDA now stands at 1.7x with the Alexion fair value inventory adjustment now behind us.

Turning to our full year guidance, we now anticipate total revenue to increase by a mid-single digit percentage up from previously low to mid-single digit. Excluding COVID-19 medicines, we now anticipate a growth in the low teens percentage range.

For core EPS, we now anticipate to grow by a low double-digit to low teens percentage, which is an upgrade versus prior guidance of a high single digit to low double digit percentage increase. Based on current FX rates, we anticipate a low single digit adverse FX impact on total revenue.

For core EPS, we now anticipate a mid-single digit adverse impact on core EPS, which is a change versus last quarter reflecting current FX rates. Please advance to the next slide.

Our capital allocation priorities remain unchanged. The number one priority is to reinvest in the business.

By the end of the year, we will have started more Phase III trials than in prior years. Our high R&D productivity will also impact SG&A costs as we will have a number of new products to launch in the coming year including Airsupra in the U.S.

and [indiscernible] and also preparation for potential new launches of Dato-DXd following the positive data presented at ESMO, just a couple of weeks ago. We're continuing to expand Alexion rare disease products into more international markets, now present in 64 countries.

Many of the new modalities we're investing in, as well as the growth in our portfolio will require further investment in CapEx. In addition, we're investing in our manufacturing network, optimizing our global footprint and investing in upgrading our systems.

We also remain focused on value enhancing business development, where we believe we can best leverage our R&D and commercial capabilities. We have done a number of deals this year including CinCor and Neogene and today with Eccogene and we will continue to do so where and when we see attractive opportunities.

We have also a number of successful partnerships including with Daiichi on HER2 and Dato and Merck, Lynparza and Ionis on Eplontersen. Overall, we will continue to invest to support growth, drive innovation, and bring innovative medicines to patients quicker.

Please advance to the next slide. Continuing our commitment to showcase the use of AI across our business, in prior calls.

I've covered some examples of the use in R&D and manufacturing operations. Today I'll highlight the use of AI and advanced analytics to drive faster decision-making with a commercial organization.

Starting first with data and analytics, our in-house proprietary platform, called AZ Brain analyzes multiple large data sets, enriching the data to correct for inaccuracies, duplication and data gaps to generate actionable insights. Next, we leverage AI to improve patient diagnosis and personalized treatment approaches.

Even today, roughly 6% of EMR data is still unstructured application of novel technology to lung cancer screening enabled analysis of over 6 million handwritten documents in just one-day and led to over 25,000 high risk patients being reassessed. We plan to scale this technology to additional health systems and tumor types, including breast cancer.

We also apply large multimodal data sets to our clinical trials to help identify the right patient population for trials and to deliver more personalized precision medicines and improve the success rate of our studies. Finally, we're using AI and predictive analytics to inform more precise, tailored engagements with physicians using the preferred communication channel at a time when they're most likely to engage with potentially eligible patients.

Our investments in AI have yielded important actionable insights into how we can continue to best serve our patients globally. And with that, please advance to the next slide and I will hand over to Dave.

Thank you, Aradhana. Next slide please.

Oncology delivered solid performance in the year-to-date period with total revenues of over $13.5 billion, an increase of 20% versus the prior year driven by strong global demand, reinforcing both the value of our portfolio as well as the continued execution by our global teams. Turning now to our key medicines, in the third quarter Tagrisso global revenues grew 6% fueled by continued demand for ADAURA and FLAURA.

In China we saw some market impact from the anti-corruption campaign but we have already observed recovery into the fourth quarter Lynparza delivered 8% product sales growth in the third quarter driven by double-digit growth and establish rest of world and emerging markets. Lynparza extended its leadership position in the PARP inhibitor class globally, despite decreasing class use and the second line label restriction in ovarian cancer in the United States.

We continue to accelerate our IO portfolio with a competitive class in the third quarter. Imfinzi total revenues inclusive of Imjudo delivered 54% growth driven by new launches.

Calquence total revenues increased 15% driven both by expanded access in Europe and demand growth globally. Enhertu total revenues of $339 million in the third quarter increased 86% year-on-year and in the U.S.

Enhertu new patients share and Enhertu positive metastatic breast cancer and Enhertu low post chemo metastatic breast cancer remain above 50%. We continue to see strong demand growth globally particularly in European markets driven by recent launches of DESTINY-Breast03 and DESTINY-Breast04.

In the quarter, Enhertu became the first antibody drug conjugate approved for lung cancer in Europe and Japan. And we received approval for Calquence in China.

At ESMO, we presented updated FLAURA2 data, which Susan will cover shortly and we're excited to have been granted priority review for FLAURA2 in the United States. We also received FDA acceptance for a GN.

These two important potential treatment regimens advance our ambitions in lung cancer. Next slide please.

Looking ahead, we're well positioned within our oncology portfolio, focusing on two medicines and increasingly competitive markets Tagrisso and Calquence. We are confident and sustained leadership and future growth.

We're well on our way to establishing Tagrisso at every stage for patients with EGFR mutated, non-small cell lung cancer supported by its best-in-class, once daily oral regimen and leading benefit risk profile. With ADAURA, we have the opportunity to further accelerate testing, referral and treatment rates in the resectable setting and to expand access through global reimbursements.

The LAURA trial anticipated to read out in the first half of next year presents the opportunity to leverage our existing presence in unresectable stage three with specific and offer targeted therapy for EGFR mutated patients. Next in the frontline metastatic setting, we continue to see increased real-world duration of treatment driven by patients gaining sustained benefit on Tagrisso monotherapy.

FLAURA2 represents the opportunity to build on FLAURA, further extending duration of treatment and offering a best-in-class option for the subset of patients that may require more intensive treatment upfront. Novel lifecycle management and combination opportunities allow for continued reinforcement of Tagrisso is the backbone TKI of choice in non-small cell lung cancer.

Calquence remains the leading BTK inhibitor across all indications in the face of increasing class competition. And we've seen clear recovery in the relapsed refractory setting.

Going forward, we're confident Calquence will continue to maintain leadership globally, despite increased competitive pressures, reinforced by strong efficacy and differentiated safety. With that, please advance to the next slide.

And I'll hand over to Susan to cover key R&D highlights in the quarter.

Thank you, Dave. Over the past quarter, we've had a significant presence at key oncology congresses, including the World Conference on lung cancer and ESMO.

We continue to consolidate our leadership position in lung cancer with data from FLAURA2 unveiled at World Congress in lung cancer. These data demonstrated that Tagrisso plus chemotherapy extended the median progression free survival by nine months compared to Tagrisso alone in patients with first line EGFR mutated non-small cell lung cancer.

This is the longest median PFS that's been seen to-date in the setting. Further data to ESMO underscore the critical importance this regimen has for patients with the greatest unmet need, including those with CNS metastases at diagnosis.

In these patients Tagrisso plus chemotherapy resulted in more than 50% complete responses. FLAURA2 reinforces Tagrisso as the background therapy in EGFR mutated lung cancer, and the data have now been published in the New England Journal of Medicine.

At ESMO, we expanded on our footprint in gynecological cancers with presentation of the DUO-E data. This trial is the first to show increased benefit of combining both an immune checkpoint inhibitor and PARP inhibitor in the first-line advanced endometrial cancer setting and demonstrated a deeper benefit with Lynparza in the proficient MMR and PD-L1 positive populations.

We are in discussions with regulatory agencies around plan submission. We also had the first two positive Phase III presentations for Dato-DXd, with data from both TROPION-Lung01 and TROPION-Breast01 presented at ESMO.

These underscore its potential to replace backbone chemotherapy in these settings, with both trials demonstrating the clear efficacy improvement of Dato-DXd versus conventional chemotherapy, together with an improved safety profile. Dato-DXd best-in-class profile opens up future opportunities, the combination with both IO and platinum chemotherapy and builds confidence that its potential in earlier lines and other tumor types.

We're moving to filing in both lung and breast cancer. Next slide please.

Our bispecific portfolio is designed to display this current standard of care immune checkpoint inhibition. These molecules are engineered to simultaneously inhibit two immune checkpoints eliciting different biological effects compared with existing concurrent combinations.

And early data suggests potential both as monotherapy and in combination with existing treatments, such as chemotherapy. We're also combining our bispecifics with our ADC portfolio in Phase II trials.

We are encouraged by the early data for volrustomig our PD-1, CTLA-4 bispecific. In first-line advance lung cancer, volrustomig 750 milligrams plus chemotherapy resulted in similar objective response rate as the higher 1500 milligram dose with improved tolerability.

In Treatment naive advanced renal cell carcinoma data at ESMO demonstrated deep and durable responses at the 750 milligram dose, with a response rate of 48%, a complete response rate of 10% and a 12-month progression free survival rate of 52%. Again, we saw improved tolerability compared to the higher 1500 milligram dose.

Patients with PD-L1 low lung cancer remain a group of high unmet need. And we continue to see that current PD-1 and PD-L1 agents have more limited benefit, even when combined with chemotherapy within this patient population.

Previous data such as those from our Phase III POSEIDON trial of Imfinzi + Imjudo, demonstrate that CTLA-4 inhibition can improve the benefit in this group. This is the basis for our Phase III trial eVOLVE-Lung02 which investigate whether volrustomig plus chemotherapy can improve outcomes versus standard of care pembrolizumab plus chemotherapy.

eVOLVE-Lung02, is just one of the four bispecific trials we've announced this year with two others for volrustomig and one for rilvegostomig. Next slide please.

Our industry leading ADC development program continues to move at pace with five wholly-owned antibody drug conjugates now in the clinic, and many more in preclinical development. Recent data shared at the ASCO virtual plenary illustrates the potential of our Claudin 18.2 directed antibody drug conjugate.

Patients with Claudin 18.2 positive gastric or gastro esophageal cancer treated with AZD0901 showed an encouraging 33% confirmed response rate and a medium progression free survival of around five months. Claudin 18.2 is highly expressed in 50% to 60% of gastric cancers.

AZD0901 has potential to build on the important data we've already delivered with Enhertu in HER2 positive gastric cancer and the emerging data from MATTERHORN for imfinzi in resectable gastric cancer, thus accelerating our leadership in GI cancers. Next slide please.

Finally, I want to touch on our expanding presence in cell therapy. We now have three CAR-T's in development, all of which include our transforming growth factor receptor beta [indiscernible] armouring.

This armouring is designed to resist the immune suppressive tumor microenvironment and enhance the potential effectiveness in solid tumors. We've seen encouraging data in humans with our GPC3 [CAR-T] [ph] AZD7003 which demonstrates that this armouring is likely important for CAR-T persistence when compared to other CAR-T's targeting GPC3 without armouring.

We're also exploring the potential of our T cell receptor therapies following the acquisition of Neogene Therapeutics. TCR-T's are an emerging modality that enable the identification of intracellular targets unlocking biology that was previously inaccessible by cell therapy.

Neogene already have three open INDs, two of which have moved into clinical development. Finally, we recently announced our collaboration and investment agreement with Cellectis.

This collaboration leverages the Cellectis talent technology, which has been successfully used in the clinic to solve key challenges with allogeneic CAR-Ts and can precisely edit the genome in vivo to target the source of the genetically defined disease or tumor. We believe this collaboration will accelerate our development pipeline and unlock new ways to precisely target a broader range of cancers, as well as other types of disease.

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

Thank you, Susan. Next slide please.

Biopharmaceuticals delivered total revenue of $13.6 billion in the first nine months of 2023 driven by growth of 19% in CVRM and 9% in R&I. Key highlights from the quarter included another record breaking performance of Farxiga, now annualizing at more than $6 billion per year.

Farxiga is truly a global brand with double-digit growth across all our main regions, and the fastest expansion coming from emerging markets outside of China. In R&I, revenue growth from launches has more than offset the impact of generic competition for Symbicort in the United States.

Emerging markets continues to generate strong growth, particularly for inhaled products, such as Breztri, which grew by 69% in the quarter. And in V&I, the first commercial sales of Beyfortus generated $67 million of product sales and aligns revenue for AstraZeneca.

And we also received our final regulatory milestone from our partners Sanofi following approval by the FDA. Next slide, please.

We continue to invest in long-term research that can change clinical practices and differentiate our medicines and this is a particularly important part of our growth strategy for R&I with its portfolio of relatively young and fast growing medicines, with many years of extra liquidity remaining combined the key medicines that will drive R&I revenues grew by 42% year-on-year in quarter three. This has been driven by a combination of class expansion for modern biological medicines, and inhale therapies and our share gains within those growing markets.

On the slide here we have one example. Tezspire has quickly established a leading share in the first year of its launch in countries such as Germany and Japan.

In other examples, Breztri is now the fastest growing medicine within the triple therapy class. And Fasenra remains the leading biologic for severe eosinophilic asthma.

We anticipate continuous growth for Fasenra, following recent positive readouts from MANDARA trial in EGPA, and the MIRACLE trial for severe eosinophilic asthma in China. The growth in our four key R&I medicines has more than offset the impact of generics on all the medicines, and they now make up nearly half of the therapy area's total revenue.

And of course, we look forward to adding a fifth new medicine to this list, when Airsupra launches in 2024. In CVRM, Farxiga maintained its position as the fundamental treatments in heart failure and CKD, and it continues to broaden its use among physicians.

One of the drivers behind its recent growth has been the increase in diagnosis rates for CKD. Early diagnosis is an important factor for improving outcomes for patients.

And we hope to see this trend continue with more patients being identified at the earliest stage of the disease. Like R&I, our CVRM portfolio is evolving in a way that can generate long-term sustainable growth and after today's blockbuster products inevitably reach the end of the exclusivity period.

Our cohort of developing medicines includes [indiscernible] for ATTR, and a PDUFA date for our ATTR-PN submission is in quarter four. Assuming approval, we expect to launch that indication in early 2024.

We're also developing novel molecules that target hyperkalemia, high proteinuria, and hypertension. These are areas of high unmet medical needs in patients with heart failure and CKD.

For further details of the progress of those programs, I will now hand it over to Sharon.

Thanks, Rudd. Next slide please.

I'm delighted to be joining my first quarterly call in my new role and would first like to thank Mene and the teams for your continued support and for helping me settle in. In the third quarter we made significant progress on our fixed dose combinations with Farxiga or dapagliflozin which address pockets of high unmet medical need and where we aim to show significant benefit versus standard of care.

Balcinerone is our selective mineralocorticoid receptor modulator and in combination with Dapagliflozin, we see opportunity to see lower rates of hyperkalemia in heart failure patients with chronic kidney disease. Preclinical data has shown a separation of organ protective effects from acute effects on electrolytes, which predicts a reduced hyperkalemia risk.

The Phase IIb miracle trial aims to confirm the additive benefits of both balcinerone combined with dapagliflozin, and we will have beta later this year. We have shown significant benefits of zibotentan, our selective endothelin receptor antagonist in combination with dapagliflozin and improving fluid dynamics and reducing the risk of adverse kidney events.

We presented data from our Phase IIb venous CKD trial at the American Society of Nephrology, which I will cover in the next slide. And finally, we are in advanced stages of planning Phase III trials for baxdrostat monotherapy in patients with treatment resistant, uncontrolled hypertension, and in combination with dapagliflozin for patients with CKD and hypertension.

Baxdrostat has been shown to be effective at reducing systolic blood pressure without off target inhibition of cortisol synthesis. This treatment paradigm would offer a much-needed option for patients with CKD and hypertension.

We have already initiated a Phase III trial for zibotentan and dapagliflozin, with plans to initiate baxdrostat monotherapy by the end of the year. We are also in advanced stages of planning Phase III trials for the other two combinations.

Our ambition is to develop these four potential new medicines to extend Cardiorenal protection while addressing specific symptoms of disease. Next slide, please.

Data from the Phase II ZENITH CKD trial investigating zibotentan and dapagliflozin in patients with CKD and residual high proteinuria showed clear benefit in reducing the urine albumin creatinine ratio, a key indicator for kidney function. Zibotentan improves fluid dynamics and reduces the risk of adverse kidney events.

When combined with dapagliflozin's ability to reduce extra vascular volume, these two medicines have been shown to provide significant benefit over endothelin receptor antagonists alone, where fluid retention has been a barrier to uptake. The complementary mechanisms deliver superior efficacy and acceptable tolerability both doses were well-tolerated and offer benefits across glomerular filtration rates supporting our path to Phase III.

On the right-hand side, our IL-33 inhibitor tozorakimab has proven ability to inhibit dual pathways ST2 and RAGE/EGFR. This is important as these independent pathways are involved in different inflammatory cascades.

Dysregulation of ST2 pathway drive airway inflammation, while dysregulation of RAGE/EGFR pathway is linked to epithelial remodeling and mucus overproduction, hallmarks of chronic lung diseases. This September data was presented from the Core 2 trial for patients hospitalized with COVID-19.

Patients receiving tozorakimab had a substantially lower risk of respiratory failure or death at day 29 versus standard of care alone. These data build confidence in tozorakimab and its mechanism of action and inflammatory lung diseases.

The recently dosed MIRANDA trial updates the range of doses being investigated across our COPD program, which includes the ongoing Oberon and Titania Phase III trials. We will have data from our Phase II FRONTIER-3 trial in asthma, as well as FRONTIER-4 in COPD, which we hope to present in due course.

Please advance to the next slide. As announced this morning, we have licensed and oral glucagon like peptide one receptor agonist for the treatment of obesity, Type 2 diabetes and other cardiovascular, renal and metabolic diseases.

ECC5004 is a once daily, oral small molecule, and preliminary results have shown a potentially differentiated clinical profile. Obesity is a significant and growing market.

With over 1 billion patients living with obesity today. The majority of these patients are suffering with comorbidities such as Type 2 diabetes, heart failure, hypertension, and renal disease.

We are well placed to address the spectrum of disease associated with obesity with potential oral combinations in our existing and pipeline medicines. For example, we have recently seen data on our oral PCSK9 where the product profile is in line with our expectations and is differentiated with limited food interactions.

We are excited about the opportunity for a monotherapy and dyslipidemia as well as in combination with ECC5004. We are building a robust portfolio of novel medicines to address a broad range of cardiovascular, renal and metabolic diseases.

Please move to the next slide and I will now hand over to Mark who will cover our Rare Disease portfolio.

Thank you, Sharon. Can we go to next slide please.

Rare Disease delivered total revenue of $5.8 billion in the first nine months of 2023 at 12% year-over-year, driven by increased patient demand and new launches globally. Ultomiris grew 49% in the third quarter driven by patient demand, particularly patient naive to go on the treatment in generalized myasthenia gravis as well as successful conversion on Soliris across all indications.

As a consequence of this conversion dynamic, Soliris declined 12%. [Indiscernible], both Strensiq and Koselugo grew 21% and 81% respectively, reflecting strong underlying patient demand.

Looking at the regional breakdown in the middle, I want to highlight the performance of emerging markets, which grew 70% in the quarter. Global expansion is an important part of our strategy and we continue to benefit significantly from the AstraZeneca footprint.

We have now launched in 64 countries globally, are on track to delivering on our ambition to reach 100 countries by 2030. Lastly, I wanted to provide some context regarding our C5 franchise across neurological diseases, myasthenia gravis as well as NMOSD, as well as [indiscernible] disease atypical HUS, and PNH.

We continue to see neurology indication grow as launch is continued globally. And in the case of mg, the patient population is significantly larger [indiscernible] rare diseases.

The pie chart on the right panel, they represent revenues in the U.S., whereas the two other panels show global sales. Please advance to the next slide.

Last week, we presented Phase II data at the American Society of Nephrology demonstrating the clinically meaningful efficacy of Ultomiris in IgA Nephropathy. Ultomiris demonstrated rapid, complete and sustained complement inhibition characterized by significant and potentially disease modifying reduction in proteinuria from week four, as well as a stable mean glomerular filtration rate over 26 weeks.

IgA Nephropathy is characterized by the deposition of immune complexes in the kidney that activates the complement system, which then triggers inflammation, and causes glomerular damage. At the most prevalent, primary glomerular disease relative to other rare disease in the renal area, IgA Nephropathy is associated with substantial morbidity and mortality with approximately half of patients experiencing end stage kidney disease or death.

We see the opportunity for Ultomiris as an add on therapy to patient optimize on standard of care renin-angiotensin-aldosterone system inhibitors, and SDLT2. This data not only affirms the whole of complement intergenic property, it provides confidence for Phase III, but also accelerates our ambition to expand Ultomiris into additional indication and border patient population.

With that, please advance to the next slide. And I will hand over the call back to Pascal for his closing remarks.

Thank you, Mark. Next slide please.

I spoke at the start of this call about how we are building a pipeline for the future. And our aim to deliver sustainable industry leading roles for the long term.

Our recent acquisition and partnership with Eccogene is a good example of this, where we hope to deliver differentiated treatment for patients not only addressing obesity, but developing combinations with other small molecule for a broad range of cardiovascular renal, metabolic diseases. In the near term, we have a rich catalyst pass with more than 20 Phase III studies due to read out before the end of 2024.

On this slide, I've called out just a few, these include LAURA, which Dave spoke to earlier and DESTINY-Breast06 which has the potential to bring in HER2 one line earlier for the treatment of hormone receptor positive breast cancer, as well as answer the question about HER2-low expression can be for patients still to have meaningful benefit from this important medicine. We should also see the first Phase III results of anselamimab in light chain amyloidosis, and a WAYPOINT trial investigating Tezspire for the treatment of chronic rhinosinusitis with nasal polyps.

Dato-DXd will be an important medicine in our portfolio and we're investing heavily behind this medicine. TROPION-Breast02 will be the next Phase III study for Date in TNBC.

This is thought to be highly responsible to top two directed therapies. Before concluding I would like to welcome Sharon to this call and say how happy I am to have Sharon on Board in our senior executive team.

And I also want to thank Mene for his contributions over many, many years. And with that, I will hand back to Andy and we'll move to the Q&A.

Thank you, Pascal. We will now go to the Q&A with all of our executive members participants shown here.

As a reminder, you can raise your hand on Zoom or type your questions in via the Q&A button. We'll try and answer as many questions as we can during the allotted time.

But please do limit the number of questions you ask to allow others a fair chance to participate. And with that, we'll move to the Q&A and the first question.

Okay. Thanks, Andy.

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

Two questions to the extent that the oral GLP-1 will be developed as a monotherapy for obesity. Should that suggest to us that AstraZeneca believes obesity is a therapeutic opportunity that is here to stay.

And we are in the early innings despite access and other challenges that it may present. And secondly, apologies if I missed it, but longer term financial targets both total revenue growth and margin guidance.

Is that still intact? Thank you.

Thanks, Dave. So maybe Ruud could take the first question.

And, Sharon, if you want to add anything step in, and then the next one will be another favorite question.

Yes, of course. Thank you so much, Steve, for the question.

Yes, it's obvious that we believe that obesity is here to stay. I think in the prepared remarks of Sharon, she was alluding to the very substantial number of 1 billion people around the world are suffering from overweight.

More importantly, we truly believe that is a unique opportunity not only to help patients to lose weight, but also to help the cardio metabolic disorders associated with overweight. And I think we are in a unique position based on our broad portfolio of products.

Of course, a lot of focus on Farxiga, but many other products in our portfolio, which makes it relatively easy to combine this new licensing of the GLP-1 with other products like an oral PCSK9. We're very pleased to see the first results coming out of our R&D pipeline, and hopefully in the near future, you will see those results.

So it makes it very attractive for combination products as well.

Steve on your second question, I think the long-term investment thesis remains very much intact. So we've talked about the growth, ambition that we have a sort of in that '21 to '25 timeframe and you've seen us deliver on a double-digit CAGR.

So that remains intact. And then, post 2025 to 2030, we've said we would be -- we would have industry leading top line growth.

And what you see today in the pipeline, whether it's the proprietary ADCs, or the bispecifics, or some of the new readouts on studies, I think all of that points to or confidence in that growth rate in the 2025 to 30 timeframe. As it relates to operating margins, that continues to be a focus for the company.

And, again, we've not given guidance on that is our ambition. And we continue to improve on our operating margins, as we continue to invest in a new product launches and a new Phase III studies.

The next question is Gonzalo Artiach at ABG. Over to you, Gonzalo.

Thank you very much for taking my questions. Gonzalo Artiach from ABG Sundal Collier.

The first one is regarding the new drug candidate for diabetes and obesity license from Eccogene. And this licensing has been announced with quite excitement today.

So could you give us some color on what are the key points on the drug candidate that you consider more interesting to potentially position the small molecule best-in-class specifically given the fact that you have already an Amylin analog in development? And my second question is on the results from [indiscernible] on the EMERALD-1 study?

I don't know if you could give us some color here on the plans going forward for this indication? Are you planning to file a PFS results, or will you wait for OS?

And also if I'm not wrong, the study had a third arm of Imfinzi combined with base only without Bevacizumab, which is not reported in the press release today. So I don't know if you could comment on that too.

Thank you so much.

Thanks, Gonzalo. So maybe Sharon, you could take the first one and Suzanne, the same old question.

Sure. I'd love to and thank you for the question.

I think you heard the excitement in my voice as we talked about the in-licensing of ECC5004, which we think is a best-in-class, orally bioavailable GLP-1 receptor agonist. And we are excited about what we view as a differentiated clinical profile for this molecule.

It demonstrates greater tolerability than other molecules in the class with a lower reported rate of Gi adverse events. We also believe that it has a simplified CMC path with a relative lower COGS relative to the competitors.

And we have seen efficacy on par with competitors in this class, which we think will allow us to deliver an ideal target product profile to patients. Sure.

So as you mentioned, also in our portfolio, we have a long acting [indiscernible] as well as a GLP-1R glucagon dual agonist. So we are targeting both incretin and non-incretin pathways as we identify a robust cardio metabolic profile that we think will serve the complexity of disease.

Thank you, Susan.

Yes. So [indiscernible] as you say a three-arm study 600 patients were randomized to taste alone plus placebo, taste plus Imfinzi and then taste plus Imfinzi plus Bevacizumab.

So it's a local regional habitus cellular carcinoma. And it's exciting that this is the first positive Phase III study in this setting.

I would say to your question about the Imfinzi plus taste arm of course, it's important for us to show the potential for contribution of components. And in terms of your question on filing on PFS, so we're excited that what we've got is a clinically meaningful improvement in progression free survival.

But given this is a local regional setting, it's always important to have data on overall survival. So as is typical, what we will do is, we'll discuss with regulatory authorities, it may well be possible to file on PFS and then wait for OS to be supplemented during the follow up period and during the review period.

Thank you, Susan. The next question is from Andrew Baum, Citi.

First to Sharon. Could you quantify and characterize any liver enzyme elevations you saw in the Phase I with ECC5004?

And then second for Ruud with the removal of the AMP cap from Medicaid in 2024, could you quantify for us the net impact on your revenues associated once you've taken out mitigating defensive measures? Many thanks.

Sure. So I'll jump in with the answer regarding liver toxicity and ECC5004.

In preclinical studies, we saw no evidence of liver toxicity. And in the clinical Phase I study today we have seen no evidence of elevated ALT or AST, which we think is an additional feature that helps us differentiate this molecule from other competitors in the class.

So I will take the second one, Pascal. So regarding your question, Andrew, about the impact of AMP cap, you have seen in the presentation of Pascal, that we are very pleased with the very strong U.S.

growth. And that's primarily driven by volume growth, including Farxiga.

Yes, we are expecting in the impact of AMP cap in 2024. But we have very specific brand strategies in place.

Overall, we think the impact is manageable, and it will be effective in the guidance we're going to give for 2024.

Thank you, Ruud. Our next question is from Sachin Jain with Bank of America.

I have a couple for Dave and then one for Aradhana. So Dave, half of assertive launched from the end of this year.

It's not an asset you talk about much. I wonder if you could just comment your optimism for the assets and size of the initial indication.

Secondly, on [indiscernible], wonder if you could flash out the comments on the slowdown in the U.S. on the [indiscernible] implications to grow the asset into '24.

And then just one for our Aradhana. And you're not going to like the question, but any early thoughts for '24 growth outlook, consensus has '24 EPS faster than '23.

I'm not asking for guide but just pushes and pulls in the ability to accelerate growth in '24 relative to '23. Thank you.

Great. Sachin, I'm going to take the questions that you asked me just in reverse order.

So if I start first with Enhertu. When we take a look at both DB03 and DB04, we are seeing continued opportunity for growth across the globe on both of those.

On DB04 specifically, we had seen increase or a bolus effect at launch where patients in multiple lines of therapy, so multiple lines of post chemo coming on to Enhertu just really due to a lack of options for patients in these later line advanced stages. What I'm pleased to say and I think this is actually a really important aspect of Enhertu, the duration of therapy that those patients were able to stay on Enhertu was actually longer than we had even thought.

So the bolus actually has been around if you will as part of the TRXs for a longer period of time than we had originally anticipated it might be. We continue to see nice growth and now the incident share, so I think the DB04 continues to grow and we'll be moving based upon growth in two factors, one will be incident new patient share growth but then also DOT which I expect will continue to grow.

That DOT comment if I could just for a second I think also holds for DB03, where you may recall that in 03, we had 18 months of duration of therapy within the study itself. But we know that more than a third of patients were staying on therapy for greater than 24 months.

So we're continuing to see the 03, DOTs extend. And I think that's a positive piece within that.

As we take a look at CAPI, I share enthusiasm that pivot sort of could be a very important part of our breast cancer portfolio. And then perhaps Susan can talk a little bit about some of the thoughts around the CDP, that goes beyond that.

I do think that it's most likely that we will see biomarker labels across the globe, though, we do believe that the benefit in the ITT population was an important one. But there's a pretty significant number of people with breast cancer who can continue to benefit from endocrine based therapies in that advanced setting, and biomarker is still 40% to 50% of that marketplace.

So it's a sizable opportunity. And we are looking forward, hopefully any day now to an FDA announcement and approval.

Before we move to, thanks, Dave. Before we move 2024, maybe Susan, you could comment on other indications that we are considering for CAPI?

Yes, sure. So do you think this is an opportunity in a number of settings where the AKT pathway is important in limiting benefit either in combination with endocrine therapy in both breast and prostate cancer, but also in combination with chemotherapy as well.

So as well as the 291 study, we have CAPItello-290, in triple negative breast cancer, CAPItello-292 is in combination with palbociclib and other CDK 46 inhibitor potential as well as a hormonal therapy backbone in the first line. So it's got Faslodex as the hormone therapy backbone in the first line in CAPItello-292.

And then in prostate cancer, we have CAPItello-281, where capivasertib is combined with Abiraterone. And again, that's focused in p10 deficient hormone sensitive prostate cancer based on the Phase II study there.

But we also have a combination with docetaxel and again, the AKT pathway limits the response to chemotherapy and limits the apoptotic response to chemotherapy. So that's also an important study.

And based on the brocade data set, there's activity again, across the spectrum of patients, both with and without p10 deficiency in that setting.

So thanks for the question. Obviously, we won't give guidance for 2024 on this call.

We'll have to wait for early next year for that. We're actually going through our budget process right now.

And as that concludes, towards the year end, and we present that to the board and then we'll give our guidance next year. Some of the things that, obviously, you need to take into account some of the pushes and pulls in the 2024, and midterm, including currency movements.

As you know, we've had very strong growth momentum with our underlying brands. But then, we also have launches for Airsupra and [indiscernible] that Ruud mentioned that we'll be investing behind.

And then, the Phase III opportunities as well as some of these new BD opportunities, including the current product that we talked about on Eccogene. So lots of moving parts.

And we look forward to talking to you about that in early '24.

Maybe some quick addition to 2024. Actually, going back to the question Andrew asked about, AMP cap, since the announcement of this new regulation, we've really come up with very modest price increases always below inflation.

So of course, the calculation goes back many years, but we still believe that we will have an impact that is substantially lower than many other companies. And as I've said it can be certainly managed in the overall forecasting budget, forecasting for the company.

So the next question is Tim Anderson, Bernstein.

Couple questions on, Tagrisso FLAURA2 is in the New England Journal last night editorial fairly positive, based on [indiscernible] benefit, but really said it kind of comes down to how survival plays out. So the question for you is, your view on whether it hits on survival in a clinically meaningful way?

And then, the second question is on obesity. Just further business development from here it seems like if you're going to push into this space, with external assets, like today's announcement, made you go all in and do more external deals, there are other assets out there who take a much broader portfolio approach, or conversely, this was kind of one and done.

This was going to be your main asset from the outside world. Thank you.

Thanks, Tim. So the first question, maybe we could start with Susan.

And then, Dave, I think you could also comment on the commercial relevance of FLAURA2 which we believe is important for many patients. And the second question, Sharon, you could take and anything you want to add, Ruud also please jump in.

So because of key survival benefit that we've seen is very clinically meaningful with FLAURA2. And, of course, the comparator is something that's already proven overall survival benefit in the first line setting of lung cancer, which is monotherapy Tagrisso.

So I think what we're hoping to see is, maintenance of that improvement in PFS being carried through to the PFS 2 and a trend in OS, I think is very reasonable to expect. But, obviously, as the data mature, we'll continue to look at the OS endpoint.

Thanks, Susan. And, Tim, I think maybe just to build off of this, I think there's also an important tangential question just in general around the importance of overall survival as there's consideration for choices.

And I think that you referenced the editorial, I think you hear this in the editorial, but also we hear this from the community as well. That in selecting a treatment, the benefit risk profile inclusive, of course of efficacy, the side effect profile, as well as the administration are all important factors that will come into this.

So within that context, FLAURA2 is certainly something that we have heard very much as an option for those patients who would benefit from intensification brain mets, LA-58r. And on top of that clinicians are pretty well versed in the side effects that are associated with chemo and there's the ability to discontinue the chemo and FLAURA2, if approved and continue on with the monotherapy.

But we also hear and know that the monotherapy is an option that we anticipate will continue to be a really important option for the majority of patients all greater than three years overall survival demonstrated proven and understood in a tolerability profile. That's well managed.

Sure. Thank you for the question about continuing to build our portfolio.

I hope that this morning I'm conveying a story that we continue to build a strong cardiovascular, renal and metabolic portfolio with multiple medicines to treat obesity, Type 2 diabetes, dyslipidemia, hypertension, chronic kidney disease, and heart failure. So where we see opportunities to further strengthen that portfolio, we will move forward with a sense of urgency.

We never comment on business development deals that are in progress or future opportunities that we continue to scan the landscape and understand what might fit best into this growing portfolio.

Thanks, Sharon. And maybe let me add biopharma cardiovascular in particular remains very important to this company.

And for the little internal friendly competition we have Ruud beat Dave by 100 million in the first nine months of the year. So very important part of the company.

Anything you want to add on.

No. Just to reinforce that, of course, we are excited about our internal pipeline also in obesity.

It was a long-acting MLN, the GLP-1 glucagon dual agonist. But as Sharon said, we're always looking around for something what can add value is making strategically sense.

But all in all, I think we're very pleased with the progress we are making in our pipeline.

All right. Next question is Emily Field at Barclays.

I wanted to ask about the Volrustomig, actually, I saw you started Phase III in cervical and lung and you also had renal data at ESMO. Just how broad of a Phase III program are you intending on running?

How many tumor types? Secondly, when could we see the combination arm from the TL-4 study that combines the Volrustomig with Dato-DXd.

And then my last one, just how much broader in terms of addressable patients with LAURA add to the Tagrisso patient pool. Thank you.

Thank you, Emily. Susan, could you go over the first two Volrustomig questions and Dave, you could address LAURA question.

Yes. So again, I would say that we see the positioning of both Volrustomig and rilvegostomig as being appropriate in different segments of the patient population that are currently treated with checkpoint inhibitors.

So I think Volrustomig has a place where CTLA-4 inhibition, particularly adds value. And those are the areas that we will concentrate on.

I also think there's emerging data from rilvegostomig, which will probably share at congress next year. And again, we please note that we have actually started our first Phase III trial with rilvegostomig building on the great data that we saw with TOPAZ in the biliary tract setting.

So I think there's great potential for this. We are examining both rilvegostomig and Volrustomig combinations with our ADCs in different tumor types.

And we will, again, probably share updates on those in the next 12 to 24 months.

On LAURA, Emily, just in terms of the opportunity here, let me start with the headline, which is I think this is a sizable opportunity and an important chance for us to, if positive and approved, be able to meaningfully catalyze the growth within the area. We know from the specific work that we've done that there's a significant number of patients that are diagnosed that are stage-3 unresectable.

We also know that many of these patients are not getting for very understandable reasons treatment with who are EGFR mutated with IO. And so there's a very good opportunity that's there.

And I think that this will be probably the most significant Tagrisso growth driver that I would see as incremental coming into the near term. And we look forward to next year's read out.

Yes. Important growth driver across the world very much, of course in Japan where this EGFR mutations are coming.

And I think in China also beyond the growth potential also very nice differentiation in the market, as you know, is very, very competitive. The EGFR market is very competitive.

So clearly an important addition from a differentiation viewpoint and promotional opportunity for the Chinese team. Next question is James Gordon, JPMorgan.

First question was on the oral GLP-1. And the question was, do you think the products going to be competitive on weight loss, versus other orals that are well ahead in terms of development?

Or is the differentiation going to be much more about the combinability with other oral agents? And if so, which of the combos is it that you're most excited about?

That's the first question. The second question was RFS-3 I think you started Phase III, MIRANDA, did you do this new high dose carb as you announced in Phase II, in the first two studies over on the [indiscernible], under those or it should be left, and then I think we're going to wait for the third trial?

And then, if I could just [indiscernible], you mentioned potential launch next year, is the expectation about the launch in both the lung and breast cancer so you filed both of those at the end of this year, and launch both of those next year?

Thanks, James. I'm really so happy that I've delegated the task to Andy to ask people to ask only one question at a time.

Maybe, Sharon, you could take the first one, and again, Ruud, if you have anything you want to add? And then, the second one also, actually, and then Susan will take the Dato question.

Yes. Thank you for the questions.

So your first was, do we believe that this ECC5004 is competitive in weight loss? And yes, we do based on the Phase I data that we saw, it lines up very favorably with competitors in this class, which was very encouraging data.

They gave us confidence in our ability to drive forward this molecule and see a differentiated target product profile in the clinic. You also asked about which of the combinations we are most excited about and that's a little bit like asking you to choose a favorite child because we have such a broad portfolio that has the potential to combine with this molecule.

That said, thinking about Farxiga and our ability to manage hypertension driven by obesity is a very appealing combination. Thinking about our emerging oral PCSK9 was very encouraging data in Phase I.

We see an opportunity to limit dyslipidemia while managing obesity in overweight patients. And also thinking about how we're managing diabetes and the associated comorbidities gives us opportunities to also consider other mechanisms for managing heart failure and renal disease in combination with ECC5004.

So we will be testing out this molecule both in preclinical and clinical studies moving forward and identifying the most favorable combinations for patients.

So nothing to add. Are you also going to take the question about [Dato] [ph] or do I need to comment on that?

So James, a good question. Of course, as always, time will tell and the data will tell which dose is the most effective one.

But we truly believe that we have a drug which is effective. The 600 is now tested in the MIRANDA trial.

Let me remind you that also the competition is testing different dosing regimens. And see it also a little bit as an insurance premium.

We think that the 300 will be effective but of course, we try to push the effectiveness to the highest level. So hopefully, both doses will work.

But time will tell when the data will [indiscernible].

Maybe going back to the overall oral GLP-1 James, first of all, one of the two oral agents that maybe you have in mind is a twice a day agent this one will be once a day. And as Sharon explained earlier, we believe that the tolerability profile would be good.

But the important thing to keep in mind is obesity by itself is one thing, but I think the more sustainable part of that market is really obesity, patients with complicating factors. People have cardiac metabolic risk factors.

And so in that scenario, really combinations are critical. I mean, if you look at kidney disease, the Farxiga results are really exciting.

They are great, but patients still see their kidney function decline over time. So we talk about combinations in cancer, but I also think that in many of those cardiovascular metabolic conditions, combination treatment will be the future.

So a combination for kidney disease, combination for the control of hypertension, possibly a combination for -- well, actually a combination for the management of hyperlipidemia. So that's where we believe that our pipeline is best positioned, it can play a role.

So with that, maybe, Dave, do you want to or Susan, maybe cover the Dato question.

Sure. So in the United States, we didn't have to wait for bundling the 2 trials together.

So we will file those two separately. In Europe, it's better to bundle the two applications together.

But I think is a good opportunity depending on the review time lines for the review to be completed during the course of next year.

So the next one is Mattias Häggblom at Handelsbanken.

First with regard to the oral GLP-1, [Technical Difficulty] because I'm asking how long into 24 or perhaps even 25, depending on the duration of that trial, will the upside world have to wait before we can judge today's comments around the different change in profile. And then secondly, [Technical Difficulty] China, where lung cancer patients [indiscernible], whereas for their preference of a monotherapy combination therapy survey which showed a close to 80% preference for the monotherapy regimen despite the combination was set in the service for a long time to recurrence.

So I would be curious to hear if the company has [indiscernible] service based on other geographies. Again, trying to think of the 1 versus combination trials in these setting?

Thanks so much.

Thanks, Mattias. You were breaking up a little bit.

The first question, did you get fully on Sharon, although voice maybe --

It sounds like it was around the timelines for the ECC5004 clinical studies. But maybe if you could repeat the question one more time?

Can you repeat the question, the first one, actually, the second one was FLAURA2 China and 80% preference for monotherapy is it also in other geographies. But the first one, if you could repeat?

Sure. [Technical Difficulty] 2 trials in obesity, it's reasonable to expect the market could judge today's comments that you have a differentiated profile.

We see Phase II trials in obesity short as 5 weeks up to 16 plus. So I'm just trying to frame the expectations for when we can get data of these patients, which we have yet to see.

Okay. Thanks.

So Dave, do you want to take the FLAURA2 question?

Yes, I'd be happy to. I've spoken to the discussions that we've had with physicians, both in the academic but also now, especially within the community setting.

both WCLC and ESMO. And I think that what you see in the editorial is very consistent with what we are hearing across the globe.

And I think that just maybe if I put into context within this, I mean, if you look at the U.S., you've got 70-plus percent of non-small cell lung cancer patients who are with advanced disease being treated in the community. And I think that within that community context, the benefit risk that I had spoken to before of efficacy, oral convenience, tolerability profile that's really well understood and considered to be one that's well able to be managed.

This is something that really does result in the monotherapy being I think really kind of the first port of call, that first real opportunity to look at. We do also know, and I think that this is something that comes through as well in the commentary that there are patients who can benefit from a more intensified approach to it.

And within that context, I think that the editorial and others comment on that within this context, we expect FLAURA2, if approved, to be an option for certain patients that is going to be put on the table, but it's going to be put on the table in the context of multiple criteria for making the decision, not just based upon a single efficacy end point.

Sharon?

Sure. So your question regarding timelines for clinical development for ECC5004, obviously, front of mind for all of us.

Thank you for the question. So as I mentioned earlier, we are in Phase I now, and we expect to have Phase I data in hand by the end of this year.

And so we'll be moving rapidly towards Phase II. We expect to initiate 2 Phase II studies, one in obesity and one in diabetes by the end of 2024.

You are correct that these studies can vary in length, but we really want to be able to generate the outcome data that we think will add value to this program. So we are planning for studies that will span in the neighborhood of 18 months with interim analysis that will give us an early look at the data and will give us some confidence in our differentiation strategy.

Next one is Mark Purcell at Morgan Stanley.

Two questions. The first one is on your bispecific T-cell engagers [indiscernible].

You talked in the press release around the potential to replace first-generation checkpoint inhibitors. So how should we think about the magnitude of benefit you expect to see versus KEYTRUDA, for example, in the EVOLVE [indiscernible] 2 trial.

So what level of superiority are you seeking? And the second one, smart chemotherapy platform, your organic platform [indiscernible], we should get some data, I guess, for assets such as the B7-H4, maybe the EGFR SMA in 2024.

So could you give an update in terms of when we should see these data? And when do you expect to potentially move into pivotal trials with these assets?

Thank you very much.

Thanks, Mark. So I think the first question was the bispecific immune checkpoint inhibitor, Susan, you could take this one.

And the second one is also for you in terms of the B7-H4.

The bispecifics PD-1 that you said T-cell engagers. We do have T cell engagers in our portfolio, but I think we're talking about volrustomig and rilvegostomig.

Volrustomig in terms of the EVOLVE02 study, you can imagine the context of first-line non-small cell lung cancer. A clinically meaningful benefit, is something where you're looking for some months of improvement on median PFS and often an improvement of the hazard ratio with that tail.

And of course, CTLA-4 inhibition is particularly potent producing that tail inhibition. So I can't tell you what the design criteria for the study, but you'll see the size of the study, and I'm sure you can work that out.

But we're confident based on the data that we've seen. We've got the potential to improve on it.

In the patient population where checkpoint inhibitors don't currently work as well, which is clearly that lower end of the PD-L1 expression level. And then for B7-H4 lead ADC.

This is an important molecule for us because, first of all, it's the first molecule that's come out of our proprietary ADC discovery platforms. We've got a proprietary link and topo warhead on that.

You saw some data presented for other B7-H4 targeted ADCs at ESMO. So I think this is going to be an important target.

It's overexpressed in parts of ovarian cancer, endometrial cancer, breast cancer and some biliary tract cancer. We're exploring cohorts in multiple of those cancers, and we look forward to sharing data next year on this.

But we're excited by what we've seen so far. We will, obviously, because there's a competitive landscape over there, we're going to move at pace.

The next one is Eric Le Berrigaud at Stifel.

Two questions, please. First, you're presenting the CAPItello for 2024, probably you pick just a few of those.

So just because SERENA-6 is not on it, just to confirm that it's still on schedule. We're hearing from physicians that it may come quite early and maybe as early as the turn of the year.

So just to get your level of excitement and see that there is no decrease here? The second question is about V&I.

We're hearing a lot about the significant investment to come in CVRM, adding to oncology. And so you made a quick and pragmatic investment here around COVID vaccine and antibody.

How much do Astra need B&I and how much is it a distraction now to oncology, CVRM and rare disease in terms of resource allocation? Thank you.

Thank you, Eric. So maybe Susan, you could take the first one.

So again, we don't guide on interims, the SERENA-6 outcome is currently guided for beyond 2024. I would just say that our core instrument trials overall are going really well, and we're pleased with the investigator feedback we've had from the investigators who are participating in these trials.

Thank you, Susan. So maybe, let me just make a couple of comments, and I could ask is has to jump in.

It is not a distraction. I mean our focus really has been and continues to be on antibodies, and particular antibodies for patients who are immuno-compromised and we work on 3152, and we do believe that there is an unmet need out there that is not addressed and needs to be addressed.

The mortality in patients who are hematology patients, transplant patients, patients who are immunocompromised is very high, actually, 30%, 40% chance of dying if you have a blood cancer and you are infected with COVID. I'm not even talking about being hospitalized, the risk of dying if you're hospitalized, I'm talking about the risk of dying if you are infected.

So this is very high, and there is a need for those patients. In fact, we know many countries are ready to order is 3152 if it works.

So of course, as always, we cannot guarantee success in anything we do. But we believe there is an opportunity for 3152, if it does work.

And we're working on other antibodies. And for vaccines, we have a very focused strategy on new technologies that for now, we really are disclosed because we need more data.

But the 1 thing I would say is that there is actually a synergy with our other activities. If you think of hematology cancer again, doctors, hematologists, they want to protect their patients against COVID, especially during periods of increasing COVID infections.

So for us, it's really a door opener if we have antibody to offer. The door opener the team that is promoting Calquence and the same is true for immune diseases.

So there is a clear commercial strategy. And from a resource viewpoint, overall, it's limited investments in other distraction.

Iskra, if you want to comment a little bit more on where we are and what we do.

Thanks, Pascal, for the comments. So just to add, I think looking beyond the immunocompromise and I think you described unmet need very clearly.

I mean, you can also see an unprecedented demand we see with the ports that we are commercializing together with our partner, Sanofi, and there is a clear unmet need RSV in the infant population. So I really believe that we can build and leverage in our in-house, know-how the building long-acting monoclonal antibody is definitely has a need across the different populations.

And then also, I think, Pascal, as you mentioned, looking at the kind of what is next generation platform and how we can potentially contribute to bringing the new and differentiated vaccine is something that we are constantly focused on. And obviously, I will be very pleased to share more information with you in the due course.

Maybe last point in [indiscernible] was really a different story. It was really to help the world deal with this terrible pandemic.

But outside of this, what we focus on is products where we can actually be differentiated and address an unmet need. And of course, it's true for these antibodies.

On the vaccine side, we would actually only go into large investments if we believe we have something that is truly differentiated. So next one is Richard Parkes at BNP.

Hopefully you can hear me okay. I've got one for Aradhana and one for Susan.

Firstly, for Aradhana. Just on R&D spend, actually as you go into that budgeting negotiation later this year, you've had an incredible number of new Phase III starts this year.

You're also investing in new technology platforms, you managed to keep R&D spend growth to mid-single digits, I think, in the third quarter. So I'm just wondering if you could talk about the moving parts of how that growing pipeline can be funded?

How much of it can be funded through reinvestment as you -- and kind of the previous Phase III trials versus need for a step-up in the R&D spend growth trajectory into next year? I ask the question partly because we've seen other companies with -- surprising investors negatively with a step-up in R&D spend.

So that's the first one. Then secondly, for Susan, I can see you're starting a Phase III of the Part I selective inhibitor in prostate cancer.

But obviously, there's a huge potential for that drug if you can unlock potential for synergy with an ADC, with a DNA damaging payload. So I just wondered if you could talk about your enthusiasm and optimism of that program?

And potential, more broadly, and what we might see, I guess, insight to that -- your plans? Thank you.

In terms of R&D, we obviously go through a very detailed process that is both bottoms-up and top-down. And I think we've obviously said in the past that we expect R&D to be somewhere in the low 20s percentage of revenue, and what that helps us with is actually provide some discipline in terms of which projects to prioritize and so forth.

Also, I would say, as we have started a number of Phase III studies. But when you look at Phase III studies, there's also been a number of studies that we're tapering down or we've read out and so forth.

So it's a constant phase and all the Phase III expense doesn't come necessarily in 1 year, right? It's raised over the entire study period.

We start a number of Phase III studies, for example, this year, but some of that expense, a lot of that expense also goes in study starts, in the site recruitment, in the clinical study supply, et cetera. So I think we manage that and we provide that the top-down discipline, but it's a tough situation.

I think if you asked Mark or Susan or Sharon, they'll always tell me we don't have enough money for all the exciting projects that we have. So -- so we try to maintain that balance.

Thanks, Aradhana. Maybe a couple of additional points.

First of all, beyond the prioritization that Aradhana covered very well and the use of technology to make ourselves more productive, we also have launched and are implementing a redeployment of our footprint. And so we are, for instance, leveraging Canada, Toronto in North America, Barcelona in Europe.

So we are going through a process by which we locate in the strategic centers jobs should be located there. And then we have a nearshore and a far shore strategy, so we are leveraging our sites in Guadalajara and also in India for some roles, so we're doing all sorts of things that help us manage the cost of R&D.

We've been internalizing the conduct of our clinical trials. First of all, we believe that we'll deliver a better execution of our trials if we do it with our own clinical teams, but also, it reduces our cost when we internalize.

So ultimately, we stick to what we said before, which is low 20s R&D on revenues. Some people have said what is [ low 20s ].

If low 20s is low 20s, if we meant more than this, we probably would say mid-20s or something like this. So it's low 20s, and I just want to reconfirm this is our ongoing target.

Yes. Thanks for the question about saruparib, this is another program that I'm really excited about.

I think we've learned a lot about the right patient populations to treat with PARP inhibitors during the development of Lynparza. But saruparib has this improved profile which enables clear improvement and tolerability, enables you to hit the target even harder, and I think that has the potential to lead to actually better efficacy than we see with olaparib.

So it's great to see the first Phase III trial starting, you'll see more coming. And I think one interesting area is the potential for this to have combinations.

So saruparib in combination with ADCs is absolutely something that we're exploring, and we're encouraged by the early data that we've got, but it's a little early to be sharing those externally at the moment. Probably it will be another 12 months before we show those, I'd expect.

Next question is from Christopher Uhde at SEB. Christopher, we can't hear you.

Can you hear me now?

Yes. Perfect.

Go ahead.

All right. Great.

So my first question is for Sharon. Now that you taken over, I think we have a pretty good idea of what the strategy is for CVRM.

Perhaps you could talk a little bit about what the R&I sort of big picture strategy is overall? And in terms of -- so R&D strategy and integrating that with commercial strategy and how to execute on it?

And then my second question is on Farxiga. And maybe here, I'd like to start by congratulating Mene and his team, even though he's not here today, on the successful reoffer of zibotentan.

I guess it's his brain child and arguably the zenith of his achievements at AZ. So a small percentage of patients that are eligible for SGLT2 actually get it across the each approved indication.

Is the NRx split still even across the indicated patient groups and how much gas is left in the tank in the U.S. and EU across those indications?

We've got Dato, MI toplining positively, so how much impact can that have? And beyond it, are there any remaining steps you can take to convince prescribers or payers that a larger proportion of patients should be adding on SGLT2 on top of metformin or statin or BP meds or whatever before you start to bring Farxiga combos into the picture?

So like are the specific patient subgroups, for example? And there's a logical follow-through.

When the SGLT2s lose exclusivity, do you anticipate any substantial step-up in breadth of use, what might that look like? And does that impact how you view the opportunity for the novel Farxiga combo regimens like zibotentan?

So Sharon, R&I?

Yes. So I'm in a very lucky position of stepping into a very strong biopharma organization with a foundation that was built over many years by Mene, and I'm grateful for both the incredible portfolio that was established as well as the extraordinary team of scientific leaders that I have the privilege of working with.

So as we look forward to how we're going to continue to grow and invest in R&I, let's think a little bit about the successes that are already beginning to drive value for the portfolio. So looking towards Saphnelo, we have 3 Phase III studies ready to initiate.

In fact, the DAISY study in sclerosis just dosed, so that's a Phase III study already initiated with 2 more, which we expect to launch early next year. So we're very proud of the potential of Saphnelo, which was put in place through internal discovery and development programs, and we're beginning to see delivery of that promise.

Also, a strong contender in our portfolio is tozorakimab which, as we mentioned earlier, is differentiated for the competitors because it is able to inhibit both the ST2 and the RAGE/EGFR pathways. And so we really see a wonderful opportunity there to target the breadth of respiratory disease and to be able to offer a better outcome for patients.

So as we think about how we continue to build on our success and move forward, as we've mentioned, we're very interested in growing our footprint in treatments for immune-mediated diseases, and this is a continued build within the group as we expand both our capabilities as well as our capacity and we think about the new modalities that will best serve patients moving forward. So we continue to expand our pipeline and to think about what the treatment of the future maybe, and for a hint of the way we are thinking, Susan told you earlier about investments in cell therapy and the promise of those who have demonstrated in oncology.

And we have seen early clinical data published by academic experts who have demonstrated the promise for cell therapy in patients with autoimmune disease, so we'll continue to explore these capabilities and evaluate the potential for that within our portfolio. I hope that gives you some color that will also help us share our excitement and growth in respiratory and immunology.

And let's not forget, before I come to the Farxiga question, there's still a high unmet medical need in our core indications in [indiscernible] despite all the progress we have made in the last few decades, but many patients are still suffering from severe exacerbation, lung damage, so there's still a very big untapped opportunity in those diseases. Coming back to your question regarding the growth potential of Farxiga, it's still very substantial, Christopher.

Just to give you some numbers, currently, almost 1/3 of the new prescriptions are going to Type 2 diabetes, but more than 2/3 are going to CKD and heart failure. And the penetration in those 2 diseases is at the moment, despite all our efforts and also from the competition, is only 15% to 20%.

And hence, there's still a very substantial upside moving forward. Very pleasing to see that most of the guidelines around the world have now adjusted their guidelines and SGLT2 are now one of the fundamental pillars of the treatment of heart failure patients, and the same is true for chronic kidney disease.

So in that sense, the volume opportunity is very substantial. And your question about LOE, and let me reiterate again, we have a very, let's say, fragmented period of LOEs with Farxiga.

2026, the United States, but only 2028 in Europe. And beyond that, we see a very strong growth in emerging markets wherein some of those markets, roughly 10 markets, we have already lost LOE but still the brand is still growing very fast.

So I'm not going to say that there's no impact on LOE, of course, there will be an impact of LOE. But clearly, the combination products hopefully will compensate for that loss in the second part of the decade.

And we remain very bullish about the growth potential of the products let's say, in the next few years.

And Mene is not with us in the room but he is keeping an eye on us, so reminding us that we still have a number of read outs last cycle management opportunities in R&I, with [indiscernible], with Fasenra, with [Toso] [ph], so still quite a lot to come in R&I in particular, respiratory. So we move to the next question, Simon Baker at Redburn.

Can I ask, we only have a few minutes left, so can I ask everybody to ask one question, if you don't mind? Over to you, Simon.

Thanks, Pascal, and I'll behave myself. On -- [indiscernible] questions for you, Susan.

The current use of CTLA-4 is really defined by acceptable levels of toxicity, and if your bispecific is better tolerated, that broadens the scope. I'm specifically thinking about lung cancer and PD-L1 greater than 50%.

If all of Lung02 is focusing on less than 50%, are you planning to look at PD-L1 high as well? Thanks so much.

So I think in the PD-L1 high group, this is the place where at the moment, based on the current data that we have, that the addition of TIGIT seems to make a particular difference in that setting. So we obviously look at the emerging data across our bispecific portfolio, but what we're doing in terms of the initial Phase III trials that you're seeing is focusing on the area where we think get that added benefit from CTLA-4 inhibitor.

It is better tolerated than just any co-administration of the two antibodies separately rather than in one drug, where you've only binding CTLA-4 in the presence of PD-1. However, if you compare, you are still getting some increase in toxicity.

So I think we've got a much, much lower rate of the diarrhea and colitis that you see with CTLA-4 inhibition. But we have still seen some increases in liver enzyme elevation, and that's really what we try to optimize for when we're optimizing for the dose at 750.

So we have an acceptable way of drug discontinuation and holidays based on that. So I think we still need to make sure that we're optimizing the patient population that we're choosing for the relevant checkpoint inhibition profile, and that's what we're aiming to do across our bispecific portfolio.

This is the beauty of this portfolio, and volrustomig is a more logical option for PD-L1 high, Simon, and the CTLA-4 combination of volrustomig is a better option for PD-L1 low in lung cancer. So we'll move to the next one.

[Ajay Kumar] [ph], HSBC.

Just one question on the long-term financial targets, you indicated that you want to achieve faster than the industry growth. Can you run us through how you're thinking about capital allocation today in terms of, for example, you highlighted GLP-1 acquisition or you just started trials on bispecific that will position you to be there.

So what is the capital allocation regardless that you're following today that gets you to an answer? Whether there is, you won't get success in everything, but what gives you the confidence that you can deliver that industry-leading growth?

Thanks, [Ajay] [ph]. Aradhana had to step out for a minute, so let me address your question.

First of all, we don't give long-term guidance. The only thing I will say about the long term is what we said before remains our goal, so there's not much change there.

And in terms of a specific question about capital allocation, as Aradhana said a bit earlier during her comments, the priorities for us are to invest in our pipeline, reduce debt and pay our dividend, so there's no change there. And certainly, we want to continue building our pipeline.

But the -- each time we build the pipelines for [indiscernible] like we've just announced this morning, this additional growth, we believe that we can deliver industry-leading growth from '25 to '30 and beyond based on what we have today. So anything we had actually will help us grow even more during the period and beyond.

So we're always looking at today, tomorrow and the day after, the day after being new technologies like cell therapy that we want apply to oncology but also immune diseases, as Sharon mentioned, T cell engagers, gene therapy for rare diseases. In the midterm, of course, which is what I call tomorrow, is actually a large Phase III pipeline.

So that's really what we try to do. The next question is Emmanuel Papadakis, I'm rushing a little bit, from Deutsche Bank.

But we only have a few minutes, and I'd like to have everybody first to ask your question. Emmanuel over to you.

Well, go ahead.

Luisa Hector from Berenberg, actually.

It's not about the screen that I have in front of me, saying, but it's great to hear you. Go ahead Luisa, then we will look back to Emmanuel, that's okay.

So on [indiscernible] at ESMO, it became clear that this drug is absolutely delivering on the promise of ADPs in the EGFR subgroup of lung cancer. I just wondered why you think this is?

And whether you need to see any more data before you could consider starting Phase III in frontline EGFR in combination with Tagrisso? Thank you.

Thanks. So it's a good question for Susan.

Yes, sure. Thanks for the question.

So yes, in the EGFR subgroup, we did see really good activity with the hazard ratio of 0.389 group in the randomized study of TL01. So we've also got data from the ORCHARD platform study looking at the combinability of Dato-DXd with Tagrisso.

So I think that's an important piece to also put in place. So I think it is encouraging.

Obviously, as we've already said, we're going to be expanding the portfolio of Phase III trials that we have for Dato-DXd, and you'll see more of those trials in the coming months. But this is a place that obviously we can build on the great data that we just see with FLAURA2 by looking at the combination of Tagrisso with chemo, and you have the potential then to improve on the chemo piece.

So I think it's an interesting area. And, obviously, we'll be posting more trials in the coming months.

Thanks, Susan. Emmanuel, over to you.

Quick question on vemircopan the discontinuation for lack of efficacy in PNH. What cross [read does] [ph] have to the ongoing myasthenia gravis renal studies?

And where does that leave your oral strategy and ability to defend against potentially newcomers like [Takapan] [ph], et cetera? And then if I got a very quick follow-up for Ruud, you didn't mention China VBP [indiscernible] next year.

Are you no longer expecting that to be a headwind for revenues? Thank you.

Okay. Marc, do you want to cover the first one?

Yes. So to answer your first question on vemircopan in PNH.

I mean, PNH, it's absolutely essential to have a very high control of the disease, and we recommend in PNH the dual therapy between danicopan and Ultomiris. Ultomiris has a very sustained and strong efficacy over time.

I believe it's going to remain the standard of care. Vemircopan has shown efficacy but not as high as we want it to be.

Regarding the read across other indications, we are still continuing Phase II studies in MG, as you mentioned, but also in several renal indication, and we are hopeful that this indication will be successful.

Maybe just one quick addition to what Marc said. I mean they are, as you probably saw with iptacopan showed some sign of potential breakthrough IVH.

So that's why we believe C5 potentially combined with danicopan is really the best option here. Over to you Dave.

Yes. Sorry, Emmanuel, so it's clearly Farxiga is not listed in so-called batch 9.

It could go into the VBP batch 10, but that impact will be only seen then in mid late 2024, so we simply need to wait till batch 10 is announced.

Last thing with China, and Farxiga is we will, as we've said before, we will what we call consumerize it just like we did with Crestor. I mean the volume potential is still gigantic in China.

The price is relatively low, so we can definitely consumerize it and operate in a private market and deliver to patients at home for a very low cost. So we believe we should be able to transition.

There will be -- when we go VBP and we don't know exactly when because as Ruud said, it could be further delayed. When we go to VBP, we should have an initial drop and like we saw with Crestor and I hope, and belief is that it can after that grow in volume.

We take the last one question from Peter Welford, Jefferies.

Just coming back to the oral GLP-1. I just wonder if, firstly, if Ruud could perhaps comment on how important is it that this could potentially get to market at a time when you do have a successful life cycle management or other strategies for Farxiga in the U.S.

market? And overall, sort of presence, I guess, a significant presence in your CVRM portfolio in the U.S.?

And how does it leave the weekly Amylin, perhaps a question for Sharon? Is it actually possible to potentially reformulate the oral as well as an injectable for an ambient combination?

Or is the [indiscernible] monotherapy at this point within your portfolio? And I apologize.

I know I'm last, but if I've done it, just step back again. Could you just quick -- can you reiterate the mid-to-high 30% longer-term margin target?

Because that wasn't actually mentioned, but it's come up for a lot of people's questions. Thank you.

Okay. So Peter, let me do my best in order to answer your first question regarding the importance of this new assets in the combination with Farxiga.

It's fair to say that we are getting more and more excited about the other combinations in our portfolio as well. Sharon mentioned the combination with zibotentan.

We hope to show results with Amylin combination with Farxiga. And last but not least, of course, we have the baxdrostat combination.

The Phase III trial has already started for the mono component, and hopefully early next year, we will also start to Phase III in the combination of Farxiga. So those 3 will enter the market earlier than the combination with the obesity.

But of course, we will gladly do everything in order to accelerate the development also of the combination of the Eccogene compounds with Farxiga, if that makes sense. So that's what I can say at the moment.

It's high speed. There's a lot ongoing in order to make sure that we will mitigate the potential effect of an LOE in the United States as much as possible.

And I'll answer your second question, which -- I'm sorry. Go ahead, Sharon.

Yes.

Yes. I think we'll follow up.

There was a question there about how this fits into our portfolio in which we already have a long-acting Amylin agonist. So it's an excellent question, but let's just say that nobody thinks that the unmet medical need for diabetes has been fully met at this point.

And so we have multiple opportunities to address both Type 2 diabetes and obesity with the molecules in our portfolio as well as with this acquisition of ECC5004. So there is still a place for our long-acting Amylin molecule, and it is a small molecule so we anticipate that it would be combinable with a molecule like ECC5004.

So we continue to build on our portfolio, not subtract from.

And with amylin, the idea is really to combine, not replace GLP-1 but combine and provide a product that is better tolerated, add further weight loss or enable reduction of GLP-1 and better tolerability of the combination, and also [indiscernible] effect. But of course, only time will tell whether we can deliver this, and that's why we do the clinical development.

So the last question, operating margin remains certainly our key focus. But of course, we will always consider the opportunities we have.

As I said before, with what we have in our hands, we can deliver industry-leading growth post-2025, which we've said before. And if we find other additional opportunities to grow even faster, certainly, we may consider adjusting operating margin target.

But the one thing we will not do is compromise the profitability and the cash flow in absolute value. So we will only trade an adjustment in operating margin if we thought we can deliver faster, even faster growth more profit and more cash flow.

So that's sort of the bottom line, and we want to deliver for shareholders at the end of the day.

So with this, maybe we want to call it a day. And thank you very much for all your great questions, and have a good day, everybody.

Thank you.