Thank you. And good afternoon, everyone.

I'm Chris Sheldon, Head of Investor Relations at AstraZeneca. I'm pleased to welcome you to AstraZeneca's third quarter 2021 conference call.

All materials presented today are available on our website. Slide 2 has the usual Safe Harbor statements.

We will be making comments on our performance using constant exchange rates or CER, core financial numbers and other non-GAAP measures, including total revenue excluding the COVID-19 vaccine for pandemic use. As well as the impact of the pandemic vaccine on EPS and non-GAAP to GAAP reconciliation is contained within the results.

Numbers used are in million U.S. dollars and for the first 9 months of 2021, unless otherwise stated.

Please advance to Slide 3. This slide shows today's speakers from our senior executive team.

In a moment, I'll hand over to our CEO, Pascal Soriot, to begin. Please turn to Slide 4.

Following our prepared remarks, we'll open the line for questions. We'll ask that you limit yourself to one question and one follow-up question to give a fair opportunity to participate in Q&A during the allotted time.

As a reminder for those on the phone, . Please advance to Slide 5 and with that, please Pascal, over to you.

Thank you, Chris and hello everyone. The third quarter of 2021 was an important milestone for our Company with the addition of our Alexion colleagues.

Alexion has been the remarkable diversified requisite portfolio with significant growth opportunity. A great part of this success is due to the talented team globally and I very much look forward to seeing all we can accomplished together.

With the inclusion of Alexion from the 21st of July, we saw total revenue for the year-to-date of over $25 billion as an increase of 28%. If you move to Slide 6, if you don't mind.

Yes, thank you. The revenues excluding the COVID-19 vaccine for pandemic should go at 17%.

The breadth of our now expanded portfolio allows us to continue to deliver on our growth ambition in the face of ongoing industry-wide pressures related to the effects of COVID-19, which is still having an impact on patients visiting doctors or going to hospitals. Total revenue in the quarter came very close to $10 billion, $9.9 billion precisely.

A remarkable milestone, which of course was aided by our COVID-19 vaccine sales. But still excluding the vaccine, we experienced tremendous growth.

The core EPS of $3.59 is up 23% over prior year and it's excluding the vaccine, the growth is 17% reflecting continued leverage in our business. As a reminder, our vaccine has been supplied at no profit.

And therefore, the vaccine sales up to date, deliver no profit. Operating expenses growth in the quarter, reflecting part of the cost associated with the vaccine, the integration of our Alexion, and most importantly, our continued investment in our strategy to spend industry-leading pipeline and support our rates and recent launches.

We now progressively transition our vaccine to profitable. But our price will ensure the vaccine is affordable for low- and middle-income countries and therefore, the profit will remain limited.

We have updated our full-year revenue guidance, to reflect the contribution of our COVID-19 medicines in the fourth quarter. The great majority of our COVID-19 sales in Q4 will remain pandemic sales that no profit.

Therefore, the Q4 profits arising from our vaccine sales will remain quite limited and will be offset by the investment -- the limited investments in our long-acting antibody combination are 7442, there's a limited investment that we need to do, I said that it's not covered by contracts we have with governments. But essentially the limited profit from their vaccine is offset by the limited cost of SED 7442 development.

And overall, the COVID medicines will not contribute to profit in 2021. So, it's important to remember that the EPS guidance that we give reflects the performance of the underlying business being the so-called, "old AZ plus Alexion ".

So, it's a new AZ with Alexion, but excluding the COVID assets. Other than that, I will provide additional details on this important update later in the presentation.

All of our franchise is doing well. We demonstrated broad base double-digit growth with Oncology going at 16% by - - and in biopharmaceuticals, CVRM rolling at 10%, respiratory and immunology at 12%.

For rare disease, the total revenue was $1.3 billion dollar. With 0% gross, not meaningful due to the inventory reporting period but in line with our expectations.

And for Q3, it's important to remember we didn't have a full Q3 as far as is concerned. So, we didn't have the full extent of sales, but also not the full extent of R&D spends and other costs.

We're committed to following the science and news -- flow pipeline news during the quarter has been extraordinary, really, with 8 positive late-stage readouts across 7 medicines with the potential to change the standard of care in multiple diseases. If you turn to Slide 7, the performance in the field was strong across our diversified disease areas as well as across geographies.

To look specifically at the emerging markets region, growth was 10% year-to-date, excluding the contribution of the COVID-19 vaccine. China grows by 2% in the quarter due to price and volume pressures, as well as stock compensations to distributors related to VBP and NRDL negotiations.

The volume of key medicines is growing very strongly in China, but it's not free compensating for past pressures. It is clear that China is slowing down, but remain a very important market for us, and although the next few years, we expect to continue growing with, of course, a valuable growth rate depending on the year.

But still a very important market that, will contribute greatly to our Company. And the slower growth in China was compensated by the emerging markets that also in the scene in the quarter.

So overall, the emerging markets including China, go by 12% in the quarter. Again, excluding COVID-19 vaccine, which reflects the strength of our global footprint.

We will provide additional commentary on China performance later in the presentation. So please move to Slide 8.

If we look at the late-stage pipeline delivery, I would like to highlight a few regulatory approvals for free medicines. Farxiga for CKD in the EU and Japan.

Saphnelo for SLE in the U.S. and Japan and Ultomiris in the EU for children and adolescents with PNH.

We await regulatory decisions with quite excitement for AZD7442 antibody in COVID-19 prophylaxis, and also in oncology 4.52 in second-line HER2+ breast cancer, and we are of course in the process of discussing potential orders for the lab with countries around the world. So, if you move to Slide 9, I will now hand over to Aradhana Sarin our new CFO, who joins us from Alexion where she was the CFO.

For those of you who have not met Aradhana, I know you'll be as impressed as I am with her knowledge of the industry, her sense of the business and her passion for our mission to help patients and follow the science. Again, a warm welcome to Aradhana and Alexion Over to you, Aradhana.

Thank you, Pascal. I will be covering our financial performance for the third quarter and year-to-date, 2021.

Please turn to slide ten. Built-in revenue grew by 28% year-to-date and by 48% in the third quarter.

This includes our COVID-19 vaccine. Excluding the vaccine, total revenue grew by 17% year-to-date and by 32% in the third quarter with strong performance across our key disease areas.

Our reported EPS in the third quarter was negative at $1.10 impacted by an impairment charge of $1.2 billion following a strategic decision to discontinue the development of from the acquisition of our data in 2012. Our reported numbers are also impacted by a number of adjustments following the consolidation of Alexion.

One of the main adjustments is an inventory where previously Alexion health visit cost, whereas now it is recorded at fair value. As a result, cost of sales for the group was inflated by $1 billion dollars charge related to the unwind of the inventory, fair value uplift.

On a reported basis, we expect the cost of sales to continue to be high for the next 18 months or so until this inventory is sold. We also incurred higher amortization charges this quarter.

As we start amortizing the Alexion medicines over their useful economic lives. These changes do not have an impact on our core results.

Please turn to the Core P&L on Slide 11. The Core gross margin was 74.1% year-to-date, driven by the vaccine.

Excluding the vaccine, we saw a small decline in gross margin in line with our previous comments on increased pricing pressure in China and profit-sharing arrangements on several successful medicines. Core operating expenses increased 20% with year-on-year comparisons impacted by the addition of Alexion from 21st of July.

Excluding the COVID-19 vaccine, Core operating expenses increased by mid-teens percentage. Higher R&D costs are also reflective of pipeline success in the last quarter with numerous successful late-stage readouts, as well as our substantial investment in R&D, for our long-acting COVID-19 antibody combination beyond the level of government funding.

The increase in SGNA costs reflects the addition of Alexion, increased investment in new launches, including Saphnelo in lupus and Farxiga in CKD, as well as significant pre -launch investment following successful Phase III data for Enhertu, Lynparza, tezepelumab, and PT027. From a year-to-year comparison basis, you may recall that the SG&A cost in third quarter 2020 declined 1% compared to 2019 because of COVID -related lock-downs and cost reductions in areas such as This also skews the SG&A growth comparison.

Core earnings per share of $3.59 includes a negative impact of $0.03 from the vaccine with a $0.01 benefit in the Third Quarter. Now turning to slide 12 in the quarter, we saw further improvement in our core operating profit mix.

And for operating profit increased quarter-over-quarter, benefiting from the inclusion of Alexion, despite lower other operating income. We're updating our 2021 guidance to provide further details around the contribution of our COVID-19 medicines.

While we continue to expect low-twenties percentage increase in total revenue, excluding the contribution from the COVID-19 vaccine in line with our prior guidance, we now expect total revenues to increase by mid-to-high point each percentage, inclusive of fourth quarter vaccine sales. We anticipate vaccine sales in the fourth quarter to be a blend of our original agreement and new commercial Vaxzevria contract, but with the vast majority coming from pandemic agreements.

In line with prior years, we expect a step-up in total revenue in the fourth quarter. Any net profit from commercial vaccine contracts in the fourth quarter is expected to be modest, and to offset continued investment in R&D and supporting activities such as pharmacovigilance for a COVID-19 medicines, including the long-acting antibody, resulting in no material EPS contribution from these medicines in 2021.

We still expect core earnings per share to be between $5.05 and $5.40 at constant exchange rates for 2021 in line with our prior guidance. Please turn to Slide 13.

Net debt increased to $24.7 billion following the completion of the Alexion transaction. That leaves our current net debt to EBITDA ratio at around 3.1 times.

Our EBITDA is, however, reduced by the $1 billion unwind of the Alexion inventory fair value adjustment discussed previously. Excluding this non-cash impact, our net debt to EBITDA ratio would reduce about 2.7 times.

As previously communicated, we're committed to rapidly reducing our debt. Our capital allocation priorities remain unchanged.

In no specific order, we aim to maintain a strong investment-grade rating, while continuing to reinvest in the business. We will also continue to explore strategic value enhancing business development opportunities and remain committed to a progressive dividend policy, define the stable or increasing dividend.

I will now hand over to Dave Fredrickson.

Thank you and welcome Aradhana. Slide 14, please.

So, we're pleased to report that our Oncology total revenue, grew 16%, a good performance showing the momentum of new launch and the diversity of our portfolio in the face of continued headwinds from COVID-19. With that said, diagnosis rates continue to improve and are now around 5% to 10% below pre -COVID levels.

The quarter included strong performances from Calquence and HER2, solid delivery from Lynparza and Imfinzi. And on Tagrisso, the year-to-date showed growth.

However, sequential sales for the quarter were slightly down due to China dynamics, which I'll explain shortly. Let's turn to Slide 15 and go through some of the specifics.

In the U.S. underlying volume demand for Tagrisso continues to grow at low single-digit rates with rising 1st-line duration of treatment and increasing adjuvant use driving sales, partially offset by lower 2nd-line use in the pandemic impact on diagnosis and testing.

More specifically and adjuvant news, we're pleased with the good progress we've been making in moving physician practice. However, it takes time for the relatively small number of new starts in a setting that is 20 to 25% of the size of the first-line metastatic market to move the dial on overall prescriptions.

In emerging markets, growth in the year to date was 1%, within that we've seen strong growth in EM, outside China as Tagrisso gain reimbursement in more markets. In China, the strong volume growth we're seeing in the first-line and second-line is still catching up with the price discount for NRDL inclusion in March.

Following the NRDL change in the second quarter, we saw inventory build and a bolus due to first-generation TKI switches in the front line. In the third quarter, we are down sequentially as those factors were not at play.

We're confident we're moving the needle in China in front line and maintaining robust share in 2nd-line. We expect continued volume growth to offset the cut in price that we took in the coming months and for Tagrisso to resume top-line growth in China at that point.

Turning to our immuno-oncology franchise, Imfinzi grew by 17% in the year-to-date. We're very pleased that we continue to grow Imfinzi over the last several quarters despite the pandemic, solidifying and growing Pacific, and driving successful launches of Caspian in the face of competition.

All of that sets a great foundation for launches in some of the potential new indications that Susan, will speak about in a few moments. Please turn to Slide 16.

Lynparza continued to deliver strong growth across tumor types and territories, increasing product sales by 31% to $1.7 billion in the first 9 months of the year. Lynparza remains the class-leading PARP inhibitor across 4 tumor types.

U.S. sales were up 26% driven by Greater Houston ovarian, prostate, and adjuvant breast cancer, and we were pleased to see the NCCN Guidelines updated to include Olympia during Q3, Europe and established rest-of-world showed good growth in ovarian and prostate cancer, supported by continued growth in HIV testing.

China benefited from strong volume growth, due to the expanded ovarian cancer indication in the NRDL, from March offset by the associated price cut, as well as similar, albeit smaller inventory facing headwinds in Q3 as seen with Tagrisso. Please turn to Slide 17.

Calquence continues to make strong progress towards blockbuster status, driven by a robust share performance in the U.S. in chronic lymphocytic leukemia, where it has reached 52% new patient share.

Calquence has continued to show good momentum in Europe as well, with several launches including France, Germany, and the UK off to good success. Moving onto Enhertu, the year-to-date saw good momentum in 3rd-line breast and 2nd-line gastric cancer.

That success came against a backdrop of new clinical data that establishes tremendous opportunities for Enhertu in the years to come. Susan will talk to the data from DESTINY-Breast03 in a moment.

I won't steal her thunder, but within HER2, now the established leader in 3rd-line HER2+ breast cancer, we have the critical platform to really drive changes in the standards of care in second line once these data get approved. I'll now hand over to Susan to discuss our RND progress.

Thank you, Dave. Please turn to slide 18.

I want to take a minute to the account the outstanding results from DESTINY-Breast03 trial that will present to the ESMO. We saw a highly clinically meaningful and statistically significant improvement in progression-free survival, compared to just Trizma DM1, as one of the trends in overall survival at this very immature analysis.

Enhertu truly has the capacity that change the sanative care by demonstrating superior benefit over to Trizma DM1 in patients with HER2+ metastatic breast cancer in the second line. As a result, we were pleased to see the recent ESMO guideline update adding in HER2, as the new standard of care in this setting.

No new safety concerns were identified and importantly no grade 4 or 5 treatment related interstitial lung disease events were observed. This is very encouraging for the potential use of Enhertu in earlier lines of therapy.

We also saw in HER2 granted breakthrough therapy designation stasis by the FDA on the back of the 3 studies, a real testament to the importance and impact these data will have on patient outcomes. During the period, Lynparza became the first PARP inhibitor to generate positive data and first-line metastatic castration-resistant prostate cancer, in combination with abiraterone in an old comer’s population.

Prostate cancer is the second most common and the fifth leading cause of cancer death in men, globally. A new chemotherapy-free options, are desperately needed.

Please turn to slide 19. Gastrointestinal cancers such as liver cancer, are common and has seen limited innovation when it comes to improving clinical outcomes for patients.

Recently, we reported back-to-back positive readouts for our immuno-oncology franchise with HIMALAYA enhance the cellular carcinoma on TOPAZ-1 in advanced biliary tract cancer. Both indications have a large unmet need as recognized by the U.S.

orphan drug designations. These data open up the potential for Imfinzi and Tremelimumab in a broader array of settings and brings us closer to our goal to improve long-term survival for patients with different gastrointestinal cancers.

In HIMALAYA, a single high priming dose of Tremelimumab added to Imfinzi, known as the steroid regimen, resulted in a clinically meaningful improvement in overall survival when compared to the current standard of care. This regimen was selected after careful analysis of clinical and biomarker data from various trials with different Tremelimumab dosing schedules.

In the TOPAZ-1 trial, at the planned interim analysis, Imfinzi, when used in combination with standard of care chemotherapy of Gemcitabine plus Cisplatin, demonstrated an improvement in overall survival in patients versus chemotherapy alone. This is the first major global treatment breakthrough in first-line advanced biliary tract cancer in over a decade.

Our development plan for Imfinzi in liver cancer does not stop here. As we eagerly await results from the one trial, which will evaluate the use of Imfinzi in patients with local, regional hepatocellular cancer who are not amenable to curative therapy.

This is in line with our strategy to move in treating earlier stages of disease. And in the second half of next year.

Please turn to Slide 20. And now, what's next?

We have multiple Phase 2 trials starting across our pipeline. is a trial in first-line ovarian cancer for Lynparza and also have the trial in muscle-invasive bladder cancer for Imfinzi.

We'll also start a new called DESTINY-Lung04, along with TROPION-Breast01 for with our collaborators, Daiichi Sankyo. We also have two new bi-specifics, fantasize one child and solid tumors.

AZD2936, which is a PD-1/TIGIT by specific as well as AZD7789, a PD-1/TIM-3 bi-specific. Both of these have the potential to become next-generation immuno-oncology therapies.

I look forward to updating you on the progress of these and other programs soon. I now going to hand over to Ruud to take you through the biopharmaceuticals and emerging markets performance in the period.

Please turn to slide 21.

Thank you, Susan. Please turn to Slide 22.

In CVRM, total revenue was up 10% to $6 billion with a vast majority of growth coming from Farxiga's continued strong performance. Farxiga got grew 51% and remains the largest single contributor to AstraZeneca, as Greg Farxiga also continued its remarkable progress as the fastest-growing SGLT2 inhibitor globally.

Making gains in volume market share moves in by successful launches in heart failure and chronic kidney disease. Following the results of the DAPA-HF trial, we were pleased to see the European Society of Cardiology guidelines updated to include Farxiga as first-line treatment for heart failure patients was reduced ejection fraction.

Additionally, EFC guidelines now also recommend novel percussion buying this switch to Lokelma or to treat hyperkalemia, which is great news for patients. Lucuma revenues more than doubled to $122 million in the U.S., local Maria force is leadership in the branded potassium buying the market.

Reaching 58% share of prescriptions. And in Japan, its market share increased to 41%.

Please move to Slide 23. Turning to Respiratory and Immunology, total revenue was $4.5 billion with a growth rate of 12%.

The year-on-year growth benefited from the effects of COVID-19 on last year's Pulmicort sales. Farxiga delivered product sales of $901 million up 32% and is the leading respiratory biologic prescribed for eosinophilic asthma globally.

Farxiga 's performance has been driven by sustained growth in new-to-brand patient starts in both the U.S. and the EU.

Recently, Farxiga was granted orphan drug designation in years in the Fibrocaps arthritis, and using a , and the fast-track designation for the treatment of EG with or without EGE by the U.S. FDA.

Breztri with products sales of $130 million continued its global launch trajectory, rapidly gaining market share in the fast-growing triple fixed dose combination class. Breztri is now approved in 36 countries, including China, where we're seeing patient volume increase following NRDL inclusion earlier this year.

Symbicort sales were $2 billion, a slight decrease of 3% against a tough comparison in COVID-19 related stock last year. Symbicort remains the number 1 ICS LABA globally, and as today, received 42 approvals worldwide for its use as a rescue therapy for asthma.

Please turn to Slide 24. Now onto the emerging markets.

Excluding revenue from the COVID-19 vaccine, total revenue grew 10% with $7.5 billion. Growth in China for the period was 8% and growth in emerging markets, ex - China was 14%.

Decrease grew 1% in the emerging markets, reflecting the impact of inventory phasing in China, which Dave described earlier. Farxiga has had remarkable growth of 74% in the period, as it continues to benefit from increased patient access in China following NRDL inclusion last year, as well as broader access across other markets in the region.

Flu accord in China experienced some recovery from the impact of COVID-19. This comes ahead of the anticipated impact over to inclusion into the VBP program in October.

Outside of China, we saw broad-based growth across all regions. Excluding the impact of the COVID-19 vaccine, total revenue growth increased by 9% in Asia-Pacific, 12% in the Middle East and Africa, 28% in Latin America, and 15% in Russia.

I will now hand over to Mene to cover the R&D advancements in the periods.

Thank you, Ruud. Please turn to Slide 25.

Our Respiratory and Immunology portfolio continues to deliver and in August, Saphnelo and anifrolumab was approved to treat moderate -to-severe systemic lupus erythematosus in the U.S. and in Japan.

In Europe, an ad hoc expert group meeting has been scheduled where we look forward to discussing the clinical data. This quarter we also announced positive high-level results for the MANDALA and DENALI trials for PT027.

Our fixed dose combination of albuterol and Budesonide. And we anticipate increased submissions to be completed in the first half of next year.

Also in the quarter, tezepelumab was granted priority review for the treatment of asthma, accelerating the review timelines of this much needed treatment option, and tezepelumab also received Orphan Drug Designation for the treatment of the eosinophilic esophagitis. Please turn to Slide 26.

We continue to see accumulating real-world evidence that shows the enormous contribution our COVID-19 vaccine, Vaxzevria, has made in preventing hundreds of thousands of hospital admissions and deaths. And we were really proud to be one of the recipients of the Prix Galien Roy Vagelos Probono Humanum Award for the development of our COVID-19 vaccine.

Turning to AZD7442, which will be known as every shelled. We announced positive results from both the prophylaxis study and the tackle Phase III trials, which is a treatment study.

And AZD7442, is the only long-acting antibody combination, but has demonstrated the ability to both prevent and treat COVID-19 disease. In prophylaxis, there is a significant unmet medical need to protect Bonneville populations who have an inadequate response to vaccines, such as those who are immunocompromised by disease or their therapy AZD7442 is a convenient intramuscular injection and has the potential to protect these individuals for up to 12 months.

We anticipate emergency-use authorization in the U.S. towards the end of the year and have active review processes across Europe and the UK.

We recently presented data from the MELODY and MEDLEY trials for nirsevimab, which showed it is a highly effective in reducing medically attended lower respiratory tract infections and has a similar safety profile to Synagis. Regulatory submissions for nirsevimab are expected to complete in the first half of next year.

And finally, taking a look at what's next if we turn to Slide 27, please. This quarter we saw results for cotadutide, our GLP glucagon co-agonist for the treatment of NASH and diabetic kidney disease, which we presented in due course, as well as Phase II data for AZD8233, our PCSK9 inhibitor for dyslipidemia.

We also initiated Phase II trials for AZD4604, our inhaled JAK inhibitor for the treatment of asthma. Please go to Slide 28.

As I now hand over to Marc, to cover Rare Diseases.

Thank you Mene. I'm happy to join you today in my new role as Chief Executive Officer of Alexion, and excited to be part of Alexion 's next chapter with AstraZeneca.

To recoup at currently on your comments, I want to thank all of the Alexion employees across the globe for their continued dedication to the patients we serve. Since it is AstraZeneca 's first-quarter was Alexion, I wanted to briefly provide another view of the business to have more of you become acquainted with rare disease.

Please turn to slide 29. The combination of AstraZeneca and Alexion presents a unique opportunity to accelerate AstraZeneca strategy and financial developments.

Alexion fiber-approved medicine for the treatment of and divestitures in disease, including the leading C5 franchise comprised of Soliris and Ultomiris. Alexion showed a strong commercial and financial track record achieving best-in-class conversion to Ultomiris in less than 18 months from launch and delivering over $6 billion in total revenue in 2020, representing 21% growth compared to prior year.

This performance relates to the period before the merger with AstraZeneca. On the R&D side, we continue to innovate in complement with our C5 inhibitors, including a subcutaneous formulation of and Alexion 1720, the subcutaneous milli body.

Outside of general complements, we have to award factored g medicine. We also have ALXN1840, a subcutaneous, with potential application in multiple disease areas.

Overall, we have a diversified development portfolio of novel technology platforms and medicine that have the potential to deliver attractive growth opportunities. Turning now to Slide 30.

This is an early look at how we plan to establish scientific bridges between non-X-Gene AstraZeneca to be the stronger combined organization. On the development side, we continue to see potential to apply Alexion leadership and complements science to AstraZeneca order, immunology efforts, as well as bringing AstraZeneca, with precision medicine expertise to all disease.

In early research, collaboration with AstraZeneca, gene-editing to gene therapy and oligonucleotides capabilities as potential to lead to the development of novel rare disease medicine. I look forward to seeing this initial effort progress towards new opportunities to deliver transformative medicine to patients.

Please turn to slide 31. Rare disease year-to-date total revenue was $1.3 billion, representing 6% quarter-on-quarter .

Total revenue in the period were driven by strong Soliris volume growth in Neurology indications, and successful conversion to build communities. Looking ahead, we expect losses boarding line without the new endowed AstraZeneca on a compounded growth stride basis.

We reported positive Phase III for Ultomiris, degeneralized with compelling efficacy observed as early on 1 week and sustained up to 52 weeks. Unfortunately, we announced discontinuation of the Phase III for Ultomiris in ALS, on the recommendation on the independent that monitoring committee.

While this was a high-risk program, we are nonetheless disappointed in this outcome. Moving towards positive Phase III results for ALXN1840 in Wilson disease, demonstrating superiority versus standard of care on the primary endpoints of couple mobilization.

Finally, an extra exercise the option to fully acquired Caelum Bioscience and accelerate the phase development of CAEL-101 in amyloidosis. So, their customers induced characterized by autonomous proliferation of customer sale with over production of monoclonal immunology.

Please turn to Slide 32. Total revenue for Soliris declined by 2% impacted by prior-year all the timing in emerging markets.

Ultomiris grew by 31% in the period driven by strong conversion from Soliris and 40 new country launches year-to-date. Strensiq grew by 8% in the period due to underlying growth in the U.S.

Finally, what's next on Slide 33. In July, Ultomiris trial in complement-mediated thrombotic microangiopathy, one of the multiple label extension opportunities.

We also made progress with ALXN1850, our next-generation asfotase alfa now in Phase 1, for the settlement hypophosphatasia HPP bone disorder, often diagnosed in infancy or early childhood. As we move to Slide 34, I will now turn back to Pascal for closing remarks.

Thank you, Marc. In line on this Slide number 35, please, that will stride some news flow.

Can I get Slide 35? It has tried to new flow across the Company in the coming months.

In Oncology, we anticipate data from to DESTINY-Breast 04 trial in order to lower breast cancer in the first half of next year, as well as multiple Imfinzi results across lung and cervical cancers. In CVRM where we'll have data from the developed trial for Farxiga and disease data from intermulation NMOSD.

We remain on track to deliver our full year guidance. And I would like to reiterate that our EPS guidance reflects the performance of the underlying business and it's not influenced by our COVID medicines.

We are also excited with the basically core news flow ahead. I'm very, very proud of our critique on Cowen dedication and focus on the addition of Alexion will increase our commitment to bring transformative medicines to patients around the world.

Thank you all for joining and we will not take the questions.

Thank you, Chris. We'll take -- first question is from James Gordon at JPMorgan.

James, go ahead.

Hello, James Gordon from JPMorgan. Thanks for taking the questions.

The first question is about 2021 guidance and the implied Q4. So, we're about halfway through Q4, but it's an unusually wide guidance remaining so plus or minus 25%.

So as things are looking now, is the bottom end of the guidance range still fairly plausible? What would put you at the bottom versus the top for the year?

And then in terms of spend normally, Q4 was quite a lot higher on OpEx in Q3 for Astra. So, on an underlying basis x consolidates more of Alexion, of Alexion, would that normal trend be expected and it's a big step-up in OpEx in Q4 versus Q3?

So that's the first question, please. And then the follow-up, I'll do now which is just an OpEx beyond this year, so what have you been part -- I can see this quite a few phases 3 initiation plans and some of which you will and also a bit more promotion.

But other also significant offset. So, for instance, China slowing another China 's completing.

So how much of the spend is going to be incremental. There could be some offsets or some reallocations

So the last that's come out on the Munich, but just make a high-level point here is that I expense vary quarter-to-quarter. And so, we have sometimes high Q3 or low Q -- high and a lower Q4 and sometimes vice-versa.

This year -- or last year, I should say, we had a relatively low Q3 in term of expenses will probably cut our R&D expenses. And as you can look at, if you look at it for us sure we had an increase in spend in Q4.

This year we don't expect that to happen the same way. What you have to look at in Q4 is the expenses, and then, of course, had a full quarter of Alexion expenses and then the COVID R&D expenses on top.

But as it relates to Q4 it's going to be a lot -- It's not going to be like previous year where we have an increase in expenses versus history. Aradhana that you want to add more color to this?

No, I think you've covered a number of the aspects. So, we're reiterating the guidance for the EPS.

There is obviously quarter-on-quarter variability. But also, fourth quarter we'll include a full quarter contribution from Alexion, which this quarter was not a full quarter.

And then there is some seasonality, as you know, on the top line as well with the flu meds and some other products. And generally, expect fourth quarter revenue to be strong.

And then on the expense side, again, some of the elements that Pascal mentioned. So, if you think about our fourth quarter and the AZ underlying business, which again, would be -- probably more in line with fourth quarter last year, which obviously was different versus third quarter, but -- and then a full quarter of expenses, both R&D and SG&A from Alexion.

Plus, on top of that, some of these COVID -related expenses where we're investing behind the antibody and the vaccine.

Remember, also that the vaccine sales attract pharmacovigilance cost cut. So, we get enough margin, a small growth margin that cover those costs.

And so, we get to 0 profit, where we have pharmacovigilance costs just like everybody else does. In other words, effects to the R&D line, but the key message is don't expect Q3, Q4 to evolve like last year and then you can see that why we reconfirm our guidance.

Should we move to the next question? Simon Baker, on Redburn.

Simon?

questions. Firstly, one for you Pascal.

I just wonder, given the recent developments, if you could give us your latest thoughts on proposed drug pricing reform in the U.S. following the collapse and reemergence of the democrat's proposals?

And then secondly, one for Mark on Alexion. One of the things that was talented when the deal was proposed was the much larger geographic footprint of Astra versus Alexion.

I was just wondering if you could give us a timeline of when we will start to see revenues for the Alexion portfolio coming through in new territories as that push through the AstraZeneca infrastructure? Thanks so much.

Hi Simon, can I maybe ask who would change coming from the U.S. pricing and regulation, and if then you have anything you want to add to what Ruud would say, this is free.

Over to you, Ruud.

Of course, and thank you Simon for, for the question. First of all, I think it's fair to say that AstraZeneca is in favor of potential reform of the U.S.

healthcare out-of-pocket cost for too many patients are too high, which will damage to the accessibility for patients to get the right medicine at the right time. Equally, I think it's fair to say that some of the legislation is clearly not favorable for the -- our industry.

We don't believe that, direct negotiations of the government with individual companies, is it going to make a lot of sense. But it's also fair to say that, there's still a lot in the air.

At this stage, it's far from final. So, let's wait and see how it's evolving.

We are on active discussions with policymakers, influential politicians, in order to bring our arguments in front of them. So, let's not speculate too much about the final results, but let's work constructively with each other in order to try to mitigate as many as possible the risk, potentially, we will face as an industry.

Thanks Mark.

So, thank you for the question on the larger footprint of Alexion, we are already working very actively to establish teams, dedicated teams. We have an X-Gene was not the president now.

And we also engaging local regulators to gain approval and access. So realistically, I believe the first approval could be obtained in the course of 2022 but that would probably see the first revenues to be generated from 2023.

Great. Thanks so much.

Thank you, Marc. Next question is Tim Anderson, unless, Dave, you do want to anything to the U.S., no?

Thank you. But I think Ruud covered it.

Good. So next question is from Tim Anderson.

Tim, go ahead.

Thank you. Just on Alexion, again, in your move into rare diseases, specifically, just your updated thinking and assumptions about competitor products that are coming after Soliris and Ultomiris.

So, for example, Novartis has iptacopan, an oral product doing a true head-to-head versus your two products in PNH. I think that reports out mid-2022.

I'm wondering if you can remind us again what you assumed on competitive threats like that or other products like Roche's durvalumab, when you were trying to figure out what Alexion was worth. And then just building on the last question that you got.

A new geography. Can you just talk about rollout of Alexion products in China specifically?

Thank you.

Let me take the second question, because it's already in great path. Responding to it with the question of Simon.

So, if we look at the example of the China, we are already established dedicated to locally. And we are engaging local regulators to gain access to the market.

We hope to gain approval, maybe in the course of 2022 and possibly sale these products on 2023. So, I think the general answer that are provided, as China could be a good illustration for it.

Regarding your question on competition, we are well aware of the development work done by the wealthiest on the overall in the NASH and other renal indications. We're also well aware of the work done by C5 Inhibitor.

This is not something that we discovered, recently we were aware of it. We believe Soliris, and Ultomiris will remain very strong leaders in their class, due to the excellent efficacy -- short-term and long-term efficacy, in the indication,

But also in the knowledge indication, where Soliris presently indicated. And where Ultomiris has recently weathered very strong Phase III results showing very rapid onset and durable efficacy on over 52 weeks.

So, this is the strength of Alexion. We believe we have enough strength to maintain the leadership in this class.

The class is going to a bar. There would be competitors entering, but also Alexion will be moving on to other indications in the future.

Thank you very much. One follow-up question to your R&D commentary, please.

I think last quarter you talked a little bit to the fact that the COVID-19, R&D was maybe going to come down overtime. It sounds like you're now saying this is going to stick around and thinking about your commentary about the vaccine being commercial for next year.

Should we assume that an incremental R&D is actually going to run at a level for longer? That's question number 1.

And then question number 2 on Tagrisso. I take your comment about the issue with China with dephasing.

Well, can you talk a little bit to the risks that maybe the inventory level is also impacted by a competitor being on the NRDL now since since earlier this year, and if that's not a risk, could be a risk that has impact to your portfolio -- as your performance for Tagrisso for the fourth-quarter. Thank you.

Thanks, Michael. The first comment -- the first question about NRDL, I think what you need to do is firmly look at the quarter and look at the what I might call quarterly.

Then add Alexion and for Q3 we had two months plus portion of July. For Q4 we have a full quarter R&D expense.

And then the third piece is the the COVID assets. And what we said before, it's still true is that if you look at the COVID on this span, you have two types.

One is pharmacovigilance costs related to distribution of the vaccine, and two is two R&D costs developing a vaccine and the lab. So, the first part is directly correlated with the volume of vaccine we deliver.

And as you saw at the end of September, we've delivered 1.5 billion doses of vaccine globally and we continue with our deliveries. And, of course, the pharmacovigilance cost is linked to this rolling of vaccine delivered.

They're covered, as I said, by the limited gross margin we get that they extend their cut substantial. And then next year, we'll have lower volume because we will have new orders but, of course, the pandemic will be behind us, so we will be talking mostly about boosters and also some deliveries to countries that haven't gone through their first 2 doses.

Lower doses and therefore lower PPV -- pharmacovigilance of course, sorry. Then the R&D is the same.

We are now left with a little bit of R&D cost related to the new vaccine and the vaccine -- is it the 2816 looking at multiple variants of concern. Then also some expenses around the lab, but this will decline.

So is India expenses for COVID should not next year or the same as this year for sure. If you look at the quarter to quarter then and this guy said this, you would see that ASI's R&D expenses are essentially what you would have expected.

But then you have two other Alexion and you have to add COVID. So, I don't know add to this and if not, then we'll ask to call out Tagrisso.

Now, Dave, go ahead.

Great. Thanks, Michael, for the question.

And I hear the question on competition, but I'm going to also -- I'll answer that, but I want to take the opportunity just to also maybe provide some more color on China, since I know there's some questions there. So, in Q2 we commented that the frontline demand growth was robust, and that inventory did factor into the China sales.

And this is pretty typical around the NRDL timing. Now, obviously the inventory levels get drawn down in anticipation of a price reduction.

And so, we saw, now in Q3 that frontline demand remains strong. The second-line share has been resilient.

And right now, inventory levels are consistent with historical patterns. I've mentioned this in the prepared remarks, but we did also see, and we see this now but we did get a 1-time benefit from some first-generation TKI switches in the front line setting in the second quarter.

And that was 1 time and so those didn't carry into Q3. But with that said, we expect volume growth to offset the significant price reduction that we took just only 6 months ago.

And we would expect that to happen in the months ahead and that from then, top-line growth will kick in at that point. On your question specifically on competition, it's obviously a pretty dynamic marketplace here.

There's lots of new competitors that are entering. Right now, as I said, the front-line penetration that we're making is robust second line has been resilient.

We do know that NRDL is in the midst of going on. We know that in the fourth quarter in China, there is some hospital capping that takes place.

So, China does remain dynamic, but in terms of the things that we can control, I think that the demand numbers are moving in the right direction and give us confidence that we're driving access into the populations where we've got now NRDL inclusion.

The volume growth, what there is in China, is very substantial. As soon as we've watched out the price effect, we should see some growth.

Next Jain Sachin, Bank of America. Sachin, go ahead.

Quite full there. I think I understood Pascal.

He said fourth quarter wouldn't see the usual pickup. then said that the Astra underlying be flat year-on-year.

If I take last year's fourth quarter SG&A and R&D being in line add on Alexion, that still points to sequential cost story versus the numbers you can . So, I just want to be crystal clear on that interpretation.

and given that variability third quarter to fourth quarter, with third quarter high growth, fourth quarter flatter ish, what's the best indicator of cost growth into '22, please? That's question 1.

Question 2 is just shorter and simpler. On Lynparza, Dave, we discussed a number of scenarios in 2Q on the data strength at being wild-type and prior ADT failures, where within that spectrum has the data landed?

Obviously, no , but any color on the strength and confidence in that being a multi-billion opportunity? Thank you.

So, Sachin, I mean, we don't give guidance quarter-to-quarter, but I think your assumption is -- your assumption of building Q4 in line with Q3 for AZ and Alexion and COVID on top is a fair 1 for both on the SG&A, I think it's fair. Aradhana, anything you want to say on this one as well?

No, I think for fourth quarter, again, we've not given guidance per se, but the building blocks are what we mentioned which is if you look at fourth quarter AZ underlying for last year, you looked at the Alexion fourth quarter, which will be a full quarter, and then additional expenses relating to the COVID products.

And the second question, anything you want add

No, no. That was for Dave.

Yeah.

The second question from Sachin was on PROpel. I think Sachin there's a couple of things.

Obviously at this point, we've only shared the high-level results and we'll have to present the data at upcoming meeting, I think. So, within that, I'm not going to give too much insight into how we're feeling about the full results.

I think we've got to let that continue to get analyzed more through. But I think just to reiterate some of the things that we talked about last time, if approved PROpel is a blockbuster plus opportunity.

there are a handful of variables, data and regulatory that are going to effect, I think, the ultimate size of the opportunities that the whole market is obviously quite large in terms of the front-line metastatic castrate -resistant prostate cancer. I think that the things that we're going to have to learn more about as we share these data is -- class share is going to be impacted by the fact that first, remember that PARP combination treatment in this setting as an entirely new approach to the treatment of these patients.

I think that physicians and we've got both urologists as well as medical oncologists, are going to take a look at the magnitude of the RPFS benefit and ITP. They're also likely going to want to look at each our mutants as well as wild-type.

I think they will consider prior chase status. And then obviously there's quite a bit of competition with 4 or 5 competitors.

So, there's a lot of variables that are at play. That's a big meaningful market, blockbuster plus, and I think that as we get to see more of the data and share more of it with clinicians, and obviously, with health authorities will have the ability to help further refine and help with where the modeling is.

We'll provide guidance for 2022 when we provide the full year results.

Okay. Thank you.

Thank you. I have a couple of questions and I apologize for another Q4 question, but you were asked a couple of times about the wide Q4 EPS range implied in the full year guidance.

What are the biggest uncertainties over the next 6 weeks that are creating the inability to narrow the range at this time? Or is it that the Company knows exactly where it is headed within the range?

But you're just not choosing to change the prior guidance. I assume, if you were headed for low end of the EPS range that you would've told us that today.

And then the second question for Dave. What percent of U.S.

Tagrisso sales go through Medicare Part D? Thank you.

Thanks Steve. Your assumption is fair and we are certainly on track.

There's no concern on our side as it relates to our guidance. We didn't know it, I mean, maybe Aradhana wants to cover this.

But we sought to know, we stick to what we have here. There was no specific reason or concern.

Aradhana, do you want to address this?

I mean, generally, we give guidance for the year. This year, we updated the guidance in the close of Alexion, given that was a major transaction.

But other than that, I think we're reconfirming guidance and we don't want to give every quarter further updates.

And we're on track. Steve, there is really no concern that made us -- I mean, that drove our decision.

It was just sticking to what we had said half year. I mean, we're absolutely on track here.

Dave, you want to cover the second question?

Yeah. Pascal, can you just come back to me on that one?

I want to make sure I get Steve the right 1 on this, and can we just come back?

How much do you expect this will serve on Medicare Part D?

I understood the question. I need to just come back on the answer to it.

Can we come back just right after the next one?

We'll come back to it a bit later. So next question is Andrew Baum with Citi.

Andrew, go ahead.

Question to Susan and then one from -- to Dave. So, Susan, could you talk to your confidence on the bystander effect being clinically significant, and how dependent is the outcome of DESTINY-Breast03 for on that given the heterogeneous patient population?

And then second for Dave, just following on from the conversations about U.S. drug pricing proposals, and I completely understand that there's a significant uncertainty between what is circulating and what may ultimately get passed, but taking what has been proposed as the final outcome, how should we think about the potential risks to degree so from lower price entrants?

And I'm thinking of Amanateneb. If the PBMs are now on the hook for 60% of catastrophic coverage, do you anticipate that that would precipitate wide-spread use of step at its profits authorization and the like that could exert a significant downward effect on volume or pricing for Tagrisso within the Medicare Part D segment of the U.S?

Thank you.

So, I can take the first question. Thanks, Andrew.

So, I think the bystander effect is important and the basic design of the molecule is to have a link that's stable in the peripheral circulation and cleavable in the tumor microenvironment. We showed that that makes a difference, pre -clinically, and I think the totality of data across the Enhertu program, not just from the J101 data which is in low HER2 breast cancer.

We showed activity beyond what you have seen with ADCs, like TDM -1, we don't have that kind of cleavable link that just a bi-stand effect. It's not just the low HER2 breast cancer data and the DB30 high HER2 and breast cancer data, but across the totality of the program in a range of tumors that have lower HER2 expression than the highly amplified, you're seeing a range of activities beyond what you would've expected from prior designed So I think that doesn't depend the confidence and the design of And we look forward to seeing the data in the early part of next year.

Actually, as I'll show, will grow.

Thank you, Andrew, on the question. Let me also just start on Steve's question.

Part B represents 20% of the U.S. Tagrisso business and it's relevant obviously to the question that Andrew you asked as well.

I think Andrew on this particular piece that certainly the resolve of plans to try to put into place mechanisms to manage their share of catastrophic will unlikely be emboldened by the increased percentage if it goes through, as it said. I still think that it's important to keep in mind that needs to be able to get approved in the U.S.

with single-arm -- I mean, sorry, with different comparator arm. We don't know where OS is going to net out and, obviously, a China -only study.

And I also think that physician prescribing preferences as it relates to that clinical benefit that we -- our clinical strength that we see right now does remain to be an important area of influence, so we'll have to see exactly how it plays out but I think that those are the ways that we're thinking about it right now.

Thanks, Dave. Mark Purcell, the next question.

Mark, over to you.

Pascal, thank you very much. The questions on investment discipline supporting the industry-leading pipeline.

You've got a clear, very broad set of organic opportunities in front of you and you mentioned the potential for BD. So just in general, Pascal given you've given us in the part for AstraZeneca underlying revenue growth, excl vaccine of double-digit, should we also be expecting R&D growth to support that being roughly double-digit growth going forward?

And then secondly to the some of the products where there's been updates. Could you help us understand next steps now for the cotadutide and PCSK9 molecules, whether they're going to jump into Phase 3, yes or no.

And then for the MPO, you mentioned you're now going to start a Phase 2B, Phase 3. And clearly, that could be very complementary, molecule alongside Farxiga potentially combination molecule.

So maybe, Mene, if you could tell us what the plans are for , that will be really useful. Thank you very much.

Thanks, Mark. I mean, they are in dispense, whatever before, we've said before that it would be in the low 20s, 20, maybe a little bit more than 20, we're on that kind of number all the time.

That's the kind of spend or the thing we need to maintain. And of course, we need to have the projects.

If we don't have the projects, we'll reduce. Well, we tend to base to our more projects than we can fund, so we capped the R&D spend and we prioritized, and it's sometimes painful, but we do prioritize heavily.

And we've said that what we're going to do is over time reduce SG&A and that hasn't changed, and we continued working on this. You saw in Q3, we have a small average.

For Q3 and Q4, I think there's a calendarization issue of expenses that, maybe, not everybody has really considered but, overall, we continue driving operational leverage and that will continue to happen with SG&A spend as a percentage of sales that reduces. On the other question, Mene, do you want to cover this 1?

Yes. I mean, I can say that, cotadutide date will be presented soon.

The PCSK9 dates we have not had. I mean, all of these programs have met the go criteria for moving.

As Pascal said, that they will go to be reviewed and prioritized and go to governance. And then we have to formally make the Phase III investment decision based on the business case and the opportunity.

So, we have the data set to move to Phase III. We also need to have the business case to move to Phase III as well.

And they have to stack up against other opportunities that we have. Then follow them, I have to say.

From a BioPharm perspective.

Thank you. And Mene, on the 4831 products of the MPO, could you help us understand what they plan for that?

It's an integrated program, so we'll have interims obviously, and if we meet the interim analysis criteria than we've moved in to the Phase III part of the study.

Got it. Thank you.

Hi, thanks for taking my questions. So firstly, I recall that on a coal post announcement of the Alexion acquisition, Marc was definitely was comfortable around the trajectory of consensus AstraZeneca, top-line and margins pre the deal and you stated that in fact, internal planning assumptions suggested upside to that.

And for that reason, they consented to lift the margins next year and then improvement thereafter. I just wonder if Mark's comment on underlying margin assumptions still stands, or if anything has changed over the last 12 months, either be it pressure from VBP or simply a desire to invest to a greater degree unlike to address profitability.

That's the first question. The second is just on China VBP headwinds next year.

You, obviously, now got visibility on what products are going to be impacted when the defeat would be willing to quantify what kind of headwinds, you'd expect in 2022. Thank you.

Aradhana, you want to cover the first 1 and Leon could cover the second 1.

I think the first one is really around the question is one of operating leverage and we're always focused on improving our operating leverage, balanced obviously with investment in the business and Pascal, you heard him, and I'm sure my R&D colleagues will attest that we have more projects that we can fund. And then there's always some quarter-on-quarter variability.

But our ambition is to be at 30% plus for the base business and Alexion on

top. Alexion will now be going forward obviously as part of our core business, and our mixed shift in terms of the specialty versus primary care will continue to evolve, and where we see margins going will depend on how that mixable, which of our programs are more successful.

We also have some partner programs which we have lower margins. But our ambition is -- continues to be the same and we are very much focused on operating leverage.

I think there was an R&D questions for Mene. Now, with the VBP questions for China.

So, regarding VBP for 2022, I think the Batch 6 this year is just insulin and there could be coming first half of next year, Batch 7. And 1 of our major products, I think could potentially be impacted the next year.

But based on our past experience, VBP tend, we usually -- we'll not win the tender and we get a 20% to 30% price cut and lose some volume and maintaining majority of the loyal patients. I think, gradually, the sales are flattening out.

So, I think there's impact. I think the largest impact next year will be Pulmicort VBP impact actually happened already in October this year so and we'll continue to have impact on Pulmicort business.

Thanks, Leon. Time or VBP, which are the impact.

I mean, we've had quite a number of products that takes addition which are addition next year. But in terms of new batteries as loan expand next year, this we're much less affected the products in several really the main one.

The next question is go ahead. thanks so much for taking my too.

With the public offer for Sobi for AstraZeneca is an 8% shareholding and roughly $640 million position. Given the acceptance bid has now been extended twice, I'm not sure I've seen AstraZeneca 's view of the offer.

And tied to this, given your recent acquisition of Alexion, remind me if this is a strategic position or a financial one? And then secondly, with two antiviruses for COVID close to be rolled out in the marketplace, can you talk about what role you think the antibody cocktails, including long-acting prophylaxis will play in light of these recent developments?

Thanks so much.

Aradhana, you want to take the first one and Mene the second one?

Yeah. So, we can't really and don't really comment on our financial positions.

So, we can't really comment on your so-be question.

Can I just make sure I understood the question that you asked about? I wasn't sure if you're asking the question about the vaccine and the antibody or just the antibody.

Can you just repeat the question, please? So, I was wondering if the view or the long-acting prophylactic antibodies is now seen in a different light in -- given the reason developments of some polyamorous and protease inhibitors.

Not at all. Not at all.

I mean, again, I'll put it -- I'll try and articulate it reason. About 2% of the population, 2% to 3% don't respond adequately to vaccines.

Cancer patients, hematological malignancies, transplant patients, people on chronic immune suppression, right? We can wait for them to get sick and then have somewhere between 50% and and 80% protection from severe disease.

And so, they stay locked up and don't go out at all. Or you can give them a single injection and protect them for a year from getting any symptoms.

I know what I'd rather have. So --

They're not going to those people with using tablets every month or every week, right? So totally different use.

Thank you so much.

Next one is Marc were started Chris

Thank you very much. Two questions, please.

The first for Dave on Tagrisso in the U.S. I'm mindful of your comments.

Patient diagnosis from COVID only 10% lights of pre - COVID levels. You mentioned already seeing an impact of increasing treatment duration and you're stretching that adjuvant is only a modest 20% of frontline patients.

So given those, can you just help map out how we should look at degree so particularly in the U.S. market evolving over the coming years.

I think consensus expectations making quite meaningful growth. But it suggests from your comments that maybe we shouldn't.

And then the second is a question for Aradhana. Specifically, a mark of its 10-Q at the third quarter said, it has set aside $400 million for payments to you on Lynparza.

Can you let us know what you're assuming will be booked in 4Q of those 400 million? Thank you.

So, on U.S. Tagrisso, I think that the first element is that as we look at where we are right now, I think that we do continue to see rising front line duration of treatment.

I think that this is a source of growth moving forward and something that is important. I think secondly, certainly I'm optimistic that the COVID effects will wash themselves out here at some point in the not-too-distant future.

I think that the key and core element in the U.S. is the Andorra population.

While the NRX contribution to our TRXs at the moment right now is relatively modest, and I think in many respects being offset by the COVID declines, the duration of therapy that we would expect somewhere between 2 and 3 years does really begin to, over time, add up. So, I think from a peak year perspective, when we take a look at adjuvant, as we continue to move the key performance indicators, which is we continue to move testing rates, continue to move referrals, continue to move adjuvant treatment utilization, and as we get the TRX growth, I think that we're going to see peak year have good opportunities for growth.

I think it's just the time that it's going to take to get there, maybe a little longer than some folks were anticipating given the speed with which we penetrated into the frontline metastatic space.

Thanks, Dave. I have not gotten hold of the first one.

Yes. So, on your specific question, we don't give specifics around milestones but that is the arrangement as you know, that we have with Marc and that will reflect as milestones are earned in our estimates.

Next question is Emmanuel Papadakis. Emmanuel, your queue.

Thanks for taking the question. I'll be asking for Deutsche Bank.

Maybe I can take a couple of the Deutsche collaboration assets. So that's potent unnoticed TROPION101 was not listed as a 2022 readout, so it's now more likely '23.

More importantly, you announced the initiation of and PD - L1 with KEYTRUDA. So just interested in the rationale for that why PD - L1 KEYTRUDA Imfinzi.

And how do you see that sitting with , for example, where you're also obviously have an active clinical development program? And then maybe just a couple of very short ones on HER2.

Could you just give us an update on your adjuvant plan season? You did mention the lack of significant being encouraging for early and you still yet to announce anything in adjuvant.

And could you just clarify your perspective and extend to real potential exposure to the outcome of the litigation. Are you from that or does that remain to be determined?

Thank you.

So maybe, Susan, you could go over the first 1 and Dave the second 1?

Okay. Thank you.

So, I think the opportunity for datopotamab deruxtecan is extensive in many different settings, so you will see a range of different trials that we'll be I'm pursuing. Obviously, in PD - L1 high pembrolizumab is an accepted standard of care.

So, I think the design of strictly longer rate, which is being run by our colleagues at Daiichi Sankyo, is logical and in that regard. But we will be continuing to develop just this particular ADC in a number of different settings so you can expect to see more on that later.

In terms of the opportunity for HER2 in the early stages of breast cancer, again, we're continuing to look at the development of this agent to many different settings. And again, you will continue to see further trials that will be announced as we are ready to in the coming months and years.

And -- sorry. Can you just -- any perspective on clinical positioning?

Again, I think there were different opportunities for these settings. I think they add different pieces to it.

Obviously, I think that's first one to it. It's a different mechanism of action from an additional check point inhibitor in that setting.

I think again they going to have -- as you see, the evolution of the next wave of immuno-oncology agents, and the introduction of antibody-drug conjugates I actually think there's going to be an opportunity for combinations and potentially for the segmentation of the space. I think they are different opportunities, and different patients may be interested in those different opportunities, depending on their particular on their setting and their underlying fitness.

Just very quickly, Emmanual on SeaGen and Daiichi Sankyo, just for everybody's benefit. There are two things that folks can sometimes mix: there's an arbitration, there's a litigation.

The arbitration which is a private matter between DS and SeaGen is something we're not party to and so we just don't comment on. In terms of the litigation that's going on in Texas, we're working together with Daiichi Sankyo to vigorously defend against the SeaGen patent.

We consider that patent, which expires in 2024 to be invalid.

Thanks, Dave. Next question is .

Thank you for taking my question. Just the one.

In terms of initial integration costs and subsequent cost synergy from the Alexion acquisition. Now that some time has passed, how do you see the dynamic between these two factors developing of retirement?

And when do you expect cost synergies to begin to be realized Will this be quite a gradual process or more a front-loaded gain? Thank you.

Marc?

So, we had announced $500 million for the synergy from the third year close to closing. We are confirming these numbers.

To your question, when do this synergy start appearing? I can just say that they we'll start appearing to

limited extent from 2021, but the full extent the 100% of the synergies will be delivered in 2024. And obviously, it will progressively grow over time.

Thanks, Marc. Next question is Seamus Fernandez from Guggenheim.

Thanks for the question. So, I wanted to come back to VBP.

I think the comment was that we could see, I guess, what would potentially be a net reduction of about 50% for silicon? We've got the pressures from VBP this quarter.

Really two elements to this question, trying to get a better understanding of the underlying operating profit contribution. And from China going forward.

And the incremental pressure points that we could see as potential generics. I think we have patent explorations at least lifted.

least list it. Coming in China in 2024 for Lynparza, and potentially also relative to Farxiga.

So, it's just hoping you could help us clarify some of those patent timelines, and when we might see generics to those products. the operating profit contribution that you're anticipating from China, if you expect that to be meaningfully incremental going forward over the next two to three years.

And then, just as we think about VBP in China, is there a way to help us characterize the year-over-year impact of VBP, so there are limited number of surprises in 2022? Thanks.

Thanks, Seamus. It's 1 question, but it's probably a 1-hour discussion.

So, if that's okay with you, maybe we could follow up with you separately because there are so many pieces you've raised there. I'll make a general comment, which is over the next 4, 5 years we still expect on the CAGR basis -- on a carryover basis, we still expect China to go by high-single digit.

I mean, China is definitely going to be under pressure. We've said it before.

And China being China, it moves at light-speed and things happen faster than anybody expected. But we still have a strong business whereas products.

We still believe it will be a reasonable business for us. But there most like will not be 20%, 30% like we've experienced in those few years.

I mean, we're number one in the market and we -- again, it's still expected to go by high-single-digit on this year job is basis. We'll give more color on '22 when we get in January.

But in terms of individual , we could extend a follow up you. So, we get -- give a chance to the last three or four questions left.

Luisa Hector, over to your Luisa.

Thank you, Pascal. On calcine, save your question today.

I mean, it was a good quarter, just checking on what was driving growth. Any stocking benefits or is this very much the duration of use?

Perhaps some market share gains rather than COVID recovery, because your competitors still talk about the COVID impact. And for many of these, the Saphnelo launch, just a little bit more color on the target patient’s reimbursement just so we can think about the pace of that sales ramp.

And I noticed lupus nephritis Phase II, did not meet the primary endpoint, so, have you stopped development there? Thank you.

why don't you pick the other part of that The first one I missed, what product that is, it may have been one of your products for you there, but I'm sorry, I missed it.

Sorry it was Calquence.

Calquence so over to you Dave and then the next one is

Sure. So, Luisa, I mean, I think as we highlighted, I highlighted pretty pleased with the Calquence performance.

The specifics on the question that you're asking, we're seeing good growth in new patient surge in CLL. We're seeing also that correspond with good growth in TRX s.

We see that the COL update that's also taking place is happening in naive patients. And I think that's really important, obviously, in terms of getting that front line.

When I say naive, I mean BTKI naive patients. So, this is a demand story that we're seeing right now.

There's probably some on COVID elements that are in here. It's one where though there were some COVID benefits and switches from immunochemotherapy.

This is one product where we saw some benefits to that. I think that what I would say is that for us this is a demand story and one that I'm proud of the work that the team is doing to really establish this brand as best-in-class.

Okay. Let me quickly address the question about Saphnelo for lupus.

Clearly, we see some very good early response from physicians. Equally, it's pleasing to see that we see patients both in first line as well as controls.

Reimbursement is still, of course, work in progress although we're quite pleased where we are and we're still very early in the launch. But there are also a couple of clear challenges.

We are still launching these products in COVID time. Rheumatologists, specifically, are very sensitive with respect to immunocompromised patients, like as LE patients.

So, they want to have all the patients vaccinated with COVID. And equally, of course, we are still not having a permanent J-code with all the signals are looking good and there are very dedicated team in place and clearly, 2022 will be the year where we will see hopefully the fruits of our efforts here, Luisa.

There was a question on lupus nephritis, can you hear me?

Yes

Your question which is nephritis actually, the study was -- didn't meet its primary endpoint. There were 2 dose regimens.

1 was the normal regimen, 1 was an intensified regimen an actually the intensified regimen, Luisa. So very encouraging in the I think clinical --clinically meaningful benefits relative to placebo arm.

And so that is the regimen that we're taking forward right now in today's stage studies. And of course, this is another population will benefit from the lab just to add to Ruud 's comment around an immune -suppressed population that we're already going to be working with.

Actually, the next question is Viktor Sandberg. Viktor over to you.

We're trying to refresh a little bit over time, but we want to call your questions. Over to you Viktor.

Thank you very much. Thank you for taking my questions.

So, one of their rare disease portfolios, it seems like a lot of the growth case here is in neurology for your established portfolio. But given that myasthenia gravis is more of a common rare disease, I guess, versus PNH and aHUS.

How much is the high price a challenge for you to expand in that indication, especially given that maybe the competitive pipeline with will probably come in at a much lower price point if they get approved here going forward. Thanks.

the question does come to your So for the time being, only Soliris is a proof that in the two-neurology education, you have to obviously one of them. know we're the second one as gross in terms of patients have been very substantial.

You don't see the sales on Soliris grow, because we are converting Soliris to Ultomiris in the latest indication PNH and aHUS. So, you have these two opposite factors taking place.

For the gross is very strong. Most of the utilization of and myasthenia gravis is for effectively patients.

For patients -- for which any other treatment doesn't work. We have recently opened a rare study -- a Phase III study for Ultomiris.

The study is going to be five with authorities. And that we expect an approval in the course of 2022.

So, we really won't be converting Soliris equations to Ultomiris from 2022. And the level of Ultomiris hopefully, will be wider than the label of Soliris.

But then it would also, as you mentioned, all the companies entering with other mechanism in the field of myasthenia gravis. But the field of myasthenia gravis is composed of very different segments, and I think, Soliris and Ultomiris will keep retaining a strong advantage in this indication.

Thanks, Marc. We'll take 2 last questions and then we will have to close, so we respect your time.

Christopher (ph) , you want to go?

Thanks for taking my question. I appreciate it.

So, on PARP, the selective PARP, does Marc have an option for the selective PARP, or indeed any other potential PARPs going forward? And just can you -- when it comes to -- of the choices Zytiga versus XTANDI, can you remind us why you chose Zytiga for PROpel?

And what are the future plans in prostate cancer moving earlier, for example, do you risk losing out to Pfizer as non-hormone therapy, novel hormone therapy to move up the treatment algorithm? Thanks.

Thank you. We typically do not comment on our contracts.

So maybe this 1 we -- Dave, do you want to cover the second question about prostrate?

Yeah. Sure.

I'll certainly invite Susan to offer any comment on this, and I think that in terms of this, there's good and growing use of abiraterone that we see across the globe and it therefore was a very logical NHA to include within this. Now obviously there is other utilization that are non - ABI that exist.

But that's the primary reason there was in there just in terms of the choice of that. Susan, do you want to add?

No, you've covered it. Thank you.

Thank you. The last question.

Andrew Baum of Citi. Over to you.

Thanks. Just some follow-up question on the SeaGen and Daiichi arbitration.

I know you said you're not involved in the contract dispute but if it does result in a royalty paid with SeaGen, because they are found there in a portion of the molecule, would that incremental cost impact your share of the profit? And then I also just wanted to get a clarification from Dave on his sizing in the adjuvant setting.

He said, I think it was about 25% of the metastatic setting, but I thought that over 3 quarters of patients diagnosed with lung cancer in developed countries are amenable to surgery. So, any color on the step off there?

Dave?

Sure. So, I mean, I guess on the first piece, we don't really have anything more to add other than the comments that I offered on that, we're just not a party to the arbitration on that.

So, I think that's where we'll stay with right now. On the adjuvant portion, we've been pretty consistent in talking about the fact that there's far too many patients in lung cancer that are diagnosed late.

And in fact, I think it's also important to remember that we're talking about patients that are 1B to 3A. And so, you've got about 60%, 65% of patients diagnosed in stage four, the balance of those is going to be 1/8 through your 3B Pag, or your 3B population.

So, via dora indication itself is about 20% to 25% of the size of the flora indication. And I think that really the data is so impressive that we are really enthusiastic to be educating the multi-disciplinary teams on utilization of these data.

But adjuvant treatment is not something that is happening widely across the globe and it's taking us some work and some effort to really make sure that it's happening, but we're pleased with the progress that we're making and I'm confident that we will make good inroads in time into this important segment where we can really hopefully bend survival curves in this early stage.

Thank you, Dave. Let me just go very quickly through that.

And what I want to say is we continue to deliver a very strong growth. We've talked about China slowing down, and of course, we all know it's more difficult parts of the business are picking up speed.

Overall, we still see pretty strong growth this year and over the next few years. We are still in-line with the growth rate we have communicated in the past on this year job basis to 2025.

And where the pipeline is looking goes there's more to come. More to come.

So, we continue funding, of course, this pipeline. between Q3 and Q4 this year, I mean, we have definitely questions, but there's no doubt in our mind that we would deliver on our guidance.

We're very, very optimistic about it. And then, if you look at it in the quarter, some people were asking -- we will continue getting sales momentum there with a full quarter of Alexion on top because in Q3 we didn't have a full quarter there.

I think Emmanual or Matt was asking questions about the collaboration revenue, the milestone. I guide you to the consensus in terms of what you have there.

Expenses, we've talked about. So, if you take all of this into account, you can see that we expect to deliver our guidance for the year and there is absolutely no concern in our mind.

The COVID assets are delivering no profit, overall; but the good news is, we're moving progressively into a profitable mode for the vaccine. It will be always a modest profitability, but it will profitable.

And there are, particular, we believe has a substantial place in prophylaxis for patients who have immune issues like Type 1 patients, cancer patients, patients with immune suppressive therapy, etc. So, we see quite a big potential for this 1.

Next, is we see ourselves as a Company growing very strongly over the next few years. And, of course, we will continue improving our operating margin.

As we've said, no change to what we've told you in the past. Again, thank you so much for your interest in our Company and we look forward to more good news over the next few quarters.

Thank you.