This meeting is being recorded. Ladies and gentlemen, thank you for standing by. Welcome to the Sanofi Fourth Quarter 2020 Earnings Call and Virtual Capital Markets Day. We have planned for a 15-minute break between both events. You may remain connected to the Zoom link for all sessions.

I would now like to turn the call over to Eva Schaefer-Jansen, Head of Sanofi Investor Relations. Please go ahead, Eva..

Bill Sibold, Thomas Triomphe, Olivier Charmeil, and Julie Van Ongevalle; and Jean-Baptiste de Chatillon, Chief Financial Officer. Paul will make some introductory remarks, followed by our GBU heads, who will review the fourth quarter performance of their respective businesses.

Jean-Baptiste will provide an overview on the key financials, and we will then open for the dedicated Q4 earnings Q&A session. With that, I'd like to turn the call over to Paul..

Well, thank you, Eva, and welcome to everyone, and thank you for joining us today. Apparently a record number of joiners, so obviously creating a lot of interest in the story and how we're doing.

So 13 months following the announcement of our Play to Win strategy and in the year of a global pandemic, we're delivering 3.3% sales growth in constant currency, ahead of the 2.8% growth the year before. I'm extremely proud of our achievements.

Dupixent has become Sanofi's number 1 product in 2020, reaching €3.5 billion in sales and at a growth rate of 74%. Our Influenza vaccine franchise crossed the €2 billion mark, responding to the public health needs with our differentiated flu products..

Thank you, Paul. Starting with Dupixent. Sales reached €3.5 billion for the year, a growth of €1.5 billion over 2019. Strong sales momentum continued into Q4 with sales of €982 million, reflecting outstanding performance, both in the U.S. and ex U.S. across all 3 approved indications. This was all done in the backdrop of the second wave of COVID-19.

In the U.S., patient visits continue to be approximately 80% of pre-COVID levels and outside the U.S. local lockdowns prevented many patients from visiting their doctors.

Other highlights in the quarter included Dupixent's listing on the China NRDL, just 5 months after launch, 1 year earlier than the initial best case scenario, enlarging the accessible adult population with atopic dermatitis to at least 150,000 as of March, a number almost as large as the roughly 230,000 patients treated with Dupixent worldwide today.

The opportunity in China may grow to around 900,000 patients over time for adult AD alone..

Thank you, Bill. Q4 2020 delivered a strong quarter of growth in the mid-teens, driven by higher influenza sales. But before we dive further into the franchise performance, I would like to highlight the continuous strong performance across our pediatric combination vaccines portfolio, growingby 20%.

Main driver was Hexaxim, our hexavalent pediatric vaccine, especially in the rest of the world earlier, helped by a favorable phasing of our polio vaccine. Importantly, our Meningitis franchise returned to growth in the quarter, driven by catch up in the U.S. following COVID-19-related delays earlier in 2020.

Finally, as expected, the pandemic continued to weigh on our travel and adult booster vaccines. For the full year, you have seen that we grew 9% in 2020, the second year in a row of high single-digit growth at the upper hand of our mid- to high single-digit growth outlook announced at Capital Market Day in December 2019..

Thank you, Thomas. As expected, our General Medicine China business returned to growth in the fourth quarter, growing at 4%, with strong volume gains from Plavix and CoAprovel, up 78% for the year. This strong trend confirm our successful VBP building strategy, which delivered as planned. While the usual year-end true-up took place in the U.S.

in Q4, we know that globally, the decline in the Diabetes business, so significant moderation compared to previous year. This positive trend that we are seeing in our Diabetes business is mainly driven by the growth of Toujeo in Europe and the rest of the world as well as Soliqua uptake in all geographies.

With the launch of Toujeo in China in Q4, we are confident in the outlook of the Diabetes business in our key markets..

Thank you, Olivier. Similar to Olivier, I look forward to speaking with you again later today to share with you our team's strategic priorities to change the trajectory of our CHC business to grow our top line while continuously improving our bottom line. But let me now very briefly touch base on our fourth quarter performance of the CHC business.

Following the annualization of Zantac, the U.S. returned to growth with strong performance from the Allergy, Digestive and Sleep categories. And as a result, I'm happy to share, we're back to gaining share in the U.S. OTC markets since October. I would especially like to highlight the U.S.

Allergy category, which grew by 13% in Q4, with strong performance of our brands, Allegra and Xyzal, both benefiting from strong 360 marketing programs, and Xyzal from product placement and a popular chain of U.S. membership-only club.

Globally, digestive health brands, Essentiale and Dulcolax, performed well as many consumers adapted to different lifestyles during the pandemic, including a more sedentary lifestyle at home.

Outside the U.S., the Cough & Cold category was down 31%, driven by our high penetration in cough in Europe and an overall weak cough and cold season across regions because of social distancing as well as lowering pharmaceutical traffic. With that, I hand it over to our CFO, Jean-Baptiste..

Thank you, Julie. So Paul mentioned in October that we are committed to fully embrace sustainability in our Play to Win strategy, and it's happening, it's happening across the company. As an example, the finance team link the renewal of our €8 billion revolving credit facility with some of our key targets.

We had seen many green bonds in the past, but this was -- this one was the first with an ESG revolving credit facility, and you will see over time, many other proof points across the company..

We will now open the call to your questions. .

And now, we will take the first question from Pete Verdult at Citi..

Yes. Pete Verdult, Citi. Two questions. Maybe kicking off with Thomas first on vaccines. Just could you comment on where vaccination rates ended up this past winter in Europe and the U.S.

and although you've given us a split by value, could you just remind us perhaps from a volume perspective, the mix between your differentiated and commodity flu business? And then secondly, for John, on upcoming SERD data.

Is the data in-house yet? Can you remind us whether we will see PFS as well as ORR data? And should we be using the PALOMA 3 and MONARCH 2 data as the benchmarks when we assess the SERD data?.

Okay. Peter, thank you. Thomas, over to you..

Thank you, Peter. First, in regard to the vaccination coverage rate, we don't yet have final numbers because this is still ongoing by every single country in terms of North America or Europe. But it's clear to say that due to the COVID-19 pandemic, we've seen some increase in the VCR. I would expect roughly an increase of the U.S.

market by around 14%, 1-4, but again, that's not final numbers. It's with some interim IQVIA data. And in Europe, we've seen only a significant increase on the vaccination coverage rate. Also a few points, but we'll know more by -- in the next couple of months once we have the final numbers.

Now when it comes to value and volume split, overall, on the overall Flu business, if I look at 2020, you've seen that roughly, it's a balance between volume and value in terms of the 38% increase in the Flu business. And of course, as mentioned, we're going to increase further the differentiated flu portfolio.

We are very happy as we've seen the introduction of Efluelda in Europe. We believe it will be a strong driver of growth in Europe in 2021 and the years after. So I will say that we'll see more and more increase of the differentiated flu in both in volume and in value in next year..

Thank you. Thank you, Tom. John Reed, maybe you could update on what data we have in-house and the outlook for sharing data on our SERD..

Absolutely. Thanks, Paul. So we'll be sharing data on the Phase Ib study, which set the stage for the pivotal study in combination with Palbo, that'll be shared at a medical conference middle of this year. In terms of the first Palbo readout that will occur the first half of this year in the second and third-line setting as a monotherapy.

That primary endpoint is progression-free survival. Of course, we'll have overall response rates and clinical benefit rates as well as secondary endpoints, but that will be -- the PFS will be the primary endpoint..

The next question is from Wimal Kapadia at Bernstein..

Wimal Kapadia, Bernstein. So can I just ask on venglustat, please? Clearly, disappointing to see the update on GBA-PD.

But given safety continue to be favorable and the biomarker showed consistent and predictable GL1 reductions in both the plasma and cerebrospinal fluid, have your views of success actually changed for the product in ADPKD for the pivotal data in 2022? And then just tied to that, should we still be expecting kidney volume data this year, which may be fileable with FDA depending on the outcomes? And then my second question is, again, back to influenza.

Clearly, a strong 4Q and stronger than the third Q, which was above your in previous comments.

So can I just ask what drove that stronger than 3Q performance? And then secondly, how should we think about the flu progress in'21? Do you expect patients who took a vaccine this year that typically do not to fall off in '21? Or should the pandemic be in a better position ordo you expect incremental demand in '21?.

Thanks, Wimal. I'll come to venglustat in a moment. I'll make a comment before Thomas, but, maybe, let's just do flu while we have a chance. So Q4 over Q3 and also outlook for '21..

So Q4 versus Q3 it's related to the 3 drivers we've mentioned before. And clearly, COVID-19 has shown an increase of influenza rate in 2020. And therefore, there was an expansion, I will say, of the season and ended the balance between Q4 and Q3. Moving forward, we expect to see Q3 and Q4 roughly 50%-50% balance.

Of course, there are many different factors influencing that. For example, what will be the new strains? When they are announced? What's the impact? So as we get more data points, we'll be able to give you some more guidelines on that in the coming quarter.

Now when it comes to '21 outlook, what we've observed in the past is a slight decrease in this year. So there might be a couple of points down next year in terms of overall influenza this year.

But what's very, very important and very specific to the Sanofi Pasteur portfolio of influenza vaccines is that it's the growth of our differentiated flu vaccine, which come with a premium in terms of efficacy, but also a premium in terms of pricing.

And I think that from a value perspective, we'll be able to be well positioned to deliver on our mid- to high single-digit growth ambition that we have for the GBU and influenza will be a part of that..

Thanks, Thomas. And John, will come to you on data stuff, but maybe -- we are going to go through it a little bit more detail later at Capital Markets Day.

And I think, Wimal, your summary, if you like, was spot on, at least how I felt when I saw the data that was -- it's one of those sort of paradoxical moments where, although we were disappointed in Parkinson's, for those that are struggling, we increased our confidence outside of that. So maybe I'll let John answer..

Yes. Thanks for the question. Just to get to the question that you asked about the total kidney volume and when we'll have those data? That will be next year. So that's when we'll have that readout.

But in terms of the mechanistic hypothesis that we're testing, it is different from the Parkinson's situation in the context of the autosomal dominant polycystic kidney disease, the glycosphingolipid that are being impacted through the modulation of that pathway are acting like signal transaction molecules that affect differentiation of the kidney cells.

And so it really is a different mechanistic hypothesis, really an independent hypothesis compared to what we tested in Parkinson's..

Okay. John, I think we'll leave it to cover a little bit more later the read across, but I think you got to the number there. Next question..

The next question is from Jo Walton at Credit Suisse? Jo? Okay. So, let's move to Graham Parry at Bank of America Merrill Lynch.

Graham?.

Great.

Can you hear me?.

Yes..

Okay, perfect. So just going back to vaccines, again, I'm afraid.

So could you just help us understand what growth in vaccines has assumed in guidance, and in particular, for flu? I think Thomas, did you say the growth would be a couple of points down on 2020, but you're still expecting to see flu grow off that €2.5 billion base? And what sort of recovery and cadence of recovery you're expecting in Travel, Meningitis and Boosters, presumably that's all sort of second half loaded? Secondly, on Dupixent, obviously, accelerating growth in fourth quarter on prescriptions.

Can you just help us understand what's happening on pricing as you go into this year? Has there been any pressure from payers at all? Are you still enjoying pretty good coverage without too much pressure there? And then third question is just on other operating income.

That was around €100 million lower or expense, I should say, was lower -- about €100 million lower than consensus. You actually have quite a high Regeneron pay away in there.

So just are there some low level one-off gains sitting in there, if you could just help us understand the size of those?.

Okay. Well, we'll start with Thomas. I would just add that I think we would all believe as much of we love to be back traveling again. The more exotic travel, perhaps we'll be much later in the year and perhaps the beginning of the following year. But Thomas, I'll leave it to you..

Graham, basically, what I was saying is that and it's important to be precise, the overall vaccines GBU growth is expected into the mid- to high single-digit trajectory as we've committed from 2018 to 2025. When I was mentioning minus 2% to 3%, it's on the vaccination coverage rate for the full market, so not about Sanofi Pasteur.

When it comes to us, we expect influenza to remain a key growth driver of our overall trajectory next year and the years after. And again, it's about a few factors. You understood the importance of Efluelda, i.e., Fluzone High Dose growth in Europe and still in North America, that's very important. We expect also Flublok growth to keep growing.

What's also important for you to know is that we discussed it in the past, but you know that we will keep investing in our capacity. Notably in 2021, we'll have the start of our new U.S. facility for Fluzone antigen, that will start to produce from the year 2021, we've committed in the past.

But of course, that's an important driver when it comes to Fluzone High Dose. And the same thing, we had also invested into our Vaxigrip influenza trial -- vaccine, sorry, in France, in order to make sure that we can meet the demand. So that's very important moving forward for flu.

In parallel, to sustain the mid- to high single-digit growth of the GBU, the recovery in Meningitis, you've seen in the Q4 that Meningitis was turning positive. And therefore, we expect this to come back in '21, that's an important part of the driver.

As mentioned by Paul, I expect to still be impacted in '21 for the obvious reasons we know, that's more a '22 play in our view. But you've also seen, and I highlight it at the beginning of the call, that our terrific combinations have done well this year, like the previous year.

And we think that in emerging markets, they will keep their growth trajectory in '21..

Thanks, Thomas.

Bill, maybe you want to jump in on Dupi access, quarter 1 and onwards, what you see as the dynamics?.

Yes. So thanks, Graham. So first of all, we're in a really highly favorable access position. We have greater than 95% of commercial lives having established UM criteria for AD and asthma. And it's -- as we launched the product, we knew a couple of things.

We knew that we'd be in multiple indications, and we knew that there would be competition in the future. So we've strategically approached this and we've done very well. Looking ahead to Q1. Q1, you would expect, like in every other Q1, you have kind of a resetting of patients -- of insurance.

So your patient assistance programs and so forth have that impact. But we believe we're in a really strong position. Clearly, when you have competition coming in, the more companies there are, you expect some impact on gross to net.

But as I said, we started out with a plan knowing exactly how the market was going to unfold, and we think we're in a really favorable position for Q1 and 2021, in general..

Thank you. And then JB, OOI..

Yes, Graham. Yes, you spotted perfectly. Effectively, we have an accumulation of small deals. We are very active on the front of divesting some of our molecules in EP portfolio, a bit in consumer health also.

That's to execute on our commitment of the Capital Market Day, and we are effectively executing, and it's almost comparing to €100 million -- below €100 million, but quite near on Q4. Cash-wise, it's much more important what we are doing. But as you know, we are pushing down some goodwill accounting-wise when we account for those sales.

So it's not very really impacting on BOI, but Q4 was higher..

Okay. Thank you.

Next question?.

So I have on the chat 2 questions from Florent Cespedes from Societe Generale. The first one is on 2021 R&D news flow.

Specifically with regards to BIVV001 and fitusiran, and what the new time lines are? The second one is, could you be more specific and where you intend to redeploy the €500 million additional savings?.

Okay. Well, then, John, maybe you want to update on BIVV001 and fitusiran for this year? And other more broad question about news flow for this -- for 2021. Yes, John..

Yes. Thanks, Paul. So BIVV001, which is now known as efanesoctocog alfa, we have dosed the last patient is now -- the study is fully enrolled. Last patient has been enrolled. It's a 52-week study. So that we'll be reading out early in the following year.

So we're slightly delayed due to COVID, but are still expecting to have a submission in roughly the same time frame that we've disclosed previously. With fitusiran after the voluntary hold to reconsider dose and schedule, the study has now been restarted. 97% of patients remained on study.

The investigators and patients were very eager to resume, and we're delighted that we were able to get back on track with that study. We'll be having dialogue throughout the first part of this year with the health authorities in terms of what additional evidence they'll want to see in order to submit the NDA.

So we don't yet have an update for you on the timing for the fitusiran final submission..

John, broader news flow for 2021?.

Well, for 2021, we will have 8 pivotal readouts that will include the amcenestrant in the first half of the year for the monotherapy in the second, third line breast cancer as well as 2 Libtayo readouts.

And then in the second half of this year, we'll have 2 Dupixent readouts for spontaneous urticaria -- chronic spontaneous urticaria area as well as for pemphigus nodularis, so 2 more dermatology indications. We'll also have rilzabrutinib pivotal data for pemphigus vulgaris, another dermatology indication.

And then we'll have a readout for Sarclisa in the front line of myeloma context for the transplant ineligible population. So expect a rich year of news flow throughout 2021..

Thanks, John.

Maybe I'll just add, and maybe we'll talk about it a bit later, but the investigator feedback on fitusiran, and everybody was disappointed that we'd be on a voluntary hold, but actually, it's provided us with some much richer insights into the potentials for interval dosing, which while nobody wants to take a short delay, actually, we think the profile may improve.

So we'll see what the data sets. But it was -- we wouldn't have found this out, I think, unless we've been on this journey. So -- okay.

Next question?.

Yes, another question from the chat from Geoff Porges. What proportion of your volume now is in the U.S. and globally in premium brands? This is for influenza vaccines. So it's a volume question on split U.S. ex U.S.

And the second part is, are you underway with a combined flu COVID vaccine? And do you believe COVID will become another repeated new vaccine annually?.

And Thomas, just before you answer those great questions, I did neglect to throw the question to JB on the reallocation into R&D..

Yes. Thank you. I think it's an important question to read through what happened already in 2020 because it was a very significant swing. It was €0.5 billion savings in 2020 from effectively arbitrage within our portfolio. So it was happening very quickly, and you see it on my slide about savings.

That's why in 2020, already, we saw an acceleration of the spend of R&D in Specialty Care. And that's where we are, of course, investing. Efficiencies also have helped accelerating this level of spend in R&D in Specialty Care.

So you were asking of the €500 million, the next €500 million, yes, it will come -- a lot of them will come this time from COGS, which will, of course, tie up with the improvement we are expecting on the gross margin. And yes, we are looking at reinvesting them because we are gaining confidence on our top line growth.

So we -- it makes us much more confident that we can reinvest it behind our pipeline, which is, of course, more and more promising, we need to invest into it. So you remember that Synthorx, Principia, Kiadis, Kymab, all those companies we have acquired. We will have the annualizing of their costs in 2021.

So you can expect to see effectively R&D spend going up, but in a completely different context than before. Instead of being spreaded all over the place, it's really connected to our priorities in Specialty Care on -- in vaccine. Yes. I think -- I hope it gives more color to what we are executing..

Thanks JB.

Thomas?.

So back first to influenza and then I'll talk about COVID-19. So for influenza, again, I think what's important to have in mind is that with the new Fluzone antigen building coming online in 2021, you should expect a growth of both our differentiated vaccines, i.e., Fluzone High Dose, Efluelda and Flublok, Supemtek.

I do expect growth on both sides of the pond in North America and in Europe, especially for, again, Efluelda, Fluzone High Dose. You will see that in North America, you will see that in Germany. I expect maybe a significant growth in volume and in value from the differentiated flu.

Now what will be the impact on the standard dose flu remains to be seen, that's more linked to the vaccination coverage rate, as we've discussed before. Now, when it comes to COVID-19 and influenza, great question. A little bit too early to have a definitive answer. Still many things in terms of ability to do COVID-19 and flu together.

You know very well, but flu has a very specific logistics, that it's an annual vaccination. We still need to see what's going to be the need for boosting, by when and how long are the COVID-19 shots duration. So many questions to answer there. But you have noticed that we are very interested.

You have noticed that we're starting Phase 1 of mRNA flu vaccine this year, knowing that we are the influenza vaccine leader worldwide and knowing that we have 2 shots on goal with COVID-19. Should there be an opportunity, we'll be just around the corner..

Thank you, Thomas.

Next question, please?.

The next question is from Jo Walton. Okay. So let's move on to Richard Vosser at JP.

Richard?.

First question, just on China and the recovery there. Just your thoughts on the sustainability of recovery in China for your products and future price pressure. And then aligned to that, just, JB, you highlighted the increasing confidence in the growing top line. And I note that you're sort of saying General Medicine should be flat out to 25%.

So do you feel confident enough to give a target like you give for vaccines and consumer in terms of growth now.

It looks like it's all growth going forward, but just your thoughts there?.

Okay. Thanks, Richard. Jo, we've tried a couple of times, so maybe if you want to submit a question online, if you can, I would try again a little bit later, sorry, in case it's our responsibility. Let's go to China. Olivier Charmeil, maybe you have some views on the outlook..

Yes. Thank you. The market has suffered, of course, in 2020, mainly due to COVID and the definite number is not yet known for the decrease of the market, but probably in the range of 10% to 11%. The market is going to bounce back, and we are expecting for 2021 growth that is going to be significant, 6%, 7%, 8%, not to say more.

Of course, there has been price pressure with the implementation of VBP in the last 2 years. We see now that, of course, the volume growth continues to be very strong. And on the other hand, we are very happy with our performance, both on Plavix and Aprovel projected implementation of the VBP.

So the China market remains a volume market on General Medicine and on Specialty, of course. We continue to see with the registration of Dupixent and the start that chorus in the future, a significant portion of our growth will come from Specialty..

Thanks, Olivier.

JB, why are you not providing guidance on the future of the business?.

Well, Richard, I'm glad you captured my optimism, that's fine, and that's clearly where I am. Now we have, I think, a guidance, which is quite clear for 2022 with this BOI ratio. And yes, we are really committed to deliver on it. And we have a nice set of guidance out there to help you modeling it. But yes, we will deliver on 2022..

Maybe just add to that, it's our responsibility as an executive team and the wider organization to toggle that way. And remember, back in Capital Markets Day '19, we said that we wanted to be able to stick to the BOI and deliver. And today, we could.

You can just see from the numbers full year '20 with the 120 basis points improvement that we're -- you can see the line to where we're going, and you should expect us to deliver those things, and then we'll anchor from there. Next question, please..

We will take a final question from Jean-Jacques Le Fur at Bryan Garnier. Jean-Jacques, please go ahead..

We'll come back on the flu vaccine.

And for clarity, could we assume that you will be able to add again about €500 million in sales this year as you did last year? And if yes, how can we see the capacity -- manufacturing capacity if you are successful with the COVID -- your COVID vaccines, which I assume will take some of them for manufacturing? Or is the new U.S.

factory enough to deliver the additional flu doses?.

Thomas?.

Thank you. Yes, Jean-Jacques, so we have made sure that we always make sure that we secure the demand of our current vaccines. You know that we are manufacturing and supplying a lot of different vaccines that are critically needed even in COVID-19 pandemic times.

And we made sure that our supply capabilities are growing and it's not linked to the COVID-19 vaccines development that we are doing. So we have everything we need to increase this.

As I mentioned before, the Fluzone antigen building is already up and running and starting to produce as we speak now for 2021 northern hemisphere, that's very important for us moving forward..

Yes. Okay, good. Thank you. Next question, please..

Sorry, looking at sales.

We assume that you may -- you will be able to add again €500 million about?.

No. So no, again, the story of influenza is going to be a growth trajectory, which is a question in between growth from differentiated vaccines versus non-differentiated vaccines in a market, but most likely in non-pandemic period compared to pandemic period will be probably lower.

So I expect us to perform well in a declining market for flu just for next year, but we're not in the magnitude of €500 million, of course, because we are not in a pandemic situation at all. So you need to look at the continuous growth compared to the average trend of over 5 years, for example..

Okay. So time is over for the first part. So, let's meet in 12 minutes for the Capital Markets Day. Thank you, everyone. .

Ladies and gentlemen, thank you for standing by, and welcome back. We are now going to begin the virtual Sanofi Capital Markets Day 2021 portion of today's event. Following the initial presentation, we have planned for a 5-minute break before the second section of the CMD event. You may remain connected up to this Zoom link for all sessions.

I would now like to turn the call over to Eva Schaefer-Jansen, Head of Sanofi Investor Relations. Eva, please go ahead..

Thank you, Natalie, and welcome. We are looking forward to spending the next couple of hours together with you and various members of the Sanofi leadership team to share and discuss the overall progress we are making in implementing our strategy in core parts of our business as well as in transformation R&D.

As usual, you can find the slides on the Investors page of our website at sanofi.com. Moving to Slide 2, I would like to remind you that information presented in this call contain forward-looking statements that involve known and unknown risks, uncertainties and other factors that may cause actual results to differ materially.

I refer you to our Form 20-F document on file with the SEC and also our Document d'Enregistrement Universel for a description of these risk factors. Now let me take you briefly through the agenda for today.

Paul Hudson, our Chief Executive Officer, will start with opening remarks; followed by Dietmar Berger, Head of Global Development and Chief Medical Officer, who will provide an update on the late-stage priority assets; Natalie Bickford, Chief People Officer, will then introduce us to the culture change here at Sanofi, which is imperative to live on our Play to Win strategy; Olivier Charmeil, Head of General Medicines; and Julie van Ongevalle, Head of Consumer Health Care, will then discuss the new strategic priorities of their respective businesses, followed by a Q&A session.

With that, I'd like to turn the call over to Paul..

Well, thank you, Eva. Earlier today or just a few minutes ago, many of you participated in our Q4 earnings call. And I thank everyone of you for joining us and staying with us for the 2021 Virtual Capital Markets Day. It's been a little been over a year since we met at our 2019 Capital Markets Day, and where we embarked on our Play to Win strategy.

Today, we want to give you a snapshot of our progress. It has been an exciting journey for us, and I hope that you, at the end of today, will be as confident as we are in our amazing future at Sanofi. Let me start by saying that we are ahead of our 6-year plan and the one that we shared with you in December 2019.

This is even more reassuring in the backdrop of the unprecedented times that we have been facing during the pandemic. Across the organization, our teams have been relentlessly executing on this plan, and I want to take this opportunity to express my gratitude for all their hard work.

Together, we continue to be entirely focused on achieving the targets, which we have set out for 2022 and 2025. Our 3 core growth drivers have delivered in 2020, Dupixent with €3.5 billion of sales in 2020 has now reached blockbuster status in a quarter and continues to grow strongly. It is Sanofi's biggest contributor to sales growth.

And this is just the beginning for Dupixent's amazing growth trajectory. Later today, Brian Foard is going to share with you how he and his team are expanding around this mega brand in type-2 COPD, chronic sinusitis without NP and other diseases, and while we are convinced of its sales potential of being greater than €10 billion.

Our vaccine franchise has generated €6 billion in sales in 2020. Influenza was certainly the strong driver, but also the PPH portfolio grew double-digit to over €2 billion in annual sales. I'm extremely confident that we will continue on our mid to high single-digit growth ambition going forward.

Our rich pipeline is getting significant momentum as we continue to follow the science, and we are only accelerating demonstrated by 12 projects entering Phase III in 2020 alone. John and his leadership team will share with you the progress on the R&D transformation.

So looking at Slide 7, you can see how it demonstrates our ability to execute on capital allocation. Over the last 12 months or so, we engaged in multiple M&A and BD transactions, employing our capital to bolster the pipeline in existing priority areas, supported by the proceeds from the sale of our passive stake in Regeneron.

What is driving us? Adding exciting science and first-in-class technologies to our pipeline. We're doing this in areas where you are -- where we are strong from a capability perspective, where there is low marginal cost to commercialize and where accretion can be reached even faster.

Starting with Synthorx acquisition, adding 4707 that combined so well with other assets in our oncology pipeline. And for the first time today, we'll speak about 4809, fitting perfectly into our immunology pipeline. This has the potential to address a wide variety of autoimmune diseases. Moving on to Translate Bio.

I think it's worth remembering that we've had a strong relationship dating back to 2018, and that relationship has all been about trying to make sure that we're also going to be heavily involved in messenger RNA. Now in June of last year, before we'd even had a readout in mRNA, we also knew that it was an opportunity for us to simply double down.

So we widened that collaboration. We took all of the targets, all the assets, take transfers, so we could really make sure that we can participate fully in the future if mRNA becomes successful. And as we know now, certainly in a pandemic, that's proven to be the case.

On Kymera and the IRAK4, you will also hear today it's a great fit with our immunology franchise, and we're getting ready to move the first molecule of that collaboration into the clinic this year.

The Principia deal gave us full control of tolebrutinib, the brain-penetrant BTKi, a potentially truly disease-modifying asset that we put into our 4 Phase III trials straight after POC in the middle of a pandemic. We also picked up rilzabrutinib another exquisitely selective BTKi. You'll hear more about this today.

So this is the path we want to continue on to add to the sustainable growth of this company. We are consistently seeking value-creating opportunities. And here, we took decisive action to create a new European industry champion in API manufacturing.

We've started with the carve-out activities, appointed a CEO and we're on track towards a potential IPO in 2022. We will set up this company for success and plan to maintain our supply chain with EUROAPI, while reducing the complexity within our own Sanofi industrial network.

When we set out on our margin targets in 2019, I remember that many of you questioned our ability to be sufficiently disciplined to reach them. Well, we are well on our way with margin expansion and increased our BOI margin by 120 basis points in 2020.

This evidence should leave you with absolutely no doubt that we will not only achieve the 30% target in 2022, but also reach the target of more than 32% in 2025. The key drivers for this improvement will include the continued strong growth of Dupixent. And we announced today that Dupixent is expected to be accretive to BOI margin by the end of 2022.

I suspect that's faster than many had assumed. On Slide 10, you can see a snapshot of the 2020 sales performance of our 4 global business units. We created them in 2019 for more autonomy and more accountability in our execution.

Specialty Care and Vaccines are delivering healthy growth rates as we are freeing up resources across the group and investing behind our growth engines. A focus of our discussions today are the strategic choices we're making in our General Medicines and Consumer Health businesses.

In General Medicines, Olivier will explain through the importance of prioritizing core brands, key markets and digitalization. Julie will give you her management perspective and how to bring consumer health care back to growth, the progress towards a stand-alone unit and where we are importantly on the switches to OTC for Tamiflu and Cialis.

So what do we hope you'll take away from today? Well, that we set out to do everything we said we would do. Now not everything is perfect, and we don't pretend it to be the case for our challenges. But I'm really proud of the organization and delighted with the progress that we have made.

We are delivering on the fundamentals, getting us in shape to do what we need to do. So many great things are happening internally every day that are simply not visible or appreciated outside. We want to take the opportunity to simply talk about some of them today. The longer term, '23 onwards, this is about the pipeline.

I would like to ask Dietmar to update you on the status of our late-stage priority assets.

Dietmar, over to you?.

Thank you, Paul. It's my pleasure to be here with all of you today. 2020 has been a year of true progress in our R&D portfolio transformation, and John will provide you with a full update later today. I want to share highlights on the development progress of our 6 priority assets.

As you know, the COVID pandemic has posed unprecedented challenges for all of us, and I'm proud of the agility and innovative approaches to secure the continuity of our many clinical development programs.

I find it remarkable that we were able to enroll more than 4,000 new patients in clinical trials in 2020, while maintaining 98% of patients in our ongoing studies with time lines largely unaffected. So let us turn to the priority assets.

Our success story of Dupixent continues as we were able to rapidly roll out our development plan in several new indications. We initiated 3 new pivotal studies in 2020, and Brian Foard will provide more details on our ambitions in new indications later today.

We continue to remain excited about our fully owned SERD called amcenestrant, which is a potential best-in-class endocrine backbone in hormone receptor positive breast cancer across treatment lines. We expect the pivotal data from our AMEERA-3 trial in second line and third-line metastatic breast cancer later this year.

We are also looking forward to sharing the compelling combination data from our AMEERA-1 trial, which led us to rapidly initiate our first-line pivotal trial in combination with palbociclib. On fitusiran, we have encouraging news to share. First, fitusiran received Fast Track designation from the FDA in December.

And second, we resumed dosing in patients in our pivotal trial program in January, less than 3 months after we had initiated a voluntary pause. More on the fitusiran program in just a minute. For BIVV001, we completed enrollment to meet the end-of-study criterion in our pivotal trial in December.

The study includes a 52-week follow-up period and due to the COVID pandemic, we now plan to share top line pivotal results in early 2022. Venglustat continues to be a highly attractive program for us.

While we are disappointed by the results of the Phase II trial in the GBA Parkinson's disease population, biomarker data confirmed the mechanism of action of venglustat with both meaningful and predictable GL-1 reductions in plasma and the cerebrospinal fluid. More on the progress of venglustat's development in a moment.

And as for nirsevimab and tolebrutinib, our Phase III programs continue, and we remain confident in the planned submission dates of 2023 and 2024, respectively. On Slide 13, a few more details on fitusiran.

We remain committed to improving therapy for patients suffering from hemophilia through an innovative portfolio, including the first-in-class siRNA fitusiran, which has the potential to rebalance the decision coagulation cascade without sacrificing efficacy for convenience.

Later today, fitusiran's amended protocol and dosing will be presented to the scientific community in an oral presentation at the Annual Congress of the European Association for Hemophilia.

And while we cannot share all the data yet due to the conference embargo, what I can tell you is that the new protocol suggests a potentially stronger profile of fitusiran through a lower dose and extended treatment intervals. In the coming months, we will be engaging with health authorities to discuss the regulatory path forward.

So more to come on submission time lines following our alignment with the regulators. But early feedback from investigators and the hemophilia community has been positive, and the vast majority of patients are continuing the trials at this point.

And on Slide 14, I want to reemphasize our conviction that venglustat has the potential to become a transformative medicine across multiple diseases.

As a reminder, venglustat is a next-generation oral brain-penetrant glucosylceramide synthase or GCS inhibitor with clear proof-of-concept data in Gaucher Type 3 and Fabry diseases, and a potentially transformative effect in the treatment of polycystic kidney disease.

And while the recently completed MOVES-PD study demonstrates that effective GCS inhibition does not show benefit in Parkinson's, it's important to note that the underlying biology in Parkinson's disease is entirely different from rare lysosomal storage disease or ADPKD.

Biomarker findings from the MOVES-PD confirm that venglustat exquisitely targets GCS and leads to consistent, predictable GL-1 reductions in both plasma and the CSF.

And this reaffirms our confidence in moving forward with venglustat in our 3 lysosomal storage disease indications as well as in ADPKD, with even greater conviction in the safety profile of the assets.

Due to COVID, we are now expecting pivotal data in ADPKD in the first half of 2022, which leaves the submission on track for 2022, as previously guided. And with that, I hand back to Paul..

Well, thank you, Dietmar, for that update. And as I mentioned in the last CMD, not every molecule proved to be successful. But that is the natural risk you run, especially when aiming for first-in-class. I remain very confident, though, in the science, the unmet medical need and the commercial opportunity for our priority assets.

I think we have some real, real game changers in our late-stage development. So I'm now going to hand over to Olivier and Julie, who will give you an update on their strategic priorities.

The businesses they lead are a big part of our company that contribute to, amongst other things, helping us finance R&D, helping us to deliver breakthrough medicines. We will run general medicines even more efficiently being BOI accretive for the group.

And on consumer health care, we're making good progress to make it stand-alone, so it can be more agile and get back to growth..

Thank you, Paul. I'm excited to talk to you about our new priorities in General Medicine. We are in the process of drastically changing our business model. As you will remember, in the past, Sanofi's mantra was no small products, no small countries. Since then, our market environment has evolved and requires a radically different approach.

In a nutshell, what got us here will not take us there. We are now focusing on core assets and key markets. This will enable general medicine to remain a significant contributor to group BOI and will fund Sanofi's specialty care pipeline.

As you can see from the chart on the left, GenMed GBU sales have been declining consistently over the past years, mainly as a result of the loss of exclusivity of parts of our portfolio. Most of the decline has been driven by price, while overall volumes have been stabilizing in recent years.

In fact, cardiovascular and metabolic medicines remain critically important for chronic disease management among large population, especially in emerging markets where healthcare reform policies are aiming at improved patient access and affordability.

We believe that our core assets, which today, in total, represent 40% of general medicine sales have the potential to grow mid-single-digit CAGR over the period of 2020 to 2025. By 2025, we expect these core assets to grow to 60% of our sales base.

Within key markets, we will deploy our innovative go-to-market model to unlock the full potential of these markets. We are progressing well with streamlining Sanofi's long tail of small products. At the same time, we are reshaping our industrial network to reduce our cost of goods and improve our gross margin.

Our commitment is to generate the same level of sales in 2025 as we did in 2020, thus stabilizing sales of general medicine over time. This, however, excludes the sales of few API, which are expected to be deconsolidated in 2022.

The overall resilience of our business makes us very confident in our ability to deliver significant upside to current 2025 consensus estimates, coupled with an accretive and stable BOI margin ratio throughout the 2020 to 2025 period. Moving now to the next slide and taking a closer look at our off-patent established product portfolio.

We benefit from 2 important trends. First, the graphic on the left of the slide depicts that global volumes are stabilizing in recent years, following the meaningful impact from LOEs, such as Renvela, U.S.; and Plavix, japan, in prior years.

Second, Lovenox and Plavix are standard of care treatments, in treatment protocols, which offers the potential to capitalize on growth opportunity in China and emerging markets. The low molecular weight heparin market continued to grow with Sanofi as a market leader.

In addition, we expect label expansion for Lovenox into cancer associated thrombosis later this year. Regarding Plavix, the anti-platelet market continues to grow in volume, especially in emerging markets, driven by an aging population, increasing incidence of coronary artery disease and ischemic stroke.

And in China, where the penetration into the antiplatelet market is still relatively low, our successful BBB strategy delivered 90%, 9-0, volume growth in 2020. Going to next slide. In our core assets portfolio, we have 4 patented brands with meaningful differentiation potential.

As discussed earlier, we intend to focus on selected markets with class expansion opportunity. For example, PRALUENT is the only PCSK9 associated with the reduction in all-cause mortality and offering a once monthly single injection in a prefilled pen.

The cholesterol-lowering market is currently expanding at high rates, driven by improved cardiovascular outcomes. We will particularly focus on China where we launched PRALUENT in April and have already more than 5,000 patients treated. We intend to relaunch PRALUENT in Germany, which is the largest market in Europe. Now let's talk about Multaq.

This is the only antiarrhythmic drug to reduce the risk of severe hospitalization for atrial fibrillation and the only drug currently actively promoted in the U.S. New data was recently published showing the CV benefit of controlling rhythm early in AFib patients. Moving now to diabetes.

We will compete in selected markets across Europe and key emerging markets, continuing to drive market share expansion. As mentioned Toujeo our leading next-generation basal insulin, is expected to continue to grow, driven by new launches in attractive emerging markets such as China, Algeria and Turkey.

We expect further study readouts during this year in both type 1 diabetes and chronic kidney disease. Moving now to Soliqua. Our focus will be on large emerging markets, where approximately 70% of global premix use is located. In the U.S., we are shifting our promotional efforts to the post-OAD segment for patients with A1c levels above 9.

Bottom line, we have 4 differentiated core assets with potential for our key markets. With that, let me now hand over to Alexandre Germay, Head of our Global Cardiovascular and Established Product Franchise to share some more detail on our tactical approaches..

Thank you, Olivier. Hello, everyone, and very nice to be with you today. Moving to Slide 19, we have thoroughly analyzed our portfolio in the market where we compete.

Without taking from this analysis, we plan to focus on 13 key markets with our core assets, which include the U.S., China, EU5 and set a key emerging markets such as Brazil, Russia and India. As you can see from the pie chart on the slide, these markets are expected to make up roughly 3/4 of our general medicine sales in 2025.

We will continue to adapt our operating model in the other markets. Our focus on key markets correlates with a significant amplification of digital-enabled customer interaction, so that we can address the needs of our customer in a more efficient as well as impactful way.

Our goal is to conduct 70% of our HCP interaction supported by digital platforms over the next 3 years compared to only 30% in 2019. This is a bold move, and we are confident in achieving these targets. Actually, it's already well underway. 3 reasons why we are confident. First, our digital material provides relevant, trustworthy and fresh content.

We have received very positive feedback from our HCP customer, which has provided us with evidence of their acceptance and appreciation, especially during the pandemic.

Second, we have recently built our digital infrastructure to include a large-scale content factory and have already reached a critical mass on e-permission of around 60% of our HCP target universe. With this, we are already generating positive interaction with a large volume customer.

Lastly, we aim to integrate our main digital channel in all our key markets by the end of this year. This will enable us to further improve individualized customer experience and progress towards the next best action powered by artificial intelligence. With that, back to you, Olivier..

Thanks, Alexandre. Now moving to the next slide. You may remember that at the Capital Market Day in 2019, we announced our intention to streamline our products from around 300 branded product families down to 100 by 2025. We are making great progress and already reduced our mature portfolio to 180 product families by end of 2020, ahead of target.

Clearly reducing the complexity of our portfolio is a critical level to free up resources and unlock value from our core brands. At the same time, we are optimizing the remaining assets, reducing the number of SKUs and concentrating them in the top decile plans.

Reshaping our industrial network to achieve higher utilization rates and greater focus is expected to lead to cost of goods improvements and contribute to our objective of keeping the GenMed BOI margin ratio stable during the next 5 years.

In summary, on my last slide, I hope we were able to convey some of the excitements around our decisive actions that will be fundamentally changing our overall business approach and go-to-market model inside general medicine with core assets in key markets.

In executing on our plans, the GenMed business is expected to be accretive to grow BOI margin and a resilient contributor to group BOI. This transformation is already underway.

And while it will require some time before stabilization of general medicine sales will be achieved, I expect to be able to share initial successes of our strategic choice along the way. With that, I hand over to Julie..

Thank you, Olivier. I'm delighted to be here today to share with you my perspective on the role of CHC and Sanofi's transformational journey. I've only been with Sanofi for 5 months, and I'm convinced that there is a significant value to unlock in our CHC business.

I also have with me, Josephine Fubara, our Chief Science Officer for CHC, who comes with a wealth of expertise on switches. Starting on Slide 23. As you know, over the past couple of years, our CHC business has been performing below market growth.

Therefore, together with my team, as part of our Play to Win strategy, we have decided to focus on 3 pragmatic strategic priorities to unlock growth. First, we will address our legacy of a broader complex portfolio with over 250 brands. Our performance has been impacted yearly by product-related issues on many of our tail brands.

The good news is that we have a very well-diversified portfolio across countries and categories with still untapped potential in both already strong global and local brands. And we have the opportunity to build on these strong assets, embracing our complexity to unleash the potential of these brands.

You will see here similarities with what Olivier shared on GenMed, divesting where it makes sense to free up resources to focus on what adds value.

In other words, we will reduce the complexity of our portfolio by swiftly divesting our tail brands, completely reducing the number of brands we operate by roughly 60% in 2 years from over 250 to about 100 brands. We will also optimize our go-to-market model. We will remain present in all the countries we are in today.

But our model will be more tailored by geography.

At the same time, we are embracing our complexity by taking a more granular approach, not being only focused on the big categories and global brands, but focusing on attractive subcategories in key geographies based on consumer trends and our portfolio strength and opportunities, with the ambition to outperform the market as early as 2022 in these specific areas.

In addition, as you're well aware, we have 2 major switches, Cialis and Tamiflu, which are expected to be key pillars of our future growth. First, my team and I are getting -- are putting significant efforts behind these opportunities, which should contribute to reaching above-market growth from 2024.

Second key pillar of our future success is to change our mindset to become a holistic consumer-centric brand building business, a mouthful, but very important to unleash that untapped potential of our brands, delivering consumer-driven innovation and bringing sustainability at the core.

Becoming a fully integrated stand-alone CHC business is a key enabler to move faster in this journey. Finally, obvious digital, a key driver of the strategy.

And we're accelerating our digital journey by building a true data and digital edge, ranging from data-driven decision making to accelerating e-commerce and developing digital health opportunities. My vision is really to make our business the best consumer business in the world and for the world.

To achieve this, as of this year, as of now, my focus is on the flawless execution of our strategic priorities. Moving to the next slide, I want to give you an overview of the market potential. The global OTC market is a €130 billion market, which is anticipated to grow 4.5% CAGR over the next 5 years.

And when including other channels such as e-commerce, this CAGR is predicted to go up to 5.6%. As I shared on my previous slide, we are taking a more granular approach, looking at consumer and market trends. We will be focusing on a subset of the overall market to appropriately capture value and maximize our brands, be it local or global brands.

As an example, instead of looking at the allergy cough and cold big category, we will focus on allergy, where we are already well positioned and are getting ready to accelerate, as you will see on the next slide. These subcategories are a €51 billion market, overall growing faster than the market, and that, again, is excluding e-commerce.

To us, they represent today about 1/3 of our CHC business. As you can see on Slide 25, indeed, we have a rich portfolio of strong global, but mostly local brands in these fast-moving subcategories. When looking at our leading brands, we're currently ranked #3 in allergy, #1 in general pain and #3 in body pain globally.

You will likely recognize Allegra, one of our most successful Rx to OTC switches, which along with Xyzal has driven the growth of the business in the U.S., making Sanofi a preferred switch partner in the industry.

Doliprane is a local loved brand and the leader in the pain market in France with around 60% market share and a brand awareness as high as Coca-Cola at 99%. And we have more loved brands, such as Icy Hot, America's #1 topical pain relief brand or Dorflex in Brazil, #1 pain relief brand. Moving to Slide 26.

I wanted to share with you the example of the mental wellness market or more specifically sleep, which is a subcategory within nutritional. And as a consequence of the COVID pandemic, it's anticipated to grow in line with the market over the next 5 years and, obviously, faster than the market when we include e-commerce.

Based on these consumer trends and even if it's not been one of our key priorities in the past, we have decided to focus on mental wellness. And we already have some high-performing local brands, which we want to accelerate. In the U.S., we have Unison, already one of the leaders in OTC sleep and growing faster than the OCC sleep category.

We're now entering the largest and fastest-growing sleep segment, which is Natural, with the launch this year. Another one of our very well-known key brands this time in Europe is Novanuit. In December, we launched a new campaign in France with immediate double-digit impact on growth, plus 20% growth versus the market at plus 12%.

Honestly, the more time I spend on our brands, the more I see the opportunity to grow them into true loved brands, strengthening consumer engagement through insights, data and leveraging digital. And our strategic priorities are all about unleashing the potential of our numerous brands, and as a result unlocking growth.

Now on Slide 27, the creation of our stand-alone business is an important enabler to our strategy execution, and we're progressing well. The design and planning phases are complete. We expect to have operationalized the majority of our CHC legal entities by the end of 2021, and the relevant social processes are on schedule.

Being stand-alone means that we will have a fully dedicated organization, making it more agile, competitive to unleash the potential of our brands and deliver on our switches. With that, let me hand it over to Josephine to give you an update on where we are with our 2 Rx to OTC switches..

Thank you, Julie. Hello, everyone. It is my pleasure to be here with you today. On Slide 28, as mentioned by Julie, Sanofi has a successful history in switches with Allegra and Xyzal. Allegra is the fifth largest Rx to OTC switch over the last 20 years. And we have a very experienced switch team who between them have worked on every U.S.

switch over the last 10 years. With a total of €1 billion in sales potential, not only do we believe that Sanofi's Rx OTC switch pipeline is the largest in the industry so far, but more importantly, we intend to provide broad access with this switch and thereby help millions of consumers.

Tamiflu and Cialis, which we believe will be first-in-class, will have a significant impact on self-care in the U.S. and empower consumers to take ownership of their health and improve the quality of their lives.

OTC Cialis has the potential to allow more sufferers to obtain treatment with a safe, effective and reliable product without the access burden.

While OTC Tamiflu has the potential to reduce the burden on health care systems due to influenza office-based certain specializations, particularly in situations like we're currently in today with the COVID-19 pandemic, inherent with being first-in-class, these are not easy switches.

And the planning gets further complicated in the pandemic environment, particularly for Tamiflu. However, we are in continued discussions with the regulators to ensure that these time lines can be maintained. Both programs are fully underway with 16 studies initiated or completed in 2020, and half of them have been converted to virtual studies.

We are currently on track with the key studies we need to do to meet the targeted launch dates. One of those critical studies is the actual use trial, which measures whether test subjects can appropriately use the product according to the label without medical supervision under a simulated OTC environment.

We believe no other manufacturer has reached the actual use trial space in the U.S. for an OTC switch offered in erectile dysfunction medication. We believe we will be the first to do so. The first patient aim is planned for the actual use trial for Cialis this year, and in 2022 for Tamiflu.

With that, I hand it back to Julie for some concluding remarks..

data, digital, e-commerce, sustainability and excellence in execution. And our stand-alone structure will allow us to be more agile, applying fast-moving consumer goods standards while leveraging Sanofi's expertise and capabilities where more efficient. Thank you. With that, I'm handing it over to Paul..

Well, thanks to Julie and Olivier and Josephine and Alexandre. I hope you get a sense of the major transformation ongoing on those 2 businesses and how our prioritized portfolio will enable us to continue to drive growth and innovation. Now we also talked to 2019 Capital Markets Day that as part of the Play to Win, we need to reinvent the way we work.

So it is my pleasure to introduce our new Chief People Officer, Natalie Bickford, to talk about how she's going to ensure that we have the culture change that is simply so imperative to deliver on our strategy, Natalie?.

Thank you, Paul. And I have to say it is uncommon for a Chief People Officer to be invited to take part in the Capital Markets Day, so I am delighted to be here and to share with you what we're committing to achieve with our people in the service of our patients.

Let me start by sharing a quick overview of my past professional experience because, indeed, like most of the new members of the EXCOM, I haven't joined Sanofi directly from the pharma industry. Many years ago, I was the U.K. HR Director for AstraZeneca and indeed worked alongside a young Paul Hudson.

But I spent the majority of my career in highly consumer-focused businesses like Kingfisher, Sodexo and Merlin Entertainment, which are low margin, tight budget organizations where you have to place your bets and ruthlessly process your efforts.

More recently, I've been keen to get back to the pharmaceutical industry, and I felt a strong emotional engagement to Sanofi's purpose. And in particular, to the strategy laid out by Paul.

So I've spent the last 5 months listening and learning and thinking about the role that HR needs to play to support the delivery of the Play to Win strategy over the next 5 years.

And some of my first impressions are that we've had a somewhat inward looking culture with too much corporate tree call, overly bureaucratic and complex in its ways of operating. But what I've also found is that our leaders show a huge amount of energy and enthusiasm to deliver the Play to Win strategy.

They're taking accountability and they're getting actively involved in evolving our culture. Having our most senior leaders on this side is critical, but to really move things, we need to engage the entire workforce in delivering culture change. But culture can be a difficult and somewhat vague concept to grasp.

So we've identified 4 Play to Win as proxies for the new culture that we need to live and breathe. And by applying these behaviors to every decision that we make and every action that we take, real change will come.

On Slide 31, these behaviors are to stretch, which means taking calculated risks, pushing ourselves out of our comfort zone and ruthlessly prioritizing our work; to take action, which means focusing on outcomes rather than activity and delivering against our priorities; to act for our patients and customers, meaning freeing up budgets to develop our pipeline, making sure that whatever we do, we see a really clear link to how this is going to deliver better outcomes for patients; and finally, think Sanofi first, which means always prioritizing the total company over our own interest or those of our direct team or our direct business area.

On Slide 32, let me give you a brief oversight of our new Sanofi people strategy, again, built to underpin Play to Win. We wanted the company to focus and deliver in 4 priority areas. Our first pillar is healthy organization. Here, we want to create a lean and adaptive organization with clear clarity of accountability.

In 2021, we will successfully land the new Consumer Health, Gen Med and EUROAPI organizations. We will anticipate and acquire future skill needs with a clear focus on digital capability. And we must also develop a world-class talent pipeline to feed succession to key roles to ensure our future success. Our second pillar is purposeful experience.

More than ever today, we are in a war for talent. So to attract and keep the best people, we need to create a highly compelling work experience and give a real fundamental sense of purpose. Not enough people outside of Sanofi appreciate the amazing career opportunities we can and do provide.

And this year, you will see us deliver a new highly proprietary and compelling employee value proposition. Our third pillar is winning culture. We must anchor the Play to Win behaviors that I've just highlighted across the business to ensure that we leave our old ways of working behind us and embrace the new culture we need.

And in 2021, for this year, we will build the Play to Win behaviors into all of our people journeys from recruitment, through performance management, learning, reward and talent management. The fourth and final pillar, which is particularly close to my heart, is diversity edge.

We've already made strong progress on gender at a group level, but now we need to broaden our lens to cover all strands of diversity. The business and societal advantages that come from driving diversity of the workforce and an inclusive environment of really significant.

And we're also highly committed to drive our relationships with the diverse communities that we serve, including better reflecting our communities and clinical trials, driving supplier diversity and involving all our leaders in relevant local community projects.

This month, we'll launch our new Sanofi DNI strategy with clear deliverables around building representative leadership, creating a work environment where we can all bring our best self and engaging with our diverse communities.

So in a nutshell, there's a lot of work to do, but I have a clear focus on our required culture evolution and our wider people priorities. We're not starting from scratch a tool. We're building on solid foundations. But the trick now is to be highly focused on these deliverables that will tangibly drive our company performance.

And more than anything, this is a super exciting time to be part of the Sanofi story. And with that, back to you, Eva..

Thank you, Natalie. So, we're now moving to our Q&A session. Now we will take the first question from Simon Mather at Exane..

The first question, Paul, is really just maybe some guidance on general medicines. Obviously, you want to keep revenues flat between now and 2025, and you delivered €14.7 billion in 2020. If you look at consensus estimates, they are significantly below this number. And on top of this, consensus expectations for your margin are also significantly below.

I'm just wondering if you could help square the circle in terms of what base we should use for 2020? Appreciate you have the value creative API coming up. So that's one aspect. But help there would be very, very welcome. And then the second question, and maybe this is a bit premature, but just moving on to consumer health.

And you've outlined your growth aspirations and the fact to it to be a stand-alone by the end of 2022.

I'm just wondering beyond '22, how we should think about the division and whether or not Sanofi still believes they are the best holders of that asset, especially given the strong growth profile that they'll be entering in past 2022?.

Thank you, Simon. I'll let Olivier comment on the base and the things. But just my own observations coming in. When you look at our Gen Med business, this isn't a carryover of established products business. This has got some real growth driving opportunities in it and an opportunity to be more efficient.

So -- plus I think Sanofi is pretty unique in its ability to work in some of these markets and deliver with this sort of entrepreneurship. And you may say, well, doesn't everybody say that. I would say how the company was created and its legacy touched on by Olivier, no country too small, no medicine too small.

I think we have more ability to extract more value than most, which is what made us dig deeper because to get the sales back to where they were and to help you guys understand that estimation on decline is just too easy given where we think we can actually go and beat that. That's a really important fundamental piece of understanding.

And perhaps a misunderstanding I had before I came in and a much clearer now route that I see it.

Olivier?.

The general medicine base is €14.7 billion. This includes €500 million of API that will go with the EUROAPI project. Of course, I'm projecting ourselves in the next 2 or 3 years, how we are going to get there.

It's, of course, through focus on core assets and key countries where we are going to allocate significant portion of our resources, and it's also about making sure that we stabilize the degrowth of our noncore assets. So it really grows on the core assets through volume growth and, of course, stabilizing as much as we can the noncore assets..

Yes. And there's truly great work being done already. Again, just to remind everybody that we were challenged a lot by yourself, Simon and others, around sort of opening the black box of our Gen Med business. You could get a sense of why you should just make an assumption bucketing such an important piece.

So you'll see at the time as we share the progress made. That's why we think we can beat what you guys have in models and why we will update you regularly on that.

The other question was on creating a more valuable business and are we still going to be the best owner? I think our entire effort is stand-alone increased agility, provide focus, give Julie and the team the wind at their back to go and get growing faster than the market. I think the switch is such a big opportunity.

And in particular, at a time in our evolution, after Aubagio patent expiry where our focus is single-mindedly on growth and preparing for switches, and we're not thinking about anything else. And we hope to create something incredibly value here inside the organization.

Next question?.

The next question is from Luisa Hector at Berenberg..

On vaccines, you're reiterating your target of the growth to 2025. I just wondered whether you have a wider spread on that number to factor in potential mRNA vaccine disruption? And maybe with that in mind, you could comment on your mRNA flu vaccine program.

Should we see that as an extension of your differentiated offering in flu vaccine? And is there any color you can provide? Presumably, this would have to be single dose to be competitive.

And do you think regulators will require head-to-head studies and noninferiority or superiority end points? And maybe if I could just ask a quick one, a second one, on the relative profitability of general medicines versus specialty today? And how you see that in 2025?.

Okay. Luisa, thank you for those questions. We'll come back, I think, to J.B. On what we have shared or not shared around relative profitability. And we'll come to Thomas on the evolution of the business, mRNA. Look, Thomas, it's a question that's being asked all over the place.

Maybe you can give a perspective on time lines and potential areas of disruption areas? Whether we don't anticipate disruption then our own role in influenza?.

Definitely. Thank you, Luisa. So in terms of mRNA disruptions, as mentioned before, definitely, we see mRNA as a very interesting technology. That's why we started with the Translate Bio partnership in 2018, extended it in 2020. And where we see the potential is definitely in getting to new territories, especially in viral disease.

So we'll start, as mentioned before, by Phase I in flu. So now where is it going to land on the influenza? It's very early to say. We need to have the data first, and we're not there yet. I need to watch there. Sorry about that. So we are in Phase I right now. As you mentioned, I think it's very important.

I can give you my perspective on how do I see mRNA. I think it's very important to have in mind first that when you look at mRNA for flu, it's going to be very different when you look at the development of a vaccine in a pandemic situation, that leaves today for COVID-19.

When we are looking into it, when the development of a field where there is already a standard of care for flu, for example. So I'm alluding to the second part of your question, what will it mean? In flu, there is already a standard of care in terms of efficacy and in terms of safety.

So what we will want to see is that with mRNA, especially flu mRNA, in 1 single-shot, they are more stable with rapid logistics all over the world where it's required every single year to provide a shot, but at the same level of safety and standard of seasonal flu. I remind you that the safety is highly proven and very strong.

And the same level of efficacy. And I remind you that difference is that flu vaccine has seen double-digit increased efficacy when compared to standard dose flu vaccine. So there's a lot we need to see. It's still extremely exciting. That's why we're getting there. But there's a lot of things we need to see. So that's going to take a few years.

It will have Phase I, Phase II, Phase III, when it comes to seasonal flu. It will ask for comparison, as you mentioned, it will probably require a multiyear check because you want to see not only 1 year, but 2 years that it's successful.

But of course, when you look at the portfolio we have in flu and the partnership we have with mRNA in Translate Bio, that's an interesting opportunity. Beyond flu, and I think that's why it's very interesting, there's a lot of viral targets where mRNA vaccines development could be super exciting.

We have seen some targets that have been started by the competition. We are, of course, in the middle of defining exactly where we want to go. Of course, we have not communicated on that part for obvious reasons, but it's extremely exciting to look at. Outside, we can go into Phase I trials in the coming years on some viral vaccines target.

Now the earlier part of your question was more about the, I would say, target of growth for the vaccines GBU. I won't say much more specific, even though you're probably interested. But we are really looking at mid to high single-digit growth from 2018 to 2025, that was our commitment.

And I think it's very important to highlight that it's based not on one single pillar. We're not a flu vaccine company. We are a multi vaccine company. It's built on flu pillars. It's built on pediatric combinations pillar. It's built on the coming launch of RSV nirsevimab. So we have a lot of pillars that will fuel that growth. We'll take it year-by-year.

But we have this mid- to high single-digit ambition for 6 years and for every year..

Thanks, Thomas. So Luisa, it doesn't change. Our commitment has stated it doesn't change, and we'll participate in the next wave of innovation. We don't think it's an easy ride for us either, by the way, of mRNA in influenza and et cetera, we'll be there, and we know how to do it.

So Jean-Baptiste, maybe something on relative profitability?.

Yes. Luisa, I think you're asking exactly the right question. And I think you know very much what is the answer, but let me give more color with what we heard from Olivier today. Yes, Gen Med is a very accretive business, and it's a BOI play, and we've seen it today.

Not only we want to keep it stable over time in terms of size, but we want also to maintain on that what we are looking at this accretion over time. So what's going to happen relatively to Specialty Care is just that will stay where it is while we bring progressively Specialty Care at a higher level, which will help, of course, the global Sanofi.

You have a first proof point with what's happening on Dupixent. But of course, progressively, it will also happen with other products. Right now, Specialty Care is where we are investing. So the R&D effort is increasing on that area. So it will be a slow motion. But it will go in the right direction..

Thank you, J.B..

The next question is from Peter Welford at Jefferies.

Peter?.

I got a question on consumer. They actually....

Peter, we lost you. We may go to the next question....

Sorry, there you go, I am here. I think -- sorry, I think you cut me off, sorry. Right. So let's start again. A question on consumer. So curious here with regards to the Rx to OTC switches here. Obviously, Cialis is entering user trials sooner than Tamiflu. The Tamiflu potentially launching before that.

Is that just related to the complexities, obviously, of the ED market and flu? Or is there something else that we should read into what's required here? And I guess for Paul or maybe also for Julie, just with regards to how important potentially bolt-ons are in your consumer strategy? You did mention the potential need to bulk up any of your franchises.

And I guess from Paul's perspective, is this a division where there is capital allocated to be able to do that, should it be deemed the best route to growth? And sorry, just coming back then to J.B.

Just trying to understand, maybe you could give us some clarity how many years forward should we think about Gen Med still being accretive? Or maybe -- I appreciate you don't want to give the margins, but can you give us an idea for how much longer Gen Med is accretive potentially to Sanofi, if you like, the crossover, I guess, is the question? And then just to Thomas, sorry, just back on the mRNA.

Is there a Phase I, I guess, immunogenicity or biomarker type read that can give us a quick yes, no, is this as good as your vaccine? Or do we need multi-year studies to know?.

Okay, Peter. Well, I'm glad you didn't get cut off. You got quite a fistful of question. That's all I know he is. So Josephine, maybe you just want to share just some flavor around the switch time lines. I mean I think what we've tried to say is that -- and I think you touched on it, the complexity in the journey is one thing.

And of course, COVID is another. But we feel confident in and around those guidelines given, and we've reached -- with Cialis, this was outlined, first patient in an actual use study will be this year. Nobody has ever even made it that far. So we're doing things that have never been done before, which also increased the certainty over time.

But Josephine, maybe you want to add something?.

Thank you, Paul. That's a really great, I guess, answer to the question as well. So like you said, right, we are advancing the programs.

We have been able to transform, conduct a number of key studies in 2020 that actually continues to progress us towards the actual use trial for Cialis in 2021, which we are confident that we're going to be able to meet. And then for Tamiflu, we are going into actual use trial in 2022.

And the only reason you see a difference in both timings is just because of the timings from when we started both programs and where we are right with the pandemic situation. But again, like I said, we remain confident in our ability to conduct these actual use trials and progress these programs to the expected launch date as communicated..

Thanks, Josephine. The next question was really about bolt-ons and whether you'd buy things for CHC? I think what we've tried to say is that we think we have enough organically to make the progress, and we have the switches.

I think where Julie has challenged me is around whether we can add other capabilities in around digital, e-commerce, looking at China and other areas where we can accelerate our performance. But we really have to think about being accretive. I think ultimately, buying to bulk up is -- would not be where we wanted to go.

As you've seen, I think some of the clarity that Julie has brought is actually slimming down to grow faster based on better choices.

And so I think we would look to capabilities and different things, was there anything different, Julie?.

No. Again, I 100% -- I mean, obviously, agree with what you said is exactly what we're trying to do. Obviously, we're always looking at ways to grow our business, be it organically and inorganically. And our Play to Win strategy is not dependent on M&A to deliver the growth ambitions that we have.

That being said, we're, of course, constantly evaluating opportunities to provide greater scale, be it in geographies or to add on to our subcategories that we're focusing on and as well, as Paul said, accelerating our digital journey..

Thank you.

J.B., Gen Med accretion, what is your outlook?.

Well, Peter, it will be very long. This business is incredibly resilient. I love it, by the way. It's -- so 2025, but after -- it has no patent leads, there is no -- it has very little happening there. But with a very active management, we will keep it accretive for the long time..

Thanks, J.B. He loves all our businesses equally, just to point that out.

Thomas, mRNA Phase I sort of proof of concept, any fast feedback from you?.

I'm afraid there's not going to be a Phase I miracle read in vaccines. There is a litany of vaccine development even for well-known targets that have failed in Phase II or Phase III, be it non-mRNA or mRNA, it would be the same. So no. Long story short, no Phase I, Phase II, Phase III will be required.

Obviously, you want to see if you have neutralizing antibodies. If you don't, it is game over. If you have, it doesn't mean it's going to work. You need to check the ability of the host to indeed protect. So all 3 phases will still be required. I don't think it's really changing that path..

Thomas, maybe you could just -- I could ask a supplementary on behalf of Peter, which is, where is mRNA not hit-a-home run in the development so far?.

So there are a few products in the story of mRNA, where it's not always been successful. So we have -- indeed, in the past, there has been some publication, for example, on the pandemic flu mRNA trial that was not impressive at all.

You also have noticed probably that, and it's public information, that Merck has given back the rights that it had on RSV, mRNA with Moderna. So there are different areas where it's not a home run, things to look at. Again, very promising technology still, and we've seen that with COVID-19, but there are many areas where it might be applicable.

There are as many areas where it's not going to be applicable. You all know that polysaccharide vaccines, for example, which is a huge range of the portfolio today, will not be applicable to mRNA technology. So exciting technology. We're looking at it. We're more than looking at it. We're developing it, and we're going full steam.

But we'll be able to select the right niches and the right markets to be successful..

Yes. I think look -- and we said it in some of the dialogue earlier, the -- in a pandemic, I think we're the first company to accept that we're moving at record speed. But mRNA in a pandemic with a single antigen is probably the go to, no issue there at all. I think we should just be a bit grounded on what the opportunities are.

Again, we're fully participating, but we don't expect everything we try and do an mRNA to be a success. I don't think anybody should right across the spectrum because there were some areas where it was unsuccessful on the lead up. But we're thrilled that it's had some success in COVID-19.

And just to remind you, I'm not the expert that Thomas is, but when you get to the multivalent strains in terms of solutions with mRNA, then even not all mRNAs are equal in terms of what's your ability to go after multistrain. So there's -- we're going to be -- we're there. So we're not -- that doesn't scare us, but it's interesting. Okay. Good.

Next question?.

Yes, Paul. So I have 3 questions from Stephen Scala from. First one -- 2 actually going to our Gen Med team. What are the patent expirations on Multaq? Sanofi previously made the decision to deemphasize diabetes research, but why aren't week basal insulins attractive opportunities? And the last one goes to the consumer health team.

It is clear that Sanofi gains from owning consumer, but what does consumer gain by being owned by Sanofi?.

Thank you, Steve. Provocative. Maybe, Olivier, you talk about Multaq LOE..

Multaq LOE is 2029 in the U.S..

And then maybe we could look at why Julie you're interested in being part of Sanofi?.

Sure. I think -- today, I think it will be a miss not to benefit from the total Sanofi. Basically, I want the best of both worlds. I want to be able to -- I mean create more agility, more speed by becoming stand-alone. But again, it would be a miss not to benefit from the bigger Sanofi, especially in areas like science and data..

Thank you, Julie. Good to know.

And then Olivier, the weekly basal insulin, what have we missed?.

So general medicine is, of course, completely instrumental to the success of the Play to Win strategy, in funding the Sanofi specialty pipeline.

We are, at the beginning, mostly in the emerging market of the story of Toujeo, that has not been launched in China, for example, or to be more precise was launched only mid-November, we are also at the beginning of our story with Soliqua. So we have really a significant runway.

Soliqua has only been launched in a small number of countries in the emerging markets. Soliqua will be launched in 2022 -- end of 2022, '23 in China. And we all know that a significant portion of the market in China in insulin remains a premix market.

So still a long runway with our assets that have not been fully deployed especially in emerging markets. We are, of course, looking to what the competition is also doing..

Thank you..

The next question is from Seamus Fernandez at Guggenheim..

So just wanted to get a quick update on -- obviously, I apologize if I missed questions on venglustat. But as it relates to venglustat for ADPKD versus some of the data that is presented in the press release around GBA, just wanted to get a better understanding of directionally the fact that the placebo actually was performing better.

If you can provide a little bit more color in that regard? And then just, again, directionally, just remind us again of the ADPKD opportunity? I believe this is predominantly based on preclinical data that's really driving the assumptions here. But just wanted to get a little bit more color on your conviction in the wake of these data.

The second question is actually on interest in gene therapy. How has that changed, Paul, in the context of some of the updates from the agency? It seems like the path for gene therapy maybe growing a little bit more extended and drawn out. So just wanted to get a sense of how Sanofi is thinking along those lines..

Okay. Thank you, Seamus.

Maybe Dietmar, do you want to jump in and then we'll also let John Reed, if he wants to add or comment on gene therapy? Dietmar?.

Yes, right. On venglustat -- thank you for the question. Venglustat is really an interesting molecule and considering that it's a pipeline in a pill. And because it inhibits so early in the signaling cascade, we were able to evaluate different hypothesis across different types of diseases.

And I would think that there are 3 buckets, One is the lysosomal storage disease bucket, where we have good proof-of-concept in Gaucher type 3, in Fabry. And we're following up on that, obviously, with studies in those indications. And that's simply the deposition basically and the metabolic pathways that are important there.

Then you've got the ADPKD, and that's a different hypothesis around signaling actually and secretory information in kidney cells and in the formation of those cysts. That is driven largely by preclinical data, both genetic, but then also preclinical in an animal model.

That animal model has been quite predictive, actually, which gives us a lot of confidence. But it's a different hypothesis, it's different type of disease. And then you got the Parkinson's, where it was about deposition of synuclein and can actually the GCS inhibition play a role there. And again, a different hypothesis.

So the fact that what we've seen in the MOVES-PD study, demonstrated no clinical benefit, has no impact on those other indications. What the MOVES-PD study also shows is that the GL-1 levels are distinctively reduced, so the drug works. The drug does what it should. It's just that the biology in Parkinson seems to be different.

So we remain really confident with regards to the other 2 buckets of indications. And the other information we got from MOVES-PD is that the drug has demonstrated a very encouraging safety profile, so we're even more confident when it comes to that safety profile as well.

The ADPKD data, the initial data will be on total kidney volume, and we're looking forward to see those data then in 2022..

John?.

Yes. Thanks, Paul, and thanks for the question about gene therapy. We remain committed to and interested in gene therapy. We see them as essential to include that modality as one of the ways we tackle problems in the rare disease space and the monogenic disorders, where we've had such a trailblazing history at Sanofi Genzyme.

And then also, particularly in the CNS area, we see quite a bit of opportunity there. We did establish an internal capability, we call the Genomic Medicines unit recently and are -- have assembled a team in the Boston area, taking advantage of our Genzyme heritage.

Genzyme did put a couple of AAV-based gene therapies into the clinic back in the day, as well as the gene therapy ecosystem of the Boston area, and are pursuing both viral and non-viral gene therapy solutions for rare diseases and CNS. We expect to generate 2 development candidates this year in 2021 and to put those in the clinic in 2022.

In terms of the CMC and manufacturing piece of that, we've talked before about how, at least with the viral vectors, there are many similarities to those manufacturing processes and how we have historically made certain vaccines.

And so we're leveraging those manufacturing capabilities and expect to have our first GMP facility come online this year in the Leon, France area, taking advantage of that. And then finally, I would say on the BD front, we're continuing to build up our toolbox of next-generation assets for prosecuting the gene therapy space.

Final thing I would mention, because I think it is a new exciting development for us, is that with the announcement of our intent to acquire Kiadis, a cell-based -- a cell therapeutics company, in their case exploiting the NK, natural killer cell platform for oncology. Our projects there will involve genome modification of the cells.

The first project we've announced is a CD38 knockout. NK cell engineered specifically for myeloma, engineered specifically to combine with our anti CD30 antibody Sarclisa.

And that's just the first of what we see as a pipeline, as you know genomically edited, genetically modified NK cell products that we will customize for various types of cancer in the years ahead. So we're very actively establishing that capability as well..

Thanks, John. And maybe I'll just add a couple of points. I mean it's been an interesting sort of 6, 12 months in the gene therapy landscape and not least in hemophilia. I think we -- John has touched on it, but equally important is CMC and manufacturing.

I think we all anticipate the future to be where pricing will be pressurized in gene therapy and cost of goods therefore need to be proportionately lower. So we're really focused on trying to make, if you like, affordable gene therapies go to market. We'll see how far we get. We do have this extensive history in rare diseases.

And I think we're all excited about trying to continue to contribute and stand on that, and open-minded a little bit about the rest. But it's not a given the uptake of gene therapies longer term. So we have to work very hard to demonstrate the value.

And you see now, when you have breakthrough data, it's not always confirming the opportunity that you have. So I think we're approaching it the right way, very sensibly, actually. Okay. So do we have time for one more? Okay.

Yes, please?.

So, we take one last question from Keyur Parekh at Goldman Sachs..

Two questions, please. The first one for Julie. Julie, you've kind of laid down an exciting plan for kind of changing the growth outlook for the CHC business. But I'm wondering if you can talk a bit about kind of your plans from a margin/profitability perspective.

Are you seeing this kind of as a need to reinvest in the near-term with margins going up kind of post the launch of Cialis, Tamiflu? Or do you see enough scope for you to kind of take cost out and reinvest to kind of get that growth? That's kind of question number one. And then question number two, kind of for Paul and J.B.

Paul, we've obviously seen kind of some of your peers kind of do a largest acquisition.

So just wondering if you can remind us kind of what your priorities are kind of from an M&A perspective? Is it still these Synthorx, kind of Principia sized acquisitions? And then linked with that for J.B., clearly, kind of if you look at multiples, if you look at your growth outlook, the stocks seems incredibly cheap.

What's stopping you from being more aggressive on a buyback, you have enough capital, you have enough balance sheet leverage.

So why not take advantage of the cheap valuation?.

Okay. Good. So snappy questions there to finish us off, Keyur. Thank you. So a very quick comment on CHC emergence..

What I can say is that our operational profitability is expected to remain stable and among the highest in the industry. And divestments will continue in '21 and '22. And if your question is, if we have what we need to unlock the growth that we have planned? The answer is, yes..

Okay. Thank you. For me, on M&A, I guess, and maybe J.B. will comment, the capital allocation, I suppose that connected the questions really. We want to create value. We want to add to our science. We want to do things. We have said we're more in the bolt-on sort of tuck-in territory.

I think the last 4 acquisitions over the last year, I think, would support that. We're trying to do things that make sense. We don't think we're a company that needs to do a big piece to consolidate just extra revenue. We think we have efficiencies to gain, opportunities to reinvest, science to accelerate.

So I think you'd be perhaps disappointed in us even if we did try and do that. So we're sticking to the science, and we have enough in hand. And I think you have to -- you sort of have to understand that. Having a healthy balance sheet, if you want to describe it like that, is J.B's problem.

Buybacks were low on our list, maybe the last thing on our list. Because we think we can create more value for shareholders and investors a different way.

But J.B., what's your view?.

We are doing a bit of share buyback. As you know, because we can sell the dilution of any mission we do. So we've just done some at the back end of last year or beginning of this year. But as Paul said, of course, it ranks quite low in our priorities. But what we did is, again, increasing for the 25th year, our dividend.

And I think that's a nice way also to return some of the growth and wealth of the company back to our investors..

Thank you. Thanks, J.B.

Eva?.

Please stay with us. We will now have a 5-minute break, and we will be back for the second section of our CMD called Emerging Leadership in Immunology. Thank you. .

Welcome back to the R&D section of Sanofi's virtual Capital Markets Day in 2021. The Sanofi R&D leadership team is excited to spend the next hour with you to share Sanofi's emerging leadership in immunology.

John Reed will open the section with some introductory remarks; followed by Brian Foard, Global Franchise Head of Dupixent; Naimish Patel, Global Head of Development I&I; Frank Nestle, Global Head of Research and Chief Scientific Officer; and then John Reed will return to you with concluding remarks, followed by another Q&A session.

So for those who may have just joined us, I just want to quickly remind you again on the instruction how to ask the question. . And at this point, I would like to hand the call over to John..

Thank you, Eva. Well, now the real fun of this Capital Markets Day begins as we dive into some of the science behind the Sanofi pipeline. Today, we will focus the R&D update on Sanofi's emerging leadership in immunological diseases. Immunology is a very dynamic space for us, and we expect rich news flow throughout the year ahead.

Before we dive into our presentation, however, I would like to remind you that since 2018, Sanofi R&D has been undergoing a massive transformation. The first point I would make is that we have completely reshaped the pipeline in the last 3 years from heavily primary care oriented to now entirely Specialty Care.

Within Specialty Care, we have significantly expanded our portfolios in immunology, oncology and hematology. To quantify this transformation, compared to just 3 years ago, our immunology portfolio grew from 6 molecules or products in development to 15.

Compared to just 4 years ago, our oncology pipeline grew from 5 molecules or products in active development, to also 15, which will grow actually to 18, assuming successful closure of the Kiadis and Kymab acquisitions. And compared to 3 years ago, our portfolio in nonmalignant hematology grew from just 1 molecule under active development to 9.

The second point I would make is that we accomplished this pipeline transformation while maintaining fixed costs essentially flat for the last 3 years. This required enormous trade-offs, for example, exiting cardiovascular and diabetes, optimizing our sites and reallocating resources on a large scale.

Third, in parallel, we accelerated our R&D transformation through M&A and business development activities altogether, bolting on 6 companies, providing Sanofi with pipelines, platforms and talented people, especially topnotch scientists.

The new platforms for accelerating our future drug discovery included the nanobody platform of Ablynx, acquired in 2018; the synthetic biology platform, the Synthorx, acquired in 2020; the tailored covalency platform of Principia acquired last year; and the NK cell therapeutics platform of Kiadis, which we expect to close the first half of this year.

You'll see examples later today of how these platforms are empowering our pipeline. And again, big trade-offs were made to absorb these costs, the cost of these acquisitions, altogether, keeping R&D costs flat between the beginning of 2018 and the end of 2020. Okay. So on to today's presentation.

My colleagues will build on the themes that we introduced at last year's R&D day investor event.

We will illustrate how our teams leveraging the 3Ps of pathways, deep expertise in biological networks; connected disease biology; patients using molecular profiling, digital and data to dissect disease heterogeneity and move towards precision medicine approaches for solving health care problems; and finally, platforms where today we will focus on differentiated platforms for drug discovery.

These 3Ps of pathways, patients' insights and platforms are supported by a foundation of improving capabilities that accelerate execution, reduce cycle times and improve overall R&D productivity.

So with that brief introduction, I hand over to Brian Foard, Global Head of the Dupixent franchise, to share our vision and plans for Dupixent, the cornerstone of Sanofi's immunology pipeline. Brian, over to you..

Great. Thank you so much, John. And again, I really want to thank everybody for joining us for today's event. We are extremely pleased with Dupixent's performance in 2020. The brand has performed exceptionally well throughout this pandemic.

And that really speaks to an amazing team of individuals around the world, but also the strength and the uniqueness of our profile and its acceptance among both physicians and patients around the world.

Now you probably heard a lot about this amazing medicine at our Dupixent R&D event this past June, where we expanded on the innovative science behind Dupixent. And since then, our confidence has only grown in Dupixent's ability to lead the transformation of the treatment of type 2 inflammatory diseases.

So now as you look at Slide 8, as you can see from the NBRx chart on the right-hand side, when you look at the combined prescriptions of both dermatologists and respiratory specialists, Dupixent has emerged as the #1 biologic in the U.S.

And we enter 2021 in a great position to further accelerate that growth with approximately 230,000 patients on therapy across 47 countries and 3 foundation indications. Now this growth is also supported by a best-in-class profile with clinical data out to 3 years.

So let's move on now and we're going to share with you a bit about how we're building a mega brand with Dupixent. So this next slide really dimensionalizes the significant growth opportunity in dermatology with a primary focus on atopic dermatitis, our Dupixent's first indication.

Now Dupixent is indicated as young as 6 years of age in moderate to severe patients who are not controlled on topical corticosteroids. And we are currently evaluating Dupixent in patients below the age of 6. Now today, with an estimated 2.2 million biologic-eligible patients in the U.S.

alone and only 5.1% market penetration to date, the growth potential remains significant. And as we expand beyond the U.S. to our top 8 markets, that eligible patient population more than doubles to 4.9 million.

And this includes the opportunity created by our record NRDL approval in China, and that will add approximately 900,000 eligible patients over time. Now beyond geographic expansion, I really want to draw your attention to another dimension of growth. We are in the clinic with 4 adjacent dermatology indications and also AD patients below the age of 6.

There is no other advanced therapy pursuing as many dermatologic diseases. Now this strengthens Dupixent's leadership position among dermatologists while also addressing patients suffering from debilitating dermatologic conditions. Now if these studies are successful, we estimate that we would add approximately 500,000 patients in the U.S.

alone who could benefit from Dupixent in these adjacent indications and also the age expansion. So in summary on this slide, you can see we have an unparalleled opportunity to reach many more patients suffering from dermatologic diseases driven by underlying type 2 inflammation. So now turning to respiratory.

We see a very similar opportunity for leadership in asthma and adjacent respiratory indications. Despite a more developed U.S. asthma marketplace, the biologic penetration rate remains extremely low at actually only 17%. Thus, there's ample opportunity to grow via the market, but also via market share. As we exited 2020, our U.S.

NBRx share was approximately 25%. There's also significant opportunity to expand outside of the U.S. marketplace where Dupixent is already a leading respiratory biologic in large markets, such as Germany and Japan. If you look at our top 7 markets alone, we estimate there to be about 1.9 million biologic-eligible patients.

And additionally, there remains significant unmet need in moderate to severe asthma patients in China.

So consistent with our approach in dermatology, we're also investigating adjacent respiratory indications driven by type 2 inflammation, most notably, our type 2 COPD program, a highly underserved patient population where no therapies have been approved for almost a decade.

Now beyond our currently approved asthma indication of 12 and above, we expect to add approximately 600,000 patients eligible for Dupixent in the U.S. alone through age and indication expansions in respiratory.

Again, this uniquely positions Dupixent as the leading advanced therapy in specialty respiratory and certainly supports our leadership ambition in diseases driven by underlying type 2 inflammation.

So I'm now happy to transfer the call over to Naimish, our Head of Immunology Development, to discuss Sanofi's deepening leadership in type 2 immunologic diseases beyond Dupixent. Over to you, Naimish..

Thank you, Brian. So at our Dupixent R&D event last June, we dove deeply into the biology of type 2 inflammatory diseases and explained why unlocking both IL-4 and -13 are critical for Dupixent. The mantra was, it takes 2 to tackle type 2 inflammation.

And I'm now thrilled to introduce Sanofi's next wave of molecules for type 2 diseases beyond Dupixent. So our approach of developing the next wave of molecule really leverages our deep understanding of the type 2 inflammatory cascade. Here is a very simplified depiction of the process.

On the left here, type 2 inflammation starts with allergens or pathogens contacting the epithelial barrier surfaces, such as the skin, airways or GI tract. This leads to alarming events with mediators such as IL-33 or TSLP.

And in the next step, OX40, OX40-Ligand costimulation plays a critical role in immune programming with Th2 cell differentiation, expansion and memory T cell formation. This is well -- this is where you can almost say the blueprint is created for chronic inflammation and chronic disease such as atopic dermatitis.

These cells then produce cytokines such as IL-4, IL-5, IL-13. And these cytokines stimulate and prime effector cells like eosinophils and mast cells, and they lead to tissue pathology, allergic responses and symptoms such as skin itching, thickening and atopic dermatitis.

So from this, you can easily see how the mechanism of Dupixent in blocking IL-4, IL-13 potently inhibits type 2 inflammation in diseases such as atopic dermatitis, type 2 asthma and CRSwNP. You can also see how rilzabrutinib, a molecule acquired by Sanofi with the Principia acquisition, targets type 2 inflammation.

The BTK enzyme drives allergy by mediating B cell expansion and production of IgE and activation of mast cells, eosinophils and basophils. Thus, rilzabrutinib, a potent and extremely specific BTK inhibitor, we believe, has a significant potential to treat type 2 disease.

And as another example of how Sanofi is really leading with innovation, I will share with you in just a moment 3 new programs for rilzabrutinib that will start this year. But there are more areas to explore.

We are also looking upstream in this pathway to develop therapies that afford potential to treat diseases that are not just purely type 2, but also nontype 2 and mixed phenotype. This is where our anti-IL-33 monoclonal antibody, itepekimab, is being investigated to reach more COPD patients than any other biologic has attempted.

And today, I'm excited to share with you for the very first time the compelling Phase II data that led us to launch our Phase III trials in COPD.

And finally, we believe that OX40-Ligand is truly a unique target for type 2 diseases because it represents a critical costimulatory step that leads to the programming of immune response for chronic diseases like atopic dermatitis.

The Kymab KY1005 monoclonal antibody, that Sanofi announced intention to acquire, holds promise to reprogram immune response so that durable disease control may be approached for across -- approached across a number of indications.

And we look forward to discussing more about the promise of anti-OX40-Ligand once the acquisition of Kymab is finalized later in the first half of this year. So now we'll dive deeper into these key molecules, starting with itepekimab, our anti-IL-33 for COPD. So itepekimab could be the first molecule to treat most COPD patients.

And on a personal note, as a pulmonologist who's been practicing for a number of years, it's quite disheartening to think that so few new mechanisms have entered the COPD treatment paradigm over the last 20 years despite the fact where COPD is a leading cause of mortality worldwide.

But today, I'm glad to say we really believe that we think we're about to change this. We think -- we took the unique step of studying itepekimab across a spectrum of moderate to severe COPD because of the known effects of IL-33 on both type 2 and nontype 2 inflammation.

This is supported by published data, shown here on the left in the graph, demonstrating that IL-33 levels in advanced COPD patients who are former smokers are elevated compared to healthy controls. And here on the right, for the first time, we're revealing the results of our Phase II study of itepekimab in COPD.

In this study of moderate to severe COPD patients, itepekimab reduced COPD exacerbations by approximately 40%, 4-0, 40% in former smokers. And importantly, this effect was similar in type 2 and nontype 2 patients.

This effect size is far and above what has been seen by any other biologic in COPD, where many competitor Phase III studies have been 20% or less in terms of exacerbation improvement. And this is for the sickest patients with COPD.

And these results have given us confidence to commence the Phase III program in a population where no biologics have succeeded. Thus, we have started our pivotal program with itepekimab. The objective of these studies is to establish that itepekimab can reduce COPD exacerbations and remove -- and improve lung function in most patients with COPD.

This, in combination with the Dupixent COPD program, has the potential to address greater than 80% of patients with COPD with frequent exacerbations. Turning now to the rilzabrutinib program. We believe this molecule, that came to us with the Principia acquisition, has the potential for a pipeline in a product, and I'll explain why.

So I mentioned in the first slide that BTK is a key driver of allergy and activation of type 2 inflammatory cells. And it would be logical then that BTK is a potential strategy to treat type 2 diseases such as atopic dermatitis, asthma and urticaria.

The problem has always been that many of the early BTK inhibitors that were first used in oncology indications in the past have tended to have significant side effects, often because of binding and inhibition of other proteins besides BTK.

And the reason why we're so excited about rilzabrutinib is that it has been designed to try and avoid these issues as Principia's innovative Tailored Covalency platform. So Tailored Covalency, what does that mean? It -- that means the drug has 2 binding sites on the BTK protein, one of which is a reversible covalent bond.

These 2 sites essentially fit like a lock and key, increasing the likelihood that the drug will bind to BTK, but making it less likely that it'll have unintended binding to other enzymes. And thus, Tailored Covalency has a potential to minimize off-target binding and minimize the risk of side effects by still -- but still maximizing potency.

And safety is a critical issue for type 2 diseases, especially among dermatologists, and we believe that rilza has the potential to deliver it. Now what is the evidence to support this potential and our commitment to further investigate this product? It is a result of the studies with rilzabrutinib.

And on this slide, on the left, you see the Phase II results in patients with pemphigus vulgaris treated with rilzabrutinib. In this study, 67% of patients treated with rilzabrutinib achieved minimal disease activity by 24 weeks.

This shows the very rapid and potent effect that rilzabrutinib has on this disease where very few patients would have such a response on steroids alone.

On the right here, in the ITP Phase II study, you can see that 50% of patients treated with rilzabrutinib for greater than 12 weeks achieved the primary end point of 2 or more consecutive platelet counts greater than 50.

This is a significant result when you consider that these patients had failed a median of 6 other therapies before entering this study. And most importantly, for both of these programs, rilzabrutinib was well tolerated with no significant safety issues. So now we would like to reveal our plans for the rilzabrutinib program.

Our goal is to develop rilzabrutinib as a pipeline in a product with expansion beyond the typical autoantibody diseases into the type 2 space.

We know for type 2 diseases, safety is of major importance to patients and prescribers, and so we believe rilza, via the Tailored Covalency platform, may be the right molecule to achieve this high bar with oral route of administration and meaningful efficacy.

This target profile may be ideal for patients with less severe disease as an option before going to biologics. Thus today, we're announcing our plan to start the Phase II studies for rilzabrutinib in atopic dermatitis, in asthma and chronic spontaneous urticaria. These diseases represent a total of 3.5 million patients with high unmet need.

And each of these indications is expected to enter the clinic in the second half of this year. So on my concluding slide here, I want to provide you with an understanding of how we're thinking about these multiple, potential first-in-class or best-in-class molecules in the type 2 space.

You saw in Brian's earlier presentation that compared to other disease areas, we're still in the very early days of type 2 disease. Indeed, it's an exciting time for patients with many potential entries into atopic dermatitis, asthma and possibly even COPD. Starting with atopic dermatitis on the left.

We are building on the foundation of our successes with Dupixent. This is a very underpenetrated market with heterogeneity in biology and in patient needs. There is space, we think, for multiple molecules that offer choices to patients to tailor to their biology and individual needs.

We're excited about promising oral programs of rilzabrutinib and the IRAK4 degrader. We also look forward to exploring the potential of anti-OX40 once the acquisition of Kymab closes. Moving now to the right to the respiratory realm.

We're pursuing oral and type 2 plus approach in asthma with rilzabrutinib to provide patients with potentially the first oral treatment to enter the asthma space for some time. We also believe that the next wave of transformative molecules in diseases like asthma require a multitargeting approach to provide step change over current efficacy.

And we'll get into this in more detail in the next session with the IL-13 TSLP program. And finally, we have the high ambition to transform COPD therapy with itepekimab now in addition to dupilumab to address greater than 80% of patients with COPD where currently there are no biologic therapies.

And with this, I hope I've been able to convince you that Sanofi has a lot more coming behind Dupixent with an immunology pipeline rich in potential first-in-class and best-in-class molecules.

For more information now on our next generation of molecules, including Nanobody bispecifics program, degrader programs and really cool science, I will turn over to Frank Nestle, Sanofi's Global Head of Research and Chief Scientific Officer..

a kinase function and a scaffold function. First-generation attempts of targeting IRAK4 kinase function using ATP-competitive kinase inhibitors validated IRAK4 as a target in indications such as rheumatoid arthritis, but did not reach the level of efficacy required to be competitive as monotherapy in the fast-moving oral immunology field.

Sanofi and Kymera's next-generation IRAK4 protein degrader, SAR444656, allows blockade of both the scaffold function of IRAK4 in addition to the kinase function. Preclinical experiments, shown on the right, demonstrate the superior inhibition of Phospho-NF-kB and a superior inhibition of combined stimulation of PBMCs with TLR and L-1 stimuli.

It also demonstrates the very potent degradation of IRAK4 protein in critical target organs, such as the skin. This data provide a convincing framework for advancing our first-in-class, I&I-focused IRAK4 oral protein degrader into the clinic. We have spoken a lot about THOR-707, our non-alpha IL-2 for immuno-oncology.

Today, I would like to introduce you to THOR-809, our non-beta IL-2, entering the clinic this year with potential in a broad range of autoimmune diseases. THOR-809 takes advantage of the same unique synthetic biology platform for precise attachment of polythene glycol to IL-2, enabling selective targeting of the IL-2 receptor alpha chain.

The key goal for THOR-809 is durable disease modification and rebalancing of the immune system through the expansion of regulatory T cells. On the right side of the slide, you can see preclinical experiments demonstrating up to 46-fold expansion of regulatory T cells by THOR-809.

This translates into superior dose-dependent inhibition and control of skin inflammation compared to cyclosporine A. Today, I hope I was able to convey my excitement with you that we're just getting started in immunology with multiple emerging immunology assets moving into the clinic this year and the creation of a sustainable I&I discovery pipeline.

I'm now handing back to John for concluding remarks..

itepekimab, the anti-IL-33 monoclonal antibody from the Regeneron alliance, now in Phase III for COPD. Itepekimab operates at a very upstream step in the type 2 inflammatory pathway.

Rilzabrutinib, the oral, reversible covalent BTK inhibitor from the Principia acquisition, now in Phase III for a dermatological indication, a molecule that we plan to explore in 8 different indications by the end of this year. Rilzabrutinib operates at a very distal step in the type 2 inflammatory pathway.

And finally, KY1005, the anti-OX40-Ligand monoclonal antibody from the Kymab acquisition, of course, pending regulatory approval, which operates at a novel point involving Th2 cells and regulatory T cells with promising data generated so far in atopic dermatitis.

The third pillar in our strategy is to expand beyond the type 2 and adjacent immuno-inflammatory pathways with innovative medicines that leverage several of the powerful platforms to which Sanofi has recently gained access.

Examples of potentially transformational molecules in this category include our oral small molecule, IRAK4 degrader that you heard about, which is incidentally, the world's first degrader molecule that will enter the clinic for a nononcology indication, accessed via the partnership with the biotech company, Kymera.

The IRAK4 degrader has the potential to play across multiple immuno-inflammatory conditions where IL-1 and IL-33 are culprits, but offering an oral medicine option. Also of note is our non-beta interleukin-2 molecule, THOR-809, which is produced using the synthetic biology platform coming from the acquisition of Synthorx.

THOR-809 has the potential to become a best-in-class expander of regulatory T cells for restoring immuno-homeostasis across multiple indications. And the multispecific nanobody should be mentioned here, coming from the Ablynx acquisition following our acquisition of that company in 2018.

We expect to put multiple Nanobody drug candidates into the clinic this year, each of which neutralizes not 1, but 2 lymphokines or cytokines that have been clinically validated as relevant disease targets.

These Nanobodies will push beyond the limits of monospecific agents helping to break the efficacy ceiling observed currently for most biological treatments. Here in our last slide, I illustrate the breadth and depth of the emerging Sanofi pipeline in immunology products and product candidates.

The molecules are organized according to the specialty care area where they're most likely to play, but I should note that many, if not most of our molecules have the potential to be effective across several areas of medicine.

You'll note that Sanofi is building a particularly broad portfolio of product candidates in the dermatology and respiratory spaces, where we aim to lead the industry. And we are laying the seeds for meaningful participation in GI and rheumatology in the future.

Altogether, Sanofi has today 15 molecules in development for immunology and inflammation indications.

Furthermore, the same immunoscience that's the foundation of our dermatology, respiratory and emerging GI and rheumatology portfolios also spreads into our hematology, neurology and immuno-oncology therapeutics areas with examples found in the BTK inhibitors, rilzabrutinib and tolebrutinib as well as our anti-CD40 ligand antibody and our emerging portfolio of complement inhibiting antibodies.

As we pointed out in our R&D investor event last year, expertise in immunoscience is a core competency at Sanofi. And we leverage the science across the company's entire R&D portfolio because it touches on almost every therapeutic area in pharma and, of course, also in vaccines.

I'll close there and open for Q&A, for which I will serve as the moderator..

Thank you, John. Yes. So we are moving now into our last Q&A session for today with an emphasis on R&D, since we are now joined by our presenters as well as Dietmar, our Chief Medical Officer. And I also have Paul and Jean-Baptiste still with me in the room.

So Natalie, can we start with the first question, please?.

So the first question is from Thibault Boutherin at Morgan Stanley..

Can you hear me?.

Yes, we can..

So I just wanted to come back on your development strategy for your new immunology assets, in particular, in terms of sequencing and combining these assets.

Would you consider using GPs as a backbone on which to potentially add new treatments? Or is your approach more to use your new immunology projects as alternatives to Dupixent and a way of ringfencing your leadership in type 2 inflammation? And if you could share your view on how to determine which patients would benefit from which pathway and how to sequence or potentially combine these assets..

Well, thanks for your questions. I'm going to call on some of my colleagues to help. But I'll start off by just saying, of course, we are early in the exploration in the clinic of many of these molecules.

And so really fleshing out their fits in the landscape of various immunological diseases is something that we'll we doing in the months and couple of years ahead. We do recognize that many immunological diseases are complex and heterogeneous.

And that's why we emphasize our efforts in the precision medicine work that Frank outlined and really beginning to better dissect the disease biology and match the right medicine to the right patient.

We think this portfolio will enable a number of different strategic approaches as the data emerge and we have better insights into really how best to position the molecules, whether they're combined with Dupixent or used for patients that don't respond as well to Dupixent or tackling with those that have maybe a more mixed picture, for example, that Naimish outlined.

Or patients that are simply their disease evolves over time and they switch to different therapies over time. Dupixent clearly is a great foundation, and it's arguably a best-in-disease solution today. But we know that there'll be opportunities to build on top and around that. So maybe I'd hand over to perhaps Frank, first.

Maybe you could embellish on that a bit, and then Naimish?.

Yes, happy to, John. And I just would like to say from a very personal opinion, I think we've built one of the most exciting emerging immunology portfolios in the industry. And all of our decisions are science and data-led. I mean this is what we have been doing over the last 4 or 5 years.

But I think -- I just would like to remind you, there's still a huge unmet need out there in immunology and inflammation. And this is really driven by efficacy ceilings. I mean if you're looking across rheumatology and dermatology and respiratory, there are massive efficacy ceilings where patients do not get the drugs they deserve.

Durable responses are really just on the horizon, but not really implemented yet. And as John was pointing out, they are really different patient population defined by their molecular mechanism. But then also in terms of market penetration, these markets grow. Physicians are experienced now with biologics.

And you can see that if the right medicine comes along, which is really transformative, patients will come and physicians will prescribe. So what you really need is a portfolio which is water-proof in the short term, medium term and long term. And I think in the short term, we have first choice, Dupixent. No question about it.

It's a stunning, stunning biologic. But with this 15 biologics and orals we're having now in our pipeline, we have also the medium- and long-term strategy to really create a sustainable portfolio. If you think about itepekimab, potentially open up the COPD space.

If you think about BTKi, about -- as really an oral immunology leader, very safe, but going into multiple different immuno mechanisms, for example, autoantibody-mediated disease or in the type 2 space.

And finally, then, our long-term strategy with an oral protein degrader, first ever, the first time ever that a pharmaceutical company is bringing an oral protein degrader targeting IRAK4 into chronic autoimmunity; or our bispecifics platform using Nanobody, where we can actually mix and match and dial in the appropriate features for winning a TPP, including the schedule of dosing, breaking efficacy ceilings and actually having, hopefully, a good cost of goods and good economics with great patient convenience.

So it's a portfolio, it's like a winning portfolio strategy..

Maybe Naimish, anything to add before we move on?.

Thanks. No, Frank and you both covered it completely. I think as mentioned, atopic dermatitis is a great example, 5% penetration, 95% of patients eligible still haven't taken any. And there's things to consider like differing biology across that segment, different individual patient needs.

So there's plenty of room for a number of different mechanisms to fit patient needs..

No, absolutely. I think one thing that's -- the heterogeneity of patients also plays out in racial differences. For example, atopic dermatitis in Asian patients compared to Caucasian patients, for example, tends to have different biology. Same for black patients. So there really is a need for different mechanisms for different patient populations. Okay.

Let's move on..

If I could just follow-up on another question. I was just wondering, I mean, obviously, there are a lot of bispecifics in development.

So if you could just maybe give us a bit more color on the points of differentiation of your bispecifics with the Ablynx platform compared to what your competitors are doing?.

Sure, yes.

Frank, you want to take that?.

Yes. I mean number one, obviously, the bispecifics have been a success in immuno-oncology. Bispecific engager, T cell engagers are really going from success to success.

However, in the I&I space, if we look at what has really happening is that a lot of bispecific approaches in I&I have failed either because targets were not properly engaged or ADEs problems were arising.

So what we actually have built over the last years since our acquisition of Ablynx, we have built probably what is the most advanced, what I call, biologics 2.0 technology using Nanobodies. And Nanobodies are very interesting because you can actually combine them like pearls on a string to make multispecifics.

So for example, we can dial in half lives by binding to albumin. We can dial in multiple targets because we can sort of combine these Nanobodies in one molecule. And actually, the clue is not only in the platform, which is differentiated.

And we have now Phase II data demonstrating that the Nanobody platform is really very effective in the clinic in chronic inflammation. But it's also the target selection. This is where the precision immunology element comes in.

We, for example, the targets we are convinced about today and, for example, the reason why we are also interested in OX40-Ligand as a target is that already in 2016, '17, we mined data sets and they told us what are the winning targets are going to be.

And already, we're seeing with the targets now in Phase II trials being winners, that we actually made the right pick. So there's more to come. This is just -- we titled this session emerging, so there will be much more coming. But we are very confident about our technology platform.

It's very differentiated, number one, with Nanobodies; and second, the choice of the targets..

Good. Eva, next question..

Yes. The next question is from Tim Anderson at Wolfe Research.

Tim?.

Can you hear me okay?.

Yes..

Yes..

Okay. I wanted to ask about 2 of your higher-priority assets, oral SERD and oral BTK, just a high-level question. So it kind of seems like everyone is claiming to be best-in-class and not everyone can be best-in-class. So in the oral SERD space, you and Roche and Astra all claim it. In the oral BTK space, you and Roche claim it.

Can you just update us on why you think your molecules are best-in-class? It seems like some of the data sets with some of the compounds are just too early to make comparative claims. And then second question on Dupixent in asthma. In China, if I understood it right, those trials are still ongoing.

What would be the timing of getting approval in China and potential NRDL?.

Okay. Good. So several questions there. Why don't we do the BTK first because that flows right from the presentation that Naimish gave. And Naimish, can I ask you to take that then and explain the differences in the various BTKs and why believe that the Principia molecule that we have, rilzabrutinib, has a potential to be the best-in-class choice..

Sure. So as I got into a little bit in the discussion we had, just the Tailored Covalency part of it. So the issue has been with a lot of BTKs that they've either had off-target side effects, such as liver function abnormalities, platelet dysfunction, atrial fibrillation, that had limited their scope in terms of the indication space.

Rilzabrutinib has been designed specifically with this platform to be very specific to the BTK enzyme and limit the off-target sort of binding to other proteins that many of these side effects often come from. And so we think it's ideal in that way for the type 2 space.

You can see some of the other BTK enzymes like -- or BTK inhibitors have tried in CSU, for example. But even though the efficacy is there, the safety hasn't been quite what is needed in that space to really be a drug that prescribers and patients feel safe taking. So I think that is the crux of the matter.

Our Phase II data, thus far, hasn't shown any similar side effects profile. So that's why we're very confident that we can enter the space with the compound we have..

Yes. And just to add a little more on that. I'm very familiar with both molecules. The Roche molecule is a fully reversible molecule. The downside with that is getting enough target exposure.

What we've learned about BTK is to get the efficacy, you have to hit the hard target hard, and you have to keep it hit hard, which is where the covalent piece, rilzabrutinib, comes in.

Because that then completely inactivates the target and keeps the exposure longer, and at the same time, that tailored aspect of it prevents you from interacting with and staying on other targets.

So we think it really threads the needle well in terms of both getting the target exposure you need, which has to be like 95% all the time in order to have the efficacy, but at the same time, avoiding the off-target.

And for that reason, we think it will outperform a fully reversible molecule, which is going to be hard to keep that target really engaged all the time. On the third, I'm going to ask Dietmar to help me with that one.

And why we think this molecule has potential to be -- why amcenestrant has the potential to be our bet, the best-in-class solution of an oral SERD for women with hormone receptor-positive breast cancer.

Dietmar?.

Yes. Happy to. Thank you, John. And before I go to the third, let me just talk about the other BTK, which is tolebrutinib. And again, the question about best-in-class comes up there. And there's really the brain penetrants.

Besides the BTK inhibition and really the impact on the innate and adaptive immunity and the impact on peripheral and central, we really think that we have best-in-class potential as well.

For all of these molecules, and I'm switching to amcenestrant here, eventually, it's going to be about benefit risk and about the application to the specific patient population. And you may know, Tim, in hormone receptor-positive breast cancer, really, that question of benefit risk becomes quite important.

We are looking forward to present more data at a conference towards the middle of the year. Really, the data around -- from the Phase Ib study around the combination with palbociclib, that data that gave us confidence to kick off a study in first-line metastatic breast cancer, exactly that combination, the pivotal Phase III trial.

But when we look at the data that we've presented so far, I find efficacy -- and you look at the data at ASCO last year, I find the efficacy data very encouraging. You do see the right clinical benefit rate. You do see the right degradation of the estrogen receptor. You do see activity in the estrogen receptor mutants, in the ESR mutants.

And you do see really encouraging safety profile, which will be important as we develop this molecule across the different lines of therapy. And the big price is obviously usage in the adjuvant setting and there, the risk profile becomes even more important.

And as we see the data emerge, I remain very confident and, let's say, even more bullish around the molecule that this really has best-in-class potential. You're going to have to see this then eventually as you see the data emerging over the year from a benefit-risk perspective..

Yes. Thanks, Dietmar. And I think that safety difference is most clearly seen in the lack of any cardiac signal that we have with amcenestrant compared to other molecules. And so to effect some cardiac ion-conducting channels of the competitor molecules that have resulted in the need to reduce the dose.

And that then also then jeopardizes the ability to cover the target and get the efficacy you need. So threading the needle on the molecules that have those cardiac toxicity issues is less than idealistic. That's not a problem with amcenestrant.

And it's why we think, particularly moving into the places like the adjuvant space where safety matters so much, that we'll have the best-in-class profile. Then the final question was about Dupixent in China. Maybe Brian, maybe we can get you into the mix here and let you handle that.

And of course, Naimish or Dietmar could chime in if you need any help.

Brian?.

Yes. Absolutely. Thanks so much, John. And obviously, we've got the ongoing program with readout in late '22, early '23. So we're looking at potential approval into '23 or early '24. And typically, we assume an NRDL approval about a year later.

Now as witnessed by our record time for Dupixent and really the local recognition of innovation, I think, by the China authorities, getting a record time for atopic dermatitis in adults, so 5 months, it could potentially be shorter than that. So we would be optimistic, but that's the current time frame we have for China..

All right. Thank you. Good. On to the next question, Eva..

So the next question is from Emmanuel Papadakis at Deutsche Bank.

Emmanuel?.

Maybe I'll take a couple of follow-ups on Dupixent. So the first one, maybe existing utilization in asthma. If you have it, could you give us a little bit of color on how use is skewed in the patient population? I'm thinking in terms of eosinophilic markers, in particular.

And perhaps your perspectives in light of that on the potential implications, if any, of the recent update particularly in the eosinophil low subgroup of patients? And then a second one on Dupixent, just the regional expansion opportunity. I mean you mentioned it earlier. It still remains extraordinarily dependent on the U.S.

How soon, for example, is the European opportunity like to mirror what we've seen in the U.S.

Is there an inflection point coming on the back of reimbursement access opening up? Or is that going to be a slower build? And maybe, Brian, you could give us a bit more color on the NRDL listing in China, and ID what kind of price cut did you have to take? When will the volume start to kick in there?.

All right, Emmanuel, thank you for your questions. I'm going to have Brian tackle those. And if there any elements around the eosinophilic phenotype that we don't cover there, maybe Naimish still help him out. But Brian, over to you..

Yes, for sure. Thank you, Emmanuel, for your questions. Really good ones. I think from a -- if you think about the asthma space, in that moderate to severe uncontrolled asthma space, it's really the way we look at it, is it's the type 2 patient population. And it's really not just identified by eosinophils.

Obviously, you think about pheno, of course, IgE levels. And we actually designate about 80% of that population is really type 2. So we really don't, again, align ourselves with just the pheno from -- or excuse me, the eos levels, so from that standpoint. Now that being said, we have access to all of those patients.

Actually, we have basically above 150, as we've shared with you guys before. Especially in the U.S., we have fantastic coverage. So we have the access of those full type 2 patient population above 150 eos levels. Now that said, you asked to compare this a little bit to what we've seen with the recent TSLP data.

And I think the recent TSLP data, again, really highlights a lot of what the organizations, both Amgen and AstraZeneca, articulated that it really largely seems to be sitting in that much smaller patient population below the 150 eos levels. Which as we articulated, that is, again, about 20% of the patient population alone.

But then if you look a bit further, as we've seen in the recent failure with OCS-dependent patients, that actually further narrows that population. Because Dupixent, as you know, without any eosinophilic biomarker, actually, we're approved for OCS patients as well, again, regardless of eosinophilic phenotype.

So we really feel strongly that our, if you will, platform, if you will, for Dupixent this type 2 platform. And our profile remains the strongest profile in asthma of all the current agents and the agents to come. Now a little bit about China. Obviously, with NRDL, that was really exciting news. Obviously, record time as we just mentioned, 5 months.

And that is a really great signal that China is continuing to recognize the innovation of these medicines. Now from a price standpoint, the price will be out and be public in the March time frame. And again, all we can really share right now is that we're extremely positive about their recognition of the value of Dupixent in China..

Good..

Brian? Sorry, if I could just add a little bit -- call out on the TSLP point. I mean going back to the slide I presented on the type 2 inflammatory cascade. You could see how Dupixent is well aligned in that sort of decision point in the cascade inhibiting IL-4 and -13 to inhibit really type 2 inflammation.

And for asthma, what that really means is airways inflammation. We know that pheno is a great marker of airways inflammation, and Dupixent has a much stronger effect on pheno and also a much stronger effect on lung function improvement in the type 2 space compared to TSLP. And the OCS population is another example of really a type 2 population.

The biomarkers aren't so reliable for OCS, but we've seen in our studies, if you withdraw the OCS, their eosinophil counts go up. And they're really just type 2 patients, and you can see that TLSP wasn't successful in that population, where Dupixent has been hugely successful in that population.

So that type 2 space, the type 2 asthma space, we think Dupixent is really the winning molecule there..

Good. Next question, Eva..

We have time for one last question from Graham Parry at Bank of America Merrill Lynch..

So just earlier when you were talking through the amcenestrant data points, you didn't highlight the proof-of-concept study in early breast cancer, but you have expressed optimism around that.

So is that data still coming? The window of opportunity study in early breast cancer proof-of-concept, is that still coming this year? Has that been delayed? And secondly, on the IL-33.

Were there any other biomarkers, other than former smokers, in the Phase II that drove the exacerbation reduction? I know you're stratifying for any of those biomarkers in Phase III.

So any potential to sort of target particular subpopulations even if the overall data set is less successful, given that this has been a very difficult indication to get meaningful data in? And finally, on Dupixent in chronic spontaneous urticaria, could be one of your biggest Phase II readouts this year.

Physicians using this off-label report mixed results, suggesting quite a heterogeneous patient population.

So is the trial set to detect that, again, use of biomarkers or anything else?.

Thanks for your questions, Graham. I'm glad we were able to get to you. Maybe I'll take the questions in reverse order. You mentioned Dupixent in CSU. The trial is ongoing. So it's -- we won't comment on what investigators may be saying.

I would only say that as we move into diseases adjacent to our core areas, like atopic dermatitis, we're going out into areas that sometimes may have a more mixed picture. And so I think we have to be prepared that Dupixent may not benefit every patient, and that's why we do have these other molecules coming.

If you think about, for example, rilzabrutinib, is a really good solution potentially for CSU if Dupixent doesn't resolve their issues. I don't know if Naimish has anything else to add on that while we're on Dupixent..

Sure. Yes. I mean there are the subpopulations in CSU with autoantibodies to the FC epsilon receptor and also autoantibodies to thyroid proteins that might have a differential response to Xolair.

The beauty of Dupixent is that the IL-4 receptor on mast cells, an important activating factor for mast cell, so it's a different pathway from what Xolair and ligelizumab are targeting. So we're definitely looking at these biomarkers. And we'll see how the outcomes come.

But we think there's actually a potential to -- we could have -- really have a differentiated population that responds to Dupixent versus what Xolair does in this space..

And then while you have the floor, Naimish, would you comment on biomarkers in itepekimab applications of COPD.

Any further insights you want to offer there?.

Sure. So to take a step back about these results for IL-33, COPD in adults is extremely common. 6% of the U.S. population has COPD. However, we're zeroing in on a very specific segment of COPD, the patients who are extremely -- having frequent exacerbations and lots of symptoms, so it's a small segment.

And within this segment, you have patients who are still actively smoking, about 30%; and 70% who are not actively smoking. And within this, the 30% who are actively smoking, they're having significant symptoms, significant exacerbations.

And they're smoking, which is essentially tobacco smoke, contributing to inhaled particles, toxins, other things into the lungs as a constant exposure. And probably -- and there's lots of biology to back this up.

The biology in those patients is probably fundamentally different than the other segment of patients who's no longer smoking, yet they're still having exacerbations, frequent symptoms and the like. And smoking, of course, causes a very diffuse sort of immune activation. So it might be a hard thing for a single agent like IL-33 to provide efficacy.

Whereas in the nonsmokers, there's pretty good preclinical evidence that the patients who are not smoking, but are extremely symptomatic, as I presented, have high levels of IL-33 in their lungs. And IL-33 is a specific contributor to both exacerbations and frequent symptoms. We don't necessarily yet have good biomarkers for IL-33 or the like.

They're certainly in development. But we think this paradigm of smoking and ex smoking also contributed by our own internal data showing that IL-33's levels tend to be elevated in former smokers versus current smokers. We're very confident that we have this population.

And the clinical data of 40% reduction in exacerbations really suggests that we've targeted the right population. Further biomarker development, of course, will -- is in the works. And we're going to have more sort of mechanistic studies to better understand how IL-33 is specifically working in these patients.

But we feel like we really have targeted the correct population..

Yes. Thank you, Naimish. I mean we're really looking forward to getting these data published and presented at meetings where we can get into more of the details. But as you pointed out, I mean, a 40% reduction in exacerbations, I mean, when you see that in COPD, it's really, really quite profound.

So we're optimistic about our Phase III program and think we've really -- we've really come on to some interesting biology here and an interesting difference between some of these subsets of patients. The final question on amcenestrant and the window study. This is in the neoadjuvant. That has been delayed because of COVID.

There were fewer women going in for those procedures, but we are re-engaging with that. And irrespective, we are pushing forward with our plans to move amcenestrant into the adjuvant space.

So Dietmar, could you provide, Graham, with an update on that?.

Right. It's exactly, as you said, John. It's a tragedy, but we do see a delay of procedures in oncology patients during COVID. Having said that, we do see solid recruitment into the study. Yes, it's delayed, but we do have started recruitment. We will be able to utilize study outcomes this year for our internal decision-making for sure.

We have not taken a final decision at what point then to present the full study data externally. But yes, we will have data this year..

Good. Well, thank you, Graham. Eva, is that all the questions we'll take for now? Or would like to....

I would like -- yes. Thank You. So I'm going to hand it now back to Paul for some concluding remarks..

Well, thanks, Eva. I don't know if you can see me. Hopefully, at least, you can hear me. I just want to thank the team for their work today and indeed for the session this afternoon. I think for all those that are following the company closely, you knew that it was going to be a transformation story for us. I personally believe we're ahead of schedule.

I think our financials are strong. We touched on them earlier. Our confidence going forward is strong. Our belief in Dupixent being a winner is strong. When you see the quality of the science and the thinking, particularly in immunology -- and it applies across actually.

But what you've heard this afternoon, I think you start to see the joined-up, connected thinking. All of our wisdom, all of the experience of this team putting together something quite incredible, recognizing subpopulations, recognizing heterogeneity where it is, understanding the value of rilzabrutinib, which I think is not well appreciated.

Everybody got excited about tolebrutinib. Us, too. Rilzabrutinib just keeps getting better and better the more we understand it. Confident on the subject, for sure, but then staying in immunology, the IL-13 TSLP Nanobody. I inherited the Ablynx deal, and I get to see the benefits of it. I'm really looking forward to doing some extraordinary stuff.

And as the team pointed out, the risks, the probability of success is so much higher in our Nanobody platform. And we're understanding enough about these platforms where TSLPs will disappoint, where 13s on their own will disappoint.

You bring them together, exquisitely, which is a word I'm learning more about at Sanofi, you really get to understand some of the magic that's going on. And then itepekimab, which was just mentioned, perhaps because of our checkered past, the enthusiasm comes late to some of our assets. So you choose to watch from your sidelines a bit longer.

40% reduction in exacerbations in COPD is completely game-changing. Yes, we have to get there. Yes, we have to get there. Nobody is ahead of us on this. So we're blazing a trail. I'm proud of the team that we're putting together.

And I can't -- you cannot miss the fact that the prioritization in gen med in consumer and the desire to free up resources continue to grow, but be as strategic. To reinvest in these assets, to double down and be here to play is what we're about.

As an Executive Committee, this is our job, is to lead the team to make the choices to deliver on the science and deliver the financials. And I know that many of you will want to see that unfold. It's okay. But we are ahead of where I expected. I'm very proud of the work that's going on. Thank you to everybody for joining..