Sanofi (SAN) Earnings Call Transcript & Summary

We're putting a lot of emphasis on the pace of delivery. We want to deliver it with more urgency, a pace that patients will be proud of. On a journey to improve R&D productivity, we brought in a whole new research team. We're establishing new capabilities for drug discovery. It's a journey, but we feel like we're making progress, and we need to stay committed to that progress.

Hello, everybody. I'm Yong-Jun Liu, the Global Head of Research at Sanofi. My expertise is in immunology. My 30 years research experience has generated 3 innovative medicines in the clinic, in the field of oncology, immunology and allergy.

My name is Dietmar Berger. I'm the Head of Global Development and the Chief Medical Officer for Sanofi. I'm a hematologist oncologist by training, and I'm excited to work on a broader portfolio. In Sanofi, I'm in clinical development because bringing new drugs to patients is really what I'm passionate about.

Hi. I'm John Shiver, Head of Vaccine R&D. It's a pleasure to participate in this event today. We're doing all we can to accelerate the pipeline and focus on the programs that will be most impactful for bringing new vaccines to prevent significant infectious disease, and I look forward to working all together to accomplish that mission. Thank you.

Good morning, and good afternoon to everyone, and welcome to Sanofi's virtual R&D event. I'm Felix Lauscher with Investor Relations. The Sanofi leadership team is excited to spend the next 2.5 hours with you to share Sanofi's unique R&D capabilities, platforms and disease pathways. If you are unable to view the presentation during the event, you can find the slides on the Investors page of our website at sanofi.com. Moving to the next slide. I would like to remind you that information presented during this event 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 and filings with the SEC and also our Document d'Enregistrement Universel for a description of these risk factors. With that, please advance to the next slide, and let me take you briefly through the agenda for today. Paul Hudson, our Chief Executive Officer; and John Reed, Global Head of R&D, will open the day with their introductions. Members of the R&D and commercial leadership teams will then present their respective areas of expertise. We will have a round of Q&As following the first 2 sessions and then a second round of Q&As at the end of the presentation. I would like to briefly provide the instructions for our 2 Q&A sessions. [Operator Instructions] Your question will be read by our panelists. Before I turn the event over to Paul and John for the introductions, we will share a brief video with you showcasing Sanofi's 3 recent R&D events as well as a preview of our planned nirsevimab event. Today is the fourth in a series of 5 R&D events highlighting the accelerating pipeline momentum building within Sanofi R&D. The virtual format of these events demonstrates our proactive approach to use technology to meet with you during these unprecedented times. [Presentation]

Well, good morning and good afternoon to everybody. Thank you for joining us for such an important event. As we've mentioned already, we've covered a lot of ground this year. And for me, it feels, in particular, special to be able to share not only the momentum that we're building, but also importantly, to share a wider group of scientists and contributors throughout the next several hours that you can start to see the bench strength that our company has. It's been 10 months for me, and it's been incredible to see the confidence starting to build and the Play to Win mindset starting to show itself. At this point, we're digging deeper and looking harder at the things that we have and the things that can change about certain medicine. We're going more ambitiously. We're going more actively, and we're going at a bigger scale in the areas where we think we can change the practice of medicine. I'm proud and, in many ways, privileged to take up this position at this point as we start to share the hidden gems of our pipeline and continue to add to them. Next slide, please. So as you saw from the video and as you can see now, we've been on a bit of a journey. And it would have been easy, perhaps, given the difficult circumstances externally to defer an R&D day or to hold it off or reconvene later in the year. There's been a couple of important learnings for me from this. One, that our science is way better than people think, and we know we have some convincing to do. We know we are still a show-me story, and we've gone out and led from the very beginning back in April with the BTKi story to get people to understand just how rich and high-quality our science is. We've put it out there for debate. We've been very pleased with how it's been received. And again, you've got used to seeing and meeting some of our teams. We've done this virtually, as we do today. And I think we've shown how agile this company actually is. I think there's a perception that we couldn't perhaps pivot so fast to a new way of working. And touch wood, without any technical malfunctions today, I think we'll have shown people what is exactly possible. Next slide, please. So we identified some key assets back in the Capital Markets Day in December. And we've made extraordinary progress right across absolutely every single area. In the past weeks alone, for DUPIXENT, we've had approval in 6- to 11-year olds in atopic dermatitis in the U.S. We've had approval as recently as last week in China for such a huge unmet need. And of course, we've had extremely strong data in eosinophilic esophagitis. And finally, we made the decision, after a rigorous hurdle to overcome, to go deeper into COPD. We've been saying from the very beginning, we think this is a $10 billion-plus asset, and we do that, stood on the shoulders of incredible science and unmet patient needs successfully matched. And so we feel confident that the data that is building will position us very well to deliver on that. We see, of course, the longer-term data with fitusiran and the annualized bleeding rates, which will be best-in-class on a true monthly dosing schedule. That, in itself, we think, can be game changing. Our SERD and the POC data we shared at ASCO, again, a strong step forward. And let's be honest, in the race of the SERDs, we were 1 of 3. I really believe now that we are out on our own and 1, 2 or 3 years ahead of all of the major competition, some going back to the drawing board. So we think we're going to play a massive part there. We have a pipeline product with venglustat, all the way through, we hope, to GBA-Parkinson's disease. And of course, the BTKi'168. What an incredible moment for this organization to have enrolled its first patient having only read out the Phase II data at the beginning of -- at the end of January, beginning of February. What a moment for this organization to show the speed of which it can move. We spent a lot of time looking at our R&D productivity. And I think we all felt the same, that while we could go back forensically and in detail, we'd rather set a new benchmark, a new speed, a new hurdle for us to overcome and match it. I think with the BTKi, 4 months after Phase II readout to have enrolled first patient says that we're serious, we're unencumbered and we're ready to move quickly. Next slide, please. So of course, out of ASCO, we had very competitive data for Libtayo. We went on to have even better day with Sarclisa. So our in-hand oncology assets starting to reveal differentiated profiles, we think, can help take share and offer additional patient benefits. As per avalglucosidase, we achieved breakthrough designation. We are a company that should be getting breakthrough designation because of the quality of our science. For sutimlimab, priority review. Again, this is a sort of standard our company should and can and is operating at. And then finally, with our anti-CEACAM5, we go into Phase III, ahead of everybody else, first in class, a long way ahead. And we think we can contribute in that population significantly. This is a significant amount of progress done over a very short period of time. There's not much changed in the 10 months other than our belief that what we have in our hands and being much more specific about what it can do and how to win has stepped a long way forward. Next slide, please. I'll just finish with this because I think this is quite important. Many companies can put this type of slide up and say we believe in our R&D function because we understand the patient, the platform, we understand the deep insights required. I don't think that every company does. I think that companies play at different elements of these. A lot of companies acquire platforms for platform's sake. We will show you today with THOR-707 that we just know how to do platform and how platform becomes medicine. And that's critical for us as we take our pipeline to a renewed level of status in the industry and beyond. So I think we do fully understand what it's like to be a patient. We have deeper insights than many other organizations. And I think we're starting to understand how to put these things together. You'll hear from our teams today. So we have momentum. We have a lot of share. We're in the fourth of fifth events, and we're very proud of the progress that we've made. With that, I'll hand over to John Reed, our Master of Ceremonies. John?

Thank you, Paul, and welcome, everyone. I'm excited to kick off this virtual R&D investor event program with you today. It's been approximately 2 years since I joined Sanofi to head the pharma R&D unit. And a lot of palpable progress has been made in the past 2 years to position Sanofi R&D for better productivity. Now I know that many of the investment community think of Sanofi R&D as a show-me story, and I can't argue with you. Looking back, it's no secret that only 2 of the last 12 new medicines that were launched by Sanofi came from our own laboratories. When I arrived at Sanofi, more than half of R&D -- our R&D investments were supporting undifferentiated molecules, for which it was difficult to make a real claim of best-in-class potential. Even we were working on biosimilars, which is an enormous distraction from an innovation agenda, in my opinion. Plus, we have way too few first-in-class medicines in the pipeline. Our investments were also spread over 8 therapeutic areas, with more than half of the R&D budget supporting primary care as opposed to specialty care. Prior to joining the company, I had heart-to-heart discussions with the Chairman and members of the Board of Directors about what we needed to do to transform Sanofi's pipeline and evolve our R&D organization towards industry competitive levels of productivity. I believe we're on the right path, and we'll share with you today a few of the highlights that illustrate that. Let's move to Slide 10. Let me start by saying a little more about how we are transforming Sanofi R&D. On this slide, you may recognize the 4 pillars of the company's strategy. I want to just take a minute to run through what the 4 pillars mean specifically for us in R&D. The first pillar is focus, focus on priorities. As I mentioned previously, more than half of the Sanofi R&D budget historically went towards support of primary care indications. But frankly, the company didn't have much that we could say was truly practice-changing innovation coming out of that effort. So we made a tough decision to exit research on primary care indications and redeploy those resources for priority indications of oncology, immunology and rare diseases, indications where the science is rich with target opportunities and where the path to go/no-go [ to send you ] to the clinic is rapid. Exiting cardiovascular and diabetes at Sanofi R&D has been a very heavy lift. It's a massive transformation of our organization, but we're getting it done, and this frees resources to drive rapid progress in specialty care. The second pillar is called lead with innovation. Now I know every pharma company says they're innovating. So what does this mean in the Sanofi context? Two dimensions are relevant here. First, a commitment to investing in first-in-class or truly differentiated best-in-class molecules. We're moving towards that ambition, and I'll show where we stand in a moment. The second dimension is expanding our drug discovery platforms that enable creation of highly differentiated, one of a kind molecules that tackle targets and harness biology in very novel ways. This has been accelerated by the acquisitions of Ablynx with its nanobody platform, and more recently, of Synthorx, pioneers in synthetic biology. Our presentation today will cover some of this innovation. I turn next to the third pillar, accelerate efficiency. We have been relentlessly improving our clinical operations and embedding digital and real world data capabilities to bring our new medicines to patients even faster. My colleague, Dietmar Berger, our Global Head of Development, will cover some of this later today. It makes me especially proud when you see the way our people stepped up to battle against COVID-19. Putting clinical trials together in as little as 3 weeks, from concept to first patient randomized, sustaining the drug supply chain through truly heroic efforts, displaying inspiring creative problem solving to keep 94% of our patients on clinical studies, and that represents a portfolio of over 300 clinical trials. It's very impressive what the colleagues have accomplished. When it comes to the final pillar, reinventing how we work, we've substantially simplified our ways of working. We've streamlined governance. We've fostered greater team empowerment. And we're fundamentally reinventing the culture of Sanofi R&D. Dietmar will talk more about this later as well. Now I know that may sound trivial, but the historical context of the changes is, frankly, a notoriously bureaucratic company with layers and layers of required approvals and reviews and committees. For example, when I arrive at Sanofi, I discovered no less than 33 committees that made demands on the time of our clinical development teams. We cut that to 3 governance committees. As another example, when I arrived, it took 14 signatures and often several months for portfolio funding decisions to be processed so that the budget could be made available to the team to execute. Now it takes less than 72 hours. These sorts of changes in Sanofi's business processes and practices have been incredibly liberating for our R&D people, allowing them to spend more of their time on the pipeline with fewer distractions. Let's move to Slide 11. If we turn to Slide 11, this transformation is allowing us to significantly accelerate our priority assets, as Paul mentioned. We provided updates already on DUPIXENT, on the BTK inhibitor, on our SERD at the prior investor days. Today, you'll hear about fitusiran and BIVV001 for hemophilia. And you'll hear about venglustat for several monogenic disorders and for Parkinson's disease. And soon, we'll devote an investor event to nirsevimab, a passive immunity strategy for prevention of RSV infection in infants. Slide 12, please. Okay. So while we're putting a spotlight on these so-called priority molecules, you're probably wondering, how is the overall Sanofi portfolio shaping up. Here are the aspirations we set back in early 2019 when I announced a new strategy for the Sanofi R&D. We are already close to achieving our portfolio reshaping objectives in a little -- less than -- a little more than a year. As we stand here today, about 75% of the molecules in our development pipeline have the potential to be either first or best in class. Around 2/3 of the projects in our research pipeline are biologics, which, compared to traditional synthetic molecules, tend to yield faster cycle times and a higher probability of success. And finally, around 2/3 of our development assets are internally derived, which, of course, brings better economics because they're wholly owned, unlike many molecules derived from external partners. Looking at these metrics on the pipeline together with the positive news flow that we recently announced for DUPIXENT, the update provided on our oncology pipeline and data from our investigational brain-penetrant BTK inhibitor, I hope that you'll agree with me that momentum is indeed building at Sanofi R&D. Next slide. So let's briefly review the plans for today's program. We have 4 sections, platforms, pathways, patients and capabilities that are allowing us to move with greater pace. In the platform section, we'll feature THOR-707, an engineered version of interleukin-2, IL-2. THOR-707 provides the perfect example of how we can use the Synthorx synthetic biology platform to develop highly innovative treatment approaches. In this case, boosting the impact of cancer immunotherapy. In the disease pathway section, we will use venglustat to illustrate how we are leveraging our understanding of lysosomal storage diseases and the glycosphingolipid pathway to invent new medicines with potential applications that go well beyond our rare diseases. In the patient insights section, we will explain through fitusiran and BIVV001 our expanding focus on patient insights and here illustrating our ability to understand patient needs and deliver practice-changing patient offerings, in this case, for hemophilia. And finally, in the capabilities section or what I like to call the moving with pace section, we will share with you how we have applied our scale and our platforms to rapidly battle the COVID-19 pandemic. A lot of information here to digest, but I hope by the end of the event that you'll share my confidence in Sanofi's ability to continue to change the practice of medicine and deliver solutions for patients in need. So without further ado, I now hand over to Yong-Jun to start the platform session, where we'll describe some of our unique drug discovery tools. Yong-Jun?

Thank you, John. Good morning, and good afternoon, everyone. Let's move to the next slide. At Sanofi, we have built industry-leading technology capacities, which allow our scientists to design better molecules, to expand the druggable universe and to drive innovation in vaccine design. We are especially proud of 3 recently added capacity, as highlighted here in the blue boxes, all invented and created by our scientists at Sanofi and Sanofi Companies. I will introduce the trispecific antibody platform and the nanobody platform, and Marcos will introduce the Synthorx platform. On my next slide. Our protein engineers at Sanofi have created a trispecific antibody platform based on the crossover new variable domain technology. As you remember, we highlighted our first trispecific antibody for neutralizing HIV in 2017. This trispecific antibody has entered the clinical studies with initial clinical results expected next year. This is a very important validation of our trispecific platform. Today, I would like to show you a trispecific T-cell engager for cancer immunotherapy. As you know, most, if not all conventional T-cell engagers are bispecific antibody, targeting T-cell receptor for T-cell activation signal 1 and a tumor antigen. Our trispecific antibody allowed us for the first time to add a third component, the anti-CD28 co-stimulation at signal 2, which is critical for promoting T-cell survival and establishing T-cell memory. Next slide. Here, our first trispecific T-cell engager, 257, targeting CD38, a human multiple myeloma antigen. Because over 95% of all human multiple myeloma express CD28, targeting CD28 not only provides the T-cell co-stimulation signal 2, but also provides a second cancer cell targeting. Our preclinical study recently published in Nature Cancer showing that our trispecific T-cell engager demonstrated a 3- to 4-log higher killing potency in vitro in multiple myeloma cells compared to daratumumab. We have already initiated our first-in-human study for treating relapsed and refractory multiple myeloma and non-Hodgkin's lymphoma. We hope this trispecific T-cell engager will achieve the level of efficacy of our CAR-T. This is super exciting. On my next slide. Now we would like to show you a tetra-specific nanobody based T-cell engager to illustrate the power of our nanobody technology. Because nanobody is 1/10th the size of a conventional antibody, we can easily target more than 3. Here, our first target is anti-human serum albumin, a clinical validated technology for half-life extension. This nanobody is linked to 2 nanobodies targeting tumor antigen 1 and tumor antigen 2. Targeting 2 tumor antigen is far superior than targeting 1, because 2 targeting can provide stronger tumor binding and reduced binding to healthy, normal tissues. These 3 nanobodies is then linked to a T-cell engager, such as anti-CD3 or anti-TCR. Because nanobody can be expressed in yeast, our technology offers faster production cycle time at a lower cost. Importantly, we have one of the broadest and dominant IP in the field of nanobody. In summary, I have introduced 2 T-cell engagers to highlight our trispecific antibody platform and nanobody platform. I would like to emphasize that our scientists are making a very robust pipeline for targeted therapy across oncology and immunology. Last year, Sanofi Research delivered 3 multi-specific nanobody clinical candidate for the development. We expect to deliver 3 to 5 clinical candidates using these 2 multi-specific technology annually for the next several years. Let me now hand over to Marcos who will talk to you about Synthorx, the latest addition to our toolbox. Marcos?

Thank you, Yong-Jun, and hello, everyone from sunny San Diego. Let me start by saying that at Synthorx, we are very excited about joining the Sanofi family and the quest for innovative medicines for patients. As shown on my first slide, the Synthorin platform is based on novel synthetic biology. The unique achievement of our scientific founder, Dr. Romesberg and his team, was to expand the genetic alphabet with the creation of a new DNA base pair that we term X and Y. By adding X and Y to the natural DNA base pairs, AT and GC, we can expand the number of amino acids that can be used to make proteins from the naturally occurring 20 to up to 172. This vastly increases the chemical diversity available for fine-tuning the pharmacology and drug properties of biologic therapeutic agents. And as shown on the next slide, we do this employing an E. coli strain that has been a workhorse for decades for protein production of biologic drugs such as insulin. The strain is slightly engineered to replicate plasmids connecting the new X-Y base pair and transcribe mRNA and tRNA containing X and Y to be able to produce proteins containing a new amino acid at the specified position by the new X-Y base pair. Our first application is site-specific PEGylation of cytokines at the new amino acid residue. Cytokines are very powerful movers of immune function, yet none of them have critical drug properties. And in most cases, PEGylation addresses that. An example is shown on the next slide. Aldesleukin clinical IL-2 is an approved cytokine for the treatment of metastatic melanoma and renal cell carcinoma. In fact, aldesleukin was the first immuno-oncology drug driving durable responses before the term was coined much later. But aldesleukin is hard to dose because of its dual pharmacology. It induces the proliferation of tumor-fighting CD8+ T and natural killer cells, but it also promotes the proliferation of suppressive CD4 regulatory T-cells, or Tregs, and activates type 2 and 18 cells and eosinophils, which leads to eosinophilia, the driver of vascular leak syndrome, or VLS. The induction of Tregs and cells triggering VLS is caused by IL-2 engagement of the alpha chain of the receptor. And this is why multiple companies are developing not-alpha IL-2 tracks for immuno-oncology indications. Next slide, please. Our solution to the dual IL-2 pharmacology of IL-2 is THOR-707 at single site specifically PEGylated IL-2 via vial conjugation to a new amino acid residue in THOR-707 that blocks engagement of the alpha chain of the IL-2 receptor as shown on the left panel of the slide. But this is done without affecting engagement of the receptor signaling complex on CD8+ T and NK cells. And because of that, THOR-707 maximally expands those cells without expanding Tregs or inducing eosinophilia, both in animals and more recently in patients, as I will show you in just a few minutes. While we were at it, we discovered a second IL-2 variant, THOR-809, currently in preclinical development. THOR-809 is tuned for weak engagement of the IL-2 receptor signaling complex, as shown on the right panel cartoon, unless the alpha chain of the receptor is present at high levels. And of course, that only happens on Treg cells. And because of that, THOR-809 selectively expands Tregs without activation of CD8+ T or NK cells and shows therapeutic efficacy in an animal model of delayed-type hypersensitivity. And the importance of this is that Tregs expansion is of value for the treatment of autoimmune diseases to restore tolerance to outdoor antigens that elicit pathogenic responses. What is common to both THOR-707 and THOR-809 is that the uniquely positioned PEG chain on these IL-2 variants confirms 2 important attributes. First, it fine-tunes IL-2 pharmacokinetics for optimal pharmacodynamic response; and second, it shields the new amino acid from immune surveillance, eliminating the risk of antidrug antibodies. And we have, by now, clinical confirmation, that's the case. Next slide. Very briefly. We have previously demonstrated that THOR-707 shows the expected not-alpha IL-2 pharmacological profile driving in monkeys substantial expansion of lymphocytes with no eosinophil expansion. That's shown on the right panel of the slide. I'm moving to the next slide. Today, I'm very excited to present for the first time early clinical biomarker data from our first-in-human study, HAMMER. And this data confirmed what we have seen in our preclinical models. This slide shows promising early biomarker data comparing to the clinical stage IL-2 therapeutics from Nektar and Roche. Already at the second dose level, 16 micrograms per kilo, THOR-707 elicited robust expansion of tumor-fighting CD8+ T and NK cells, comparable for CD8 or above for NKs, the one observed with the recommended Phase II dose of the Roche molecule and above that of Nektar's for both cell types, and without significant expansion of Tregs and eosinophils, as shown on the right panel of the slide. As I mentioned before, we have not observed ADAs in any patients. Importantly, those biomarker data allowed us to move THOR-707 into part 2 of the HAMMER study, combination with PD-1 checkpoint inhibitors. And of course, we're very excited about this. And on the next slide, we are showing the competitive landscape for IL-2 drugs. Comparing to other IL-2 molecules, we are confident that THOR-707 has the potential best-in-class profile when we take into account all critical drivers of the ideal target profile. Not-alpha specificity for receptors, sustained peripheral exposure, dosing convenience, differential impacts on effector versus regulatory T-cells, no observation of vascular leak syndrome, good tolerability and low-risk of antidrug antibodies. Next slide, please. While I have focused so far on PEGylated cytokine Synthorins, our precision cytokines, our expanded genetic alphabet platform has the potential for much wider application in protein therapeutics. Our next area of focus will be multi-specific biologics to enable the design of biologics with geometry that is not possible to attain via recombinant DNA methods. Specifically, we're looking to combine the benefits of our platform with the nanobody platform that Yong-Jun touched on. I'm moving to my final slide, next slide. I want to leave you with key take-home messages. First, our unique expanded genetic alphabet technology gives us the ability to turn interleukins into precision drugs for oncology and autoimmune diseases. Our most advanced candidates, THOR-707 and THOR-809, harness the dual pharmacology of IL-2, respectively targeting not-alpha and decreased beta approaches to fine-tune receptor binding. In the case of THOR-707, to regulate tumor-killing cells without expansion of immunosuppressive regulatory T-cells and eosinophils. And in the case of THOR-809, to suppress autoimmunity without a regulation of effector cells. As I show you, THOR-707 is already in the clinic and biomarker data suggests it could become the partner of choice for checkpoint inhibitors. And we expect Phase I results and the recommended Phase II dose by 2021. Beyond our IL-2s, we will have further precision cytokines entering the clinic over 2021 to 2023. And last, but not least, the Synthorx platform has the breadth and power to deliver for patients multiple preclinical candidates in the coming years, including nanobody targeted cytokines, nanobody drug conjugates and multi-specific nanobodies. And of course, we are very excited about that. And with that, I would like to hand it to John Reed to take you into Sanofi's focus on disease insights. John?

Thank you, Marcos, and it's great to have you on the Sanofi team. Having heard now about the unique drug discovery tools, let me introduce this next session where we'll focus on how we can leverage a deep understanding of the biology of disease pathways to discover new medicines that are applicable to multiple disorders. Let's move to Slide 29. When I ask myself where do we have core competencies in disease biology that stand out among peer pharma companies, I see differentiated strength in 2 areas: human immunology and monogenic disorders or so-called rare diseases. The umbrella of human immunology shown on the left of this slide encompasses our work on vaccines, immuno-oncology, immunology and inflammation, multiple sclerosis and hematology. The science of immunology unifies Sanofi R&D across all therapeutic areas, whether it's seeking ways to dial up the strength of the immune system for fighting cancer or protecting against pathogens or whether it's driving to dial down the immune system for autoimmunity and inflammatory diseases. In each of these therapeutic areas that are touched by immunoscience, Sanofi has already marketed products or will soon have a marketed product, reflecting our historical success in taming the immune system through the medicines we've developed. On the right, Sanofi is a long-standing market leader in rare monogenic disorders through our Genzyme heritage. Let's move to the next slide, Slide 30. First, I want to touch on immunology. On this slide, we show an extremely overly simplified depiction of just some of these cell types that play major roles in the immune system and their interrelationships. The cell types include, on the left, B-cells and their progeny responsible for antibody production or so-called humoral immunity for protection against many types of pathogens. In the middle are shown various types of T-cells, both immunostimulatory, Th1, Th2, Th17, and immunosuppressive regulatory T cells. Altogether, they form the foundations of cellular immunity, playing master regulator roles in immune responses, both beneficial and pathological. At the lower right are depicted effector cells, particularly cytolitic killer T-cells and natural killer, or NK cells, that provide our principal defense against virus infected cells and cancer cells. And then various types of innate immune cells, also figured here prominently as either upstream or downstream protectors against pathogens or culprits in disease context. And here, we just show microphages and eosinophils as representative examples. Next slide. Now overlaying where our approved and experimental medicines come into play, you immediately get a gist of the breadth and depth of Sanofi's commitment to immunoscience. By intervening at critical nodes in these complex immune networks, we can selectively modulate very specific behaviors of the immune system. And with that, we aim to either bolster protection from pathogens and cancers or to squelch the over-reactive network connections that account for autoimmunity in chronic inflammation. From this work has already come several approved products, including DUPIXENT and KEVZARA for chronic inflammatory diseases, AUBAGIO and Lemtrada for multiple sclerosis, and Libtayo and Sarclisa for cancer as well as several molecules currently in development, including the brain-penetrant BTK inhibitor for MS that we've talked about, including the non-alpha engineered IL-2 that Marcos just presented for immuno-oncology, and many others shown here and not shown here, and including our work on vaccines. My point is, when you think of Sanofi R&D, think immunoscience. It is a core competency of our company. Let's move to Slide 32. Now in monogenic disorders, Sanofi Genzyme pioneered this field, starting with enzyme replacement therapies to address a range of lysosomal storage diseases. Slide 32 shows how we built on the launch of Cerezyme for Gaucher's disease way back in 1994 to develop over the past 2 decades a portfolio spanning multiple rare genetic diseases. In our pipeline today, we are progressing olipudase alfa, the first enzyme replacement therapy for Niemann-Pick disease. And we just presented positive results from the Phase III COMET trial of avalglucosidase alfa in late-onset Pompe's disease, which represents a next-generation more potent enzyme replacement therapy. So with that background, Karin and Pablo now are going to take you through the development of Venglustat in several rare and not so rare diseases. Their presentation will highlight how Sanofi's deep insights into lysosomal biology, emanating from our decades-long commitment to lysosomal storage diseases, has opened new doors of opportunity for tackling a broad range of illnesses. We expect this to be a recurring theme as we leverage our expertise in rare diseases and parlay it into novel ways to tackle common diseases. So over to you, Karin.

Thank you, John. It's really a pleasure to be here today and talk about venglustat. Let's move to the next slide. Venglustat is an oral small molecule invented by Sanofi scientists. One of them, my colleague, Pablo here today. So to start, lysosomal storage disorders are rare monogenetic disorders where patients are born without certain enzymes located within lysosomes. Absence of a specific enzyme leads to the accumulation of lipids called glycosphingolipids. The most common approach to treat these disorders are enzyme replacement therapies and substrate reduction therapies. Venglustat is an oral substrate reduction therapy that works by inhibiting glycosine ceramide synthase, or GCS, which is a central regulator of glycosphingolipid metabolism. The same biology has been implicated in some not so rare diseases with very high unmet need, for example, polycystic kidney disease and Parkinson's disease with GBA mutations. Next slide, please. This slide shows the broader role of glycosphingolipids. Glycosphingolipids are critical components of cell membranes and have multiple functions, which include modulating membrane proteins, cell surface signaling and regulating pathways. Given this broad role, you can see why the accumulation of glycosphingolipids had a profound impact on patients with lysosomal storage disorders, but potentially also other disorders where a disturbance of all the glycosphingolipid metabolism has been implicated. Next slide, please. Here, we depict how GCS acts as a central regulator of glycosphingolipid metabolism. This is a very complex diagram, but the key take-home messages are that by inhibiting GCS with venglustat, we can potentially intervene in the GL1, GL3 and GM2 pathways. That these, respectively, have been implicated in Gaucher Type 3, Fabry and GM2 gangliosidosis as well as in autosomal dominant polycystic kidney disease and in patients with Parkinson's disease with GBA mutations. Here, this table shows that if we achieve our target profile with venglustat, it will be the best-in-class oral GCS inhibitor across a range of treatment dimensions. As well as the convenience of a once-daily dosing, venglustat is highly selective and potent. It effectively crosses the blood-brain barrier, and it has the potential to address a broader range of glycosphingolipid pathologies than currently approved GCS inhibitors do. All this translating into the potential to help more patients. On this slide, we illustrate how we intend to leverage venglustat's mode of action in the central nervous system and in key organs. Because of its ability to penetrate the brain, we believe venglustat will have the potential benefit in 2 rare lysosomal storage disorders, namely Gaucher Type 3 and GM2 gangliosidosis. In each case, there are no currently approved treatments. We also believe that venglustat could offer a new treatment option for Fabry since patients not receiving enzyme replacement therapy account for around 40% of the approximately 3,000 diagnosed Fabry patients in the U.S. In addition, Fabry patients with lower disease burden are often completely undiagnosed. On the right side, you can see that the eligible patient numbers become dramatically larger when we move beyond lysosomal storage disorders. The number of Parkinson patients with GBA mutations are around 78,000 in the U.S. Venglustat also potentially addresses polycystic kidney disorder with PKD 1 or 2 mutations. ADPKD is, in fact, the most prevalent monogenetic disorder and affects around 140,000 patients in the U.S., representing a major unmet need and an opportunity to reach more and more patients. Next slide, please. Here we show proof of concept that has been demonstrated in 2 Phase II studies. On the left, venglustat is associated with an increase in blood oxygenation level dependent signaling in Gaucher Type 3 patients. Change in signaling is a surrogate marker for increased functional activity in the brain and also supports our belief that venglustat is not only present but also bioactive in the brain. On the right, you can see a clear trend towards reduced lysosomal GL3 storage in Fabry over 3 years, suggesting an increased and sustained beneficial effect of venglustat over time. I should also add that venglustat's safety profile in these early clinical studies has been reassuring. We have by now treated over 250 patients and some for several years. This gives us confidence as we move into studies in younger patients since we acknowledge the importance to intervene early in the disease progress. Next, yes, thank you. My last slide describes the transformative potential of venglustat in polycystic kidney disease. Here, we see scope to improved patient outcomes compared to current standard of care, Tolvaptan. Tolvaptan, in addition, in 69.5% of patients in the clinical trials, causes a side effect, polyuria, which is very unpleasant and poses a risk for dehydration. And this reinforces the need for new treatment to these patients. On the right of this slide, you can see that in the venglustat arm kidney volume barely increased over the treatment period, whereas there was a substantial rise in the untreated arm. This shows effect on the disease by venglustat in this mouse model. So based on these promising early data, we initiated the STAGED-PKD Phase III study last year. This is a study in 640 patients that, in stage 1, uses total kidney volume as the primary endpoint, which, by itself, may be enough for an accelerated approval in U.S. In the larger second stage, we look at endpoints associated with renal function for full approval in the U.S. and rest of the world. We have -- we're happy to say that we have completed enrollment in the stage 1 and have initiated stage 2 based on the favorable safety and tolerability we have seen to date. And we expect the first results by end 2021. Let me now hand over to Pablo, who will talk to you about our plans for venglustat in Parkinson's disease with GBA mutations. Please, Pablo. Thank you.

Thank you. Thank you, Karin. It's great to be able to share the progress with venglustat in all these indications. It's been a long journey, and it's great to see how venglustat is starting to help our patients, and are declaring clinical proof of concept as we anticipated from our preclinical studies. Now we move to Slide 42. I'm really excited to also have the opportunity to discuss why venglustat could become the first disease-modifying therapy for GBA-Parkinson's disease. The way I see it is a successful therapy will target the right patient with the right mechanism and the right molecule. And from a clinical point of view, GBA mutations are not only a risk factor for Parkinson's disease, but more importantly, they're associated with a more aggressive form of the disease. GBA mutations are present in about 5% to 10% of Parkinson's patients, depending on the their ethnicity. And the graph on the left show the increased frequency of dementia in GBA carriers. Importantly, the accelerated disease progression in patients with GBA mutations has been observed on both motor and nonmotor features, which brings me to my next point, which is in the middle scheme. From a mechanistic point of view, the acceleration of the disease can be explained by this pathogenic feedback loop. Whereas the decrease in glucocerebrosidase activity, the GCase activity, due to the GBA mutations, will lead to glycosphingolipid accumulation, which can, in turn, help the aggregation of alpha-synuclein. The aggregated alpha-synuclein can then further reduce enzymatic activity and propagate the vicious cycle. We have robust scientific data demonstrating that the reduction in glycosphingolipid by GCS inhibition can disrupt the feedback loop and reduce the pathology and even reverse phenotypes in disease models. Thus, venglustat has the potential to exert a genuine disease-modifying impact in GBA-related Parkinson's. And lastly, we have the right molecule to target the CNS. You can see on the right, we show evidence of target engagement in the CNS from the Phase II MOVES-PD study. This was the first industry sponsored study in the genetic form of Parkinson's and includes 240 patients carrying GBA mutation. The graphic shows a clear dose-dependent reduction in GL1 glycosphingolipids in the CSF after 4 weeks. And the study is now fully enrolled, and we expect proof-of-concept readout in the first half of next year. If positive, we'll move swiftly into a Phase III. Next slide, please. I want also to extend my comments for those patients with sporadic Parkinson's disease who do not carry a GBA mutation, yet they still have glycosphingolipid pathways altered. In these patients, we've been gathering preclinical evidence that -- of the potential therapeutic benefit of venglustat. Here, we have demonstrated that the loss of GCase activity, the enzymatic activity in patients with synucleinopathies that do not carry GBA mutations, such as sporadic Parkinson's and Lewy body dementia patients as seen on the left. In addition, by blocking GCS, glucosylceramide synthase, in model systems carrying wild-type GBA alleles, in this case, we can reduce the conversion of alpha-synuclein to toxic oligomers, as seen in the middle graph as well as improve behavioral phenotypes in animal models of disease, as seen on the graph on the right. As a consequence, when we move to our Phase III program, FDA has recommended that we include about 20% of patients with GBA mutations to test whether therapeutic intervention with venglustat might be more broadly applicable to the overall idiopathic Parkinson's community. In the next slide, we have additional evidence of the critical role of lysosomal and glycosphingolipid pathways from the genetics of Parkinson's disease. In this light, we show many of the known genetic drivers of Parkinson's, LRRK2 mutations, alpha-synuclein, GBA and the lysosomal storage disease gene and how they conspire to reduce GCase activity and lysosomal function. By inhibiting glycosphingolipids with venglustat, we could potentially restore normal lysosomal function and alter disease progression. And then at Sanofi, also, the patient-centric innovation means more than just novel molecules and mechanisms, as I've just explained. We're also advancing our digital footprint. The ambition is to expedite clinical development in Parkinson's by using what has the potential to be the first validated digital endpoint for Parkinson's disease. We call it the PD-FIDI, the Parkinson's Disease Functional Impact Digital Instrument. This is a digital tool which measures clinical endpoints and patient-reported outcomes and might allow us to better capture disease progression and achieve statistical power with fewer patients. The concept is based around a smartphone app and a device worn in the wrist to capture multiple parameters of motor functions. Including components of the UPDRS, the Unified Parkinson's Disease Rating Scale, which is the benchmark outcome as well as dyskinesia, gait, balance and patient-reported outcomes. In my next slide, this is my last slide and summarizes where are we currently standing with venglustat. I'm extremely proud of how far we've come from our initial discovery that are now showing proof of concept in rare diseases patients and also a great promise to help even more patients. In the classic lysosomal storage diseases, we're running a Phase II/III Gaucher-type trial in GD3. We're starting pivotal Phase III in GM2 gangliosidosis and preparing a Phase III for Fabry. We expect to make regulatory submissions in all 3 indications during 2023. And for Parkinson's, the MOVES-PD study I just discussed will produce proof-of-concept data by the first half of next year. If this supports late-stage development, we will be targeting regulatory submission by the 2025 time frame. And finally, for ADPKD, we expect pivotal results from the STAGED-PKD trial by the end of next year, and we plan to file early in 2022. In closing, I hope Karin and I have provided with a better understanding of why Sanofi selected venglustat as 1 of the 6 potential transformative assets at the Capital Markets Day last December. We will be happy to answer any questions. And I will hand it over to Felix to start the Q&A. Thank you.

Excellent. Thanks, Pablo. Let's move to Q&A now. For this first round of Q&A, we have 20 minutes allocated. [Operator Instructions] Natalie, can you please remind everyone of how to ask questions?

[Operator Instructions] Your question will be read by our panelists. Now we will take the first question from Wimal Kapadia at Bernstein.

I'm Wimal Kapadia from Bernstein. Wanted to ask on one on THOR-707. So you highlighted several interesting differentiated factors of THOR-707 versus peers, and in particular, the reduced CD4 Treg bias with retained stimulator activity of the CD8 and the NK cells. But my question is why? Is it driven by the design of the products, i.e., the single PEG chain compared to the Nektar product, which is not specifically linked to 6? Is that what drives the sustained activity? Or is it because you -- some of your peers have conjugated to the anti-FEP antibody. Just curious to explain what drives these differences in the outcome?

Yes. Thanks for your question, Wimal. Yes, it really has to do with the -- where the PEG chain was positioned and the fact that it's an irreversible conjugation to that unnatural amino acid. Let me let Marcos maybe expand a little bit on that.

Sure. Pleasure. Great question. Indeed, the positioning of the PEG is an irreversible chemistry. It doesn't come off, and it blocks alpha. And this allows to substantially increase the exposure of THOR-707 relative to what was possible with aldesleukin. And because of that, the high exposure at the target CD8+ T and NK cells drives what I would call an optimal pharmacodynamic response for the expansion of those target cells without expansion of regulatory T-cells or eosinophils.

The next question comes from Graham Parry from Bank of America Merrill Lynch.

Great. It's actually a broad high-level question, if I've only got the one. So you've laid out, John, I think your first full year results, a broad range of discovery platforms at Sanofi. So you talked about some of the partners, some of the in-house RNA, gene therapy, cell therapy, nanobodies, the monoclonal bispecific, trispecific antibodies, et cetera. You're focusing in today a little bit more on select ones, but perhaps if you could just give us a feel for what the breadth of those discovery platforms you have now, which ones you've dropped. And in particular, I think gene therapy is one. You've talked a lot about having capabilities but needing to build on. So perhaps just help us to understand where you might need to expand further as well.

Thanks for your question, Graham. I'm going to save the gene therapy one for later because we do have a slide, and we'll make some brief comments about our strategy in gene therapy at the end of the program. So we'll come back to that. But with respect to the other platforms, I think I'll let Yong-Jun Liu perhaps remark on that, and maybe I'll then supplement his comments after Yong-Jun describes. Yong-Jun?

Thank you, John. It's a very good question. So basically, the 2 platforms I highlighted, they are really critical to design drugs that can target multiple target in 1 molecule. If we think about unmet need, some of the best-selling drug, you always hear poor responder. You always hear patients become refractory. So we believe multiple targeting to stop the vicious circle of that pathology is very important. So we have this very unique technology in-house. We can target 3. I show you we can target 4. And if you look at the power of nanobody, you can link up to 8 nanobody in 1 molecule. So for us, this is a very important platform across our immunology and immuno-oncology. We are heavily invested in making of the next-generation molecule within these 2 technology. Another area we are moving into is a structure-based drug design. I think that's very important. There are many examples of nondruggable target that become druggable. So we invest heavily in structure biology, in artificial intelligence, in collaboration with DNA-encoded library. So we want to convert nondruggable target into druggable target. We also invest in protein degradation. And we want to be sure our scientists are not limited by technology. Thank you.

Yes. Thanks, Yong-Jun. I guess maybe the other 2 things I would add, Graham, is that we're excited about the momentum building in the antibody drug conjugate space. So we -- at the ASCO session, the satellite event we did there, we featured '701, our first antibody drug conjugate, to move into late development from Sanofi. So we are anticipating doing more things with that platform. And for example, expanding it beyond conventional IgG antibodies into the nanobody platform, where we can really tune the pharmacology exactly where we want it from either very short-lived to very long-lived molecules, and we think that will play well in terms of an antibody drug conjugate. So that's one area. And then we're building more and more expertise around -- in the small molecule space, around the greater technology, where one makes the bidentate molecules that grab the ubiquitination machinery and aim it at a desired target. So we're doing more in that space both internally and through external partners. Let's move on to next question, and we'll come back to that gene therapy thought at the end of the meeting, Graham.

The next question is from Pete Verdult at Citi. Pete?

Yes. Thanks. Pete Verdult, Citi. Just for John, Marcos or Yong. I mean, you're clearly wanting to showcase these 2 platforms. Could you perhaps give the audience a bit more steer when we're going to see data for THOR-707? When 809 might actually enter first-in-human studies? And on the nanobodies, are we -- could we get any data in 2021? Just wanting to get a better steer as to how far into next year we need to wait before we see more data on these assets.

Yes. Thanks for your questions, Peter. Marcos, why don't you take the first session on THOR-707 and THOR-809? And then, Yong-Jun, you can give an update on when we think some of these multi-specific nanobodies will start to see the light of day in terms of appearing in the clinic? So Marcos, over to you first.

Sure. We were delighted to present for the first time biomarker data today, early biomarker data. We intend to present further on initial biomarkers later this year. And next year, we're going to present more complete biomarkers together with dose escalation in combination with a PD-1 checkpoint inhibitor. And then we expect to see proof-of-concept for the monotherapy arm in solid tumors in 2022. With regard to THOR-809, we expect to file an IND next year to then move into dose escalation in healthy volunteers.

Yes. The IND would have been filed this year had it not been for COVID, Peter. So we're a couple of months behind where we wish we were, but should get in the clinic early next year. Yong-Jun, the multi-specific nanobodies there?

Yes. So you remember, we start to integrate Ablynx to Global Sanofi Research exactly 2 years ago. And this has been a very happy marriage and a productive marriage. In 2019, we delivered 3 multi-specific nanobody clinical candidates. We expect 1 will enter the clinic this year and 2 will enter the clinic next year. And it's such a productive collaboration. We expect the 2 platform will deliver 3 to 5 clinical candidates every year for the next several years. It's very exciting.

Thanks for your question, Peter.

The next question is from Richard Vosser at JPMorgan.

So just -- I know it's early with THOR-707. But on the basis of the early data, perhaps you could maybe put it into context for us relative to some of the other agents that are going with PD-1s and PD-L1s, such as TGF-beta or TIGIT, et cetera. I know Roche has, and you've compared your product to the Roche product, an IL-2, and they're pushing forward with TIGIT. So just some context of maybe the relative benefits here.

Sure. Yes. Maybe I'll make a few comments, but then I would ask either Marcos or Yong-Jun to perhaps chime in and supplement. But there are several mechanisms one could think about in terms of trying to improve -- to build the immune system to attack tumors and particularly solid tumors where it is a higher bar than the liquid tumors or the hematopoietic malignancies. We think IL-2 is really one of the most attractive opportunities there because of the expansion of -- and when you have a well-engineered version of IL-2, which frankly, has IL-15-like qualities, the ability to selectively expand the desired [ cell ] populations, effector T cells, NK cells, really allows us then to sort of dial up or amplify the immune response. And we do intend to exploit both the T-cell and the NK cell sides of that. On the NK side, for example, which I think has been somewhat overlooked by the field, we'll do combinations with ADCC-competent antibodies like our own Sarclisa and are planning studies in combination there to boost up the NK cells that hopefully would then allow that antibody that works in part by recruiting NK cells to attack the myeloma. We'll play that side of the equation as well as with multi-specific NK cell engagers. And then we'll play the T-cell side of the game as well in combination with T-cell engagers, in combination with PD-1, et cetera. We do also have other mechanisms in the clinic. We have a TGF-beta in the clinic. That is also potentially attractive with respect to reducing the production of immunosuppressive regulatory T-cells as well as perhaps helping T-cells to better traffic into tumors, a few mechanisms of relevance there. And over time, I think we'll exploit others as well. But we're really quite excited about IL-2 as a very central player in both the T-cell and NK sides of the attack on tumors. Marcos, Yong-Jun, anything to add?

Yes, perhaps very briefly, as John is saying, IL-2 has the potential to become a backbone agent in THOR-707, because of its PD responses, is really a very exciting agent. And it can be combined really with any mechanism that increases discovery of tumor agents as well as mechanisms that address the suppressive tumor microenvironment because THOR-707 is a pan-activator of T-cells and NK cells. So we believe that multiple combinations will be possible and will be explored as appropriate agents appear for target indications.

Yes. So regarding PD-1 combination, we aim to treat PD-1 nonresponder. So one example is our collaboration with BioNTech. We have mRNA technology. We can put 4 immunostimulatory molecule into one goal. So this is in Phase I, and we have the second generation coming. And also, we have a series of multi-specific antibody targeting tumor cells or targeting additional immune regulatory molecule.

Good. Richard, I hope I addressed some of your thoughts there, we're maybe, again, to use a metaphor of the brakes and gas on the car about the immune system, trying to get into attack cancer or to drive to better results for cancer patients. We're trying to play both sides of that. We've been putting a lot of the emphasis on the gas pedal with things like IL-2. Taking the brakes off with things like PD-1, TIGIT, et cetera, is also a component of that. We think you're really going to need to play both sides of that to ultimately be successful. And so that's kind of the way we're attacking that space.

The next question is from Seamus Fernandez at Guggenheim.

So my question actually is on venglustat. It looks like clearly an exciting opportunity. What would be the risks on the ADPKD side in terms of the data? The early data looks pretty compelling and obviously, good animal models there. But if you could just walk us through some of the risks that you see to that indication from a -- as it relates to that product and the mechanism? Is it clinical risk more from the perspective of the patient population and recruiting? What have you done to sort of maximize the likelihood of success?

Seamus, thanks for your question. I think what I'll do is ask Pablo first just to talk about the biological rationale, any risk associated there. Of course, the data there are contingent on animal models. But -- although I'm generally not a big fan of animal models, I would say this is one of the cases where one's confidence, I think, comes out a bit higher because you make exactly the same mutation that causes autosomal dominant polycystic kidney disease in people, and mice get exactly the same disease. So we feel more confident than usual, I would say. So let me ask Pablo to just touch on that element. And then Karin, you could talk on the clinical development program and the endpoints we're using, et cetera. So Pablo, over to you first.

Yes. Thanks, Seamus, for the question. From a mechanistic point of view, John, you hit the nail on the head. We tested it in several models, 3 models of PKD with different mutations. They are the same mutation that's in the humans. We know what the mechanism is working on the cilia. We know how the cilia reacts to the glycosphingolipid changes. And when we test in these animal models, we see a reversion of the phenotypes. So that's from a mechanistic point of view. There's a good translatability into the human patient population. Then the clinical development, it's a different risk that I'm not going to get into.

So yes, Karin, do you want to take the question? This pertains to the clinical development plan.

Yes. Of course, it's hard to say before we've seen the data. But I think -- I mean the disease pathology is clear. So we have the specific mutations. We know that kidney volume increases and then kidney function decreases and you go to end-stage renal disease if left untreated. So I think the endpoints are very clear. And we are hopeful. We have initiated stage 1 where we think that kidney volume -- or we have agreed with regulators that kidney volume is a good endpoint to -- for accelerated approval in the U.S. And we have already initiated the stage 2 based on an external view of the stage 1 data. So I think we feel as confident as we can feel about the clinical path forward.

Thanks, Karin. I think the team's also really performed heroically to get these studies recruited in the face of a pandemic. We finished the recruitment on the so-called Part A of the program where we're using total kidney volume as the endpoint. That's fully recruited. We started the second study which will use glomerular filtration rate as the endpoint, which will be needed outside the U.S. So despite the pandemic, the ClinOps team, et cetera, has done really a fabulous job in keeping patients rolling onto this study. And I think it also reflects the unmet need out there. There's not a lot to offer these patients, not a lot that's a very attractive solution for their issues. So we're -- fingers crossed, we're optimistic, though, that we can make a real difference for patients with this disorder.

Yes.

Okay, John. John, at this point, I think we have to move on to section 2 to stay within our time lines. Section 2 of our presentations. And I would like to turn the event over to Vanessa to introduce a patient insight session of today's event. Vanessa?

Thank you, Felix. And good morning, good afternoon, everyone. I hope you still have energy and have stretched your leg, as I'm personally very excited to have the opportunity to discuss with you all today about the amazing hemophilia community, the needs and what we hope our exciting pipeline will bring to these patients. And as patients are at the center of everything we do, let's listen to them first. [Presentation]

So as you've seen and heard through these patients' testimony, even if we've come a long way in treating hemophilia, even if patients are generally satisfied with what is available, there is still some way to go as current treatments do not address all patients' mutations. Each hemophilia patient experience is unique. Their age, level of activity, their past experience, their family history, all matters in what drives their needs. What is common to all patients is that currently, they have to make a trade-off between treatment burden and the activities they can carry out. If we move to Slide 48 and we dig a little deeper into current treatment limitations. Today, we have 2 treatment approaches available for patients. The first one and the major one is factor replacement therapy, which exactly replaces the missing Factor VIII or XI in the clotting cascade for patients with hemophilia A and B, respectively. As natural factors, these are complex molecules that require IV to be administered. On the nonfactor therapy side, emicizumab, currently, which attempts to substitute for Factor VIII for patients with hemophilia A only as an antibody, this molecule is amenable to subcu injection. But this approach has limitations. Factor replacement therapies are highly effective at preventing and controlling bleeds, but they carry a high treatment burden for patients by requiring relatively frequent IV infusions. Emicizumab, on the other hand, reduces the treatment burden as it can be dosed less frequently as subcutaneous injection. But there is an efficacy trade-off here as it produces only mild level of protection against bleed. And you've heard it from Cole and his mom. Patients still need to keep on-demand factor at hand. Also, mechanistically, emicizumab does not have treatment benefit in hemophilia B, and we will come back on this later. But as you can see, we are not there yet. So in short, nothing that is currently available meets all hemophilia patients' needs. No treatment today enables patients to lead active lives and achieve a quality of life comparable to someone without hemophilia, which remains our goal, and it was defined again last week during WFH Congress. So we developed fitusiran and BIVV001 to address these patients' needs, and they are now 2 of the 6 potential transformative assets in Sanofi's pipeline as we highlighted at our Capital Markets Day. So let's move to Slide 49 and talk about fundamentals and why it is very important to understand how factor levels are defining protection level against bleeds and thus, patient activity. So if we begin by the bottom of the slide, with the factor level below 5%. Those levels leave patients vulnerable, permitting only a sedentary lifestyle, and patients are at high risk of spontaneous bleedings. If we go up and factor between 5% and 15%, those still require significant adjustments to patients' lives, allowing only for mild activities. And you've seen that and heard that in the patient video. It was noting that patients at these factor levels and below still require supplementary factor for any invasive procedure. Now if we keep going up and factor level between 15% and 40%, those only require minor adjustments and they allow for strenuous activities. And it's really only when you get above 40% our hemophilia patient can have a normal life, allowing them to do all the activity considered normal by you and I or non-hemophilia patients. If we move to Slide 50, and we come back a bit more in detail about the [ trail ] that patients need to make today. As I mentioned, factor replacement therapies are very efficacious. They are producing high level of protection, but over a short period of time. They also benefit from many years of safety and efficacy experience. The downside for patients rest in the peak and troughs of factor levels over the course of the week and the treatment burden associated with frequent infusion. Our own Eloctate, the first-in-class extended half-life, still require dosing more than once weekly. And risk factor, in general, if you miss infusions in your schedule that has been defined, you can be at risk of bleeds. Now if we turn to emicizumab, who captured significant patient share since launch, largely due to its improved treatment burden. But why it fails to meet patients' needs is that it produces the level of protection which are only equivalent to around 9% of Factor VIII activity, which is far below what physicians would class as normal and not even strenuous. Furthermore, the annualized bleed rate on therapy is highly variable, depending on frequency of dosing. And while it can be given weekly, every 2 weeks or monthly, our research tells us that only 7% of patients opt for the monthly dosing, and this is because of reduced efficacy. And indeed, from the clinical program, even on a weekly regimen, we know that half of emicizumab patients still experience some bleeds. And still from our research, we know that 90% of these patients have to use additional factor to treat the bleed, meaning that patients always need to have factor at home to do dual therapy with factor and heme. So overall, with current options, patients, on average, can have strenuous activity less than 50% of the time. So now if we look at this slide, Slide 51, you understand why we're not there yet and why we need to continue to push the boundaries of treatment burden and protection levels in order to address patients' needs. With BIVV001, we do have the potential to go higher for longer. We are targeting protection for patients across the whole week with just 1 infusion, reducing the treatment burden compared with existing factors and improving the protection on a comparable weekly regimen to emicizumab. We also expect to improve the joint protection with factor level in the normal range for half of the week and at sufficient high levels to allow for strenuous activity for the rest of the week. Our heme is with BIVV001 is to be the best option for those seeking an active life. With fitusiran, our target is to bring patient convenience and efficacy to the next level. It is anticipated that patients will require just 1 minute, less than 1 milliliter subcutaneous injection once a month, the so-called 1/1/1. And critically, we aim to deliver better protection during the entire month's dosing interval. So with that, fitusiran will really be the first true high-efficacy monthly subcu therapy for all hemophilia patients A, B, with or without inhibitors, aiming for 15% to 20% of factor equivalent levels and particularly then, for the patients who are seeking the ultimate convenience without trading off efficacy. And with both products, we are aiming to get more patients above the strenuous level for at least 80% of the time. I will now hand over to Dietmar, our Head of Development, to bring you through some of the data we have to support BIVV001 and fitusiran.

Thank you, Vanessa, and good morning, good afternoon to everyone. As a hematologist and oncologist, I have treated hemophilia patients in the clinic. And I've also been closely involved in the development of emicizumab, which, as you know, has been well accepted. But I think we can do better, and we owe it to patients to do just that. On Slide 52, BIVV001 is a new class of factor therapy, which has been uniquely engineered to maintain all the advantages of factor therapy while normalizing Factor VIII levels in a once-weekly dose. Commentary on our recent preclinical data publication referred to BIVV001 as a molecular jewel, acknowledging the addition of fusions of XTEN and portions of von Willebrand factor to break the ceiling that constrains the half-life of all other Factor VIII molecules and highlighting the elegant engineering to remove them by thrombin within the context of the activated clotting cascade. BIVV001's half-life is almost 2 days. This translates into maintaining levels of Factor VIII at 40% or above for several days and 20% or above for 5 days. If I take you back to the 4 categories of protection that Vanessa mentioned, this means that we can potentially keep factor levels in the normal or strenuous range for the entire week, so that patients can enjoy an active life without any major restrictions. On Slide 53, I'm delighted to say that we just reported our first positive outcome for the Phase I repeat dose study of BIVV001. This data was revealed at the World Federation of Hemophilia meeting on June 18. What you see here is that in an exploratory analysis in 24 patients, we observed no bleeds over the 4-week treatment period and for at least 10 days after the last dose. This compares with median prior bleed rates of 48 of the previous year of 4 per month. Not only was this highly reassuring on efficacy, but the 4 weekly doses were well tolerated with no signs of inhibitors, allergic or anaphylactic reactions or treatment-related adverse events. This is encouraging as we look forward to the outcome of our ongoing Phase III program. Next, Slide 54. I want to move now to fitusiran, which is the only therapy specifically designed to bring high protection levels to patients in a true once-monthly subcutaneous format. Fitusiran is an siRNA molecule with an innovative mechanism of action, which rebalances the deficient coagulation cascade in both hemophilia A and B. It works by inhibiting the production of antithrombin 3. This, in turn, results in an increase in thrombin generation, which is the ultimate goal of the coagulation cascade. We are aware that a number of you have concerns about the safety profile of fitusiran, and this is a bit of a Déjà vu moment for me as you had similar concerns for emicizumab when it was in development. For fitusiran, we have carefully developed bleed management guidelines, and those were agreed with the FDA in December 2017. Since implementation of these guidelines, we have seen a favorable safety profile with no thrombotic event occurring in any complying patients. We now have positive data with more than 250 patients in our clinical trials and more than 4 years of experience for the longest-treated patients. On Slide 55, we also reported important new data on fitusiran at last week's World Federation of Hemophilia, supporting the product efficacy and safety in a Phase II open-label extension study. The overall median annualized bleed rate with monthly fitusiran was 0.84 in patients with and without inhibitors. As you can see from the left-hand and middle charts, there were substantial improvements in each set of patients when compared with prior treatment. For patients with inhibitors, the efficacy is at least as good as in the noninhibitor population. And this is especially important as bleeding events in the inhibitor population are hardest to treat. We observed an encouraging safety and tolerability profile for patients in this trial. 4 out of the 34 patients were deemed to have had a serious adverse event related to study drug, but that's over a median dosing period of 2.6 years and a maximum of close to 5 years, so a fairly prolonged period. Importantly, we did not detect any cases of antidrug antibody formation. On Slide 56, with its unique mechanism of action, we believe fitusiran is a potential best-in-class nonfactor therapy for hemophilia patients. This slide compares its key attributes with emicizumab. In all respects, depicted here, we think fitusiran may transform hemophilia treatment if it meets our target profile. It has the potential to be the first true once-monthly subcutaneous injection with an annualized bleed rate of less than 1, raising the standard of efficacy for all hemophilia A patients. It's also on track to be the first subcutaneous therapy to address the hemophilia B population, which, in itself, represents a $1 billion market in the U.S. alone. Fitusiran can be delivered in a single prefilled syringe with a low-volume fixed dose. And you've heard in the patients' video that one drawback of emicizumab can be injection site pain, which may be related to a larger injection volume. Fitusiran will be the first-ever product in hemophilia that won't require refrigeration. And finally, a reversal agent is available for fitusiran, whereas emicizumab stays in the body for up to 6 months without an option to remove it, except in plasma exchange. On Slide 57, I want to wrap up, we believe patient experience will drive choice in hemophilia. And we are all well advanced in Phase III studies for both of our exciting new agents. Our pivotal study of BIVV001 in previously treated hemophilia A patients started last year, and we are planning for submission in the first half of 2022. Meanwhile, 2 of the 3 ATLAS studies of fitusiran are fully enrolled, and we're close to completion of the third with a pediatric study also enrolling. We target submission for fitusiran in a broad population of hemophilia A and B patients with and without inhibitors in the second half of 2021. Now to Slide 58. Sanofi is not stopping there. And our ultimate aim is to provide a true cure for hemophilia so that all patients can achieve a normal life. We're working on a gene therapy approach based on in vivo administration of a lentiviral vector. We believe this will overcome the shortcomings of the adeno-associated viral-based gene therapies currently undergoing development in terms of pre-existing antibodies, declining Factor VIII levels and inability to treat pediatric patients. We expect our approach to be more durable and target entry to the clinic by 2022. With this outlook, we conclude our section on patient insights and on our exciting portfolio in hemophilia. So now moving on to our next section. I came to Sanofi roughly a year ago with fresh eyes, and I want to give you some insights into how we are improving our capabilities from a development perspective. Then, my colleague, John Shiver, will take you through how we have been able to leverage this in practice with our response to the COVID-19 pandemic. On Slide 60, as we are moving from a primary care to a specialty care focus in R&D, it's imperative for us to build an agile and innovative development engine. This slide gives a summary of the 4 main dimensions we are focusing on to expand our capabilities. The first dimension is enhancing patient centricity and integrating the patient voice more broadly into our approach to clinical development. As examples, we are embedding patient-related insights into our disease strategies, as you heard from Vanessa, to help us determine and address unmet needs. We're making it easier, as an example, for patients to participate in clinical trials through telehealth, home delivery, digital tools, e-consent and patient portals. The second dimension is to optimize our use of digital and real-world evidence. You heard on our DUPIXENT R&D call how we are utilizing our proprietary Darwin platform with its access to nearly 450 million live medical records to help inform our line extension strategy in type 2 inflammatory diseases. We are also using artificial intelligence for candidate and indication selection, and I know many of you are already aware of the efficiency opportunities that digital brings across the entire R&D process. The third dimension is focusing and simplifying our footprint. With a focus on specialty care and vaccines, we can use this as an opportunity to make our R&D operations more efficient and complement this with investment into leading-edge technologies, including our recently announced evolutive vaccine facility, which will be the first factory of this type across the industry. This is a new type of manufacturing plant designed around the central unit, housing several fully digital production modules that will make it possible to produce 3 to 4 vaccines simultaneously versus only 1 in current industrial sites. And I find this pretty exciting. The fourth and final dimension is examining new ways of working and engagement models. As a central component, we're building an integrated development organization with full alignment around our therapeutic areas, which have end-to-end responsibility of the development process. John told you in December about cutting multiple layers of bureaucracy to help the efficiency and rigor of our decision-making, and he referred to it today again. You've also heard about us taking smart risks, for example, making informed investment decisions based on early clinical data. I will come back to this in a couple of minutes in the context of our BTK inhibitor. In the future, we see a place for more enhanced collaborations like the I-SPY collaboration breast cancer that we announced at our recent ASCO event as well as our important long-term partnership with BARDA, which John Shiver will speak to during his presentation. On Slide 61, I want to expand on our digital strategy. We recognize we have our work cut out in this area. But I think some of the examples you've heard about today, like the application of Darwin and the use of innovative digital endpoints in our Parkinson's studies with venglustat as well as our award-winning paperless digital factory in Framingham, speak to a company that is arguably developing a leadership position on several fronts. We're also looking forward to working with our recently joined Chief Digital Officer, Arnaud Robert, to accelerate our digital strategy and implementation in R&D. There is a lot of information on this slide. So we'll just leave you with a take-home that digital brings fresh opportunities to transform our company. And we have multiple pilots of full-blown programs underway across the entire R&D continuum to leverage these opportunities. On my last slide, Slide 62, I said I would come back to the topic of taking smart risks and flawless execution to improve our pace in development. Our brain-penetrant BTK inhibitor 168 is an excellent example. Here, we began with Phase I and II studies that were conducted 1 year faster than benchmarks due to efficient trial design, home delivery of study drug and other measures. We're especially proud that we were able to maintain our studies and patient commitments despite the COVID-19 pandemic. Prior to Phase III readout, we already began planning Phase III studies across the full spectrum of multiple sclerosis. That happened at risk, and we later made the decision to rightsize the control arm in primary progressive MS so that we could accelerate study completion while still maintaining adequate statistical power. And as Paul told you earlier, we're now delighted to say that the first patient has been enrolled in our pivotal Phase III study in relapsing remitting multiple sclerosis. This is just 4.5 months after readout of the Phase II data. By taking smart risks and focusing on flawless execution, we have accelerated the development of this potentially best-in-disease molecule and are on track to make expected regulatory submissions beginning in the first half of 2024. With that, I want to thank you for your attention, and I hand over to John Shiver to start our conversation on vaccines.

Thank you very much, Dietmar. We feel privileged to play our part in the company's response to the COVID-19 pandemic, which, as you know, is the largest global public health crisis in a century and which is galvanizing our industry like never before. I want to start my presentation with a short video, which underscores the urgency with which we are addressing the COVID pandemic. [Presentation]

Okay. Very good. So Slide 63 shows the landscape of more than 160 vaccine candidates in development for COVID-19. This is unique. We have never seen a single disease with such an intensity of vaccine development in such a short time. One thing that's very important here to look at are the technologies underlying these clinical candidates. Less than half are based upon the proven vaccine technologies of recombinant protein-based live virus or whole inactivated viruses. These validated approaches form the basis of successful vaccines across a range of viral diseases, including influenza, herpes zoster, yellow fever, measles and human papillomavirus, to name but several. What this means is the majority of COVID-19 vaccine candidates, around 60%, specifically all gene delivery-based platforms, such as mRNA, DNA and vector vaccines, are based on unproven platforms that have never produced a licensed vaccine. This means many of the candidates that you read about are at risk of suboptimal efficacy or safety or even outright failure. My next slide develops this theme further. So Slide 64 summarizes the different safety and efficacy profiles of the main platform approaches used in antiviral vaccines. The main advantage of gene delivery-based approaches is the short time it takes to deliver a clinical candidate when compared to recombinant protein vaccines where you first have to build the expression system in bacterial, mammalian, yeast, or in the case of our recombinant protein candidate, insect cells, to generate the protein. On the flip side of the gene delivery approach are the numerous unknowns in terms of efficacy, duration of protection, safety, but also the lack of an established infrastructure for industrial-scale production, which applies significant execution risk. Virus-based approaches come with significant safety concerns and hence are not pursued by the western companies. So let's advance to Slide 65. And so on this slide shows our 2 complementary differentiated approaches that Sanofi is taking towards the COVID-19 vaccine. By employing 2 different platforms, we believe we'll have a greater chance of success and achieving our goal of developing an efficacious and safe vaccine. On the left side, you see our recombinant baculovirus-based candidate, our most advanced candidate. This utilizes the same U.S.-licensed cell-based technology which we employ for the large-scale manufacturing of our Flublok influenza vaccine. This candidate has been developed in collaboration with BARDA and via our unique arrangement with GSK, normally our fierce rivals, but in this case, our allies, who are supplying their proven AS03 adjuvant. The advantages of our baculovirus approach are: this is a derisked technology with established capacity in place that we can leverage. It is unknown yet if it will require boosters to maintain an effective immune response to the virus, but these, of course, could be given if needed. On the right side, you see our innovative messenger RNA vaccine approach which is based on natural mRNA encased in lipid nanoparticles. This arose from an extension of our 2018 collaboration with Translate Bio, who have the only established large-scale mRNA manufacturing capacity. Because of the investment we and Translate Bio had already made in these programs, we believe we can accelerate the development of our COVID-19 candidate, and we can leverage the large-scale capacity that is already in place as a result of their long history in pulmonary application, which requires large doses. In common with any innovative approach, we have not yet fully elucidated the safety profile, of course. However, it may have a differentiated safety as well as potency profile compared via natural versus a modified mRNA. On Slide 66, I am pleased to announce that we have accelerated the time lines for our baculovirus candidate vaccine by 2 months compared with our original plan announced during our Q1 results. This is a result of a huge coordinated effort by our R&D and industrial affairs teams. On the right-hand side, you see the number of levers that we're pulling to get this vaccine today as quickly as possible into humans, including optimizing clinical studies and production of vaccine components at risk. The result of this effort is shown in the time lines on the left. So having obtained the necessary preclinical data in August, we plan to start a Phase I/II study in more than 400 subjects in September, with preliminary data expected to read out in December. Assuming this meets our target profile, we will move immediately into a confirmatory Phase III program. In parallel, based on the Phase I/II data, we intend to seek emergency use authorization in January 2021 with up to 100 million doses available and to make regulatory submissions with the aim of gaining approval as early as June of next year. On Slide 67, we show that we're working intensely with our pharma colleagues, our contract manufacturing partner and our adjuvant supplier, GSK, to put in place the capacity to deliver 1 billion doses of our baculovirus vaccine in 2021. There's obviously a degree of uncertainty around this as vaccine manufacturing is uniquely complex, something we are acutely aware of as one of the leading vaccine suppliers for many decades. And let's not forget, we're telescoping a process that would normally take many years. The baculovirus expression system is a high-yield expression system, and we aim to optimize the number of batches we run at our various facilities so that we're confident we have the capability to deliver the 1 billion doses next year. On Slide 68, I want to shift gears and update you on our mRNA vaccine candidate. Together with Translate Bio, we have screened hundreds of lipid formulations so that we get the right pharmacokinetics for the lipid nanoparticles to deliver natural messenger mRNA into muscle. We're now at the stage of IND-enabling studies for the lead nanoparticle. At the same time, we've identified multiple antigen mRNA constructs from the virus and have packaged these into lipid nanoparticles for preclinical testing. We're making good progress with our partner, and our intention is to move a candidate vaccine from this program into the clinic in the fourth quarter of this year. By applying the same urgency we have shown with our baculovirus candidate, we could potentially expedite the process in order to obtain regulatory approvals before the end of 2021. Where we will have major advantage over the other RNA platforms' vaccines in development is that we start with established manufacturing capabilities that can be scaled up quickly, if needed. Translate Bio has been investing in mRNA manufacturing for more than a decade and has successfully established ongoing 100-gram single-batch production at its large-scale facility. Translate Bio has demonstrated 250-gram single-batch mRNA production, and work is underway to achieve this scale on an ongoing basis, which would allow commercial mRNA vaccine volumes to be produced. In total, this could provide us with the capacity to supply in the range of 90 million to 360 million doses annually by the first half of 2021 and with the flexibility to extend to other pandemic targets. On my final slide, #69, COVID-19 is the biggest global health scourge for a century. The world needs multiple vaccines and the capability to supply billions of vaccine doses. This is not a situation of winner takes all. At Sanofi, we believe we can be a key player in the fight, and we're working day and night to advance our 2 complementary differentiated vaccine candidates. This slide summarizes the key take-homes. It is worth saying again that our recombinant protein-based vaccine candidate has the best risk profile among the advanced COVID-19 vaccine candidates, in our view, and we have been pulling out all stops to accelerate our development time lines. We aim to afford emergency use authorization in January 2021 with up to 100 million doses and for approval in June 2021 with the capacity of 1 billion doses in 2021. I will leave you to read the rest of the detail. But let me just say, I am proud that Sanofi is once again able to demonstrate and build upon its commitment to global public health. The urgency with which we're moving speaks to a company which is passionate, fully engaged and able to leverage our unique experience and capabilities in vaccines. With that, I would like to hand over to John Reed for his concluding remarks.

Thank you, John. I'm sure I speak for all of us when I say we're rooting for your success. Let me now bring us to a closure. Before we turn over to your questions, though, there is one loose end that I wanted to address, and this is pertaining to the question that Graham Parry asked earlier, and it concerns a question I often get, and that is about Sanofi's intentions in the field of gene therapy. Let's move to Slide 71. I think it's appropriate that I introduced this topic immediately following John Shiver's presentation on vaccines because the same know-how and technology that Sanofi Pasteur has used for decades to generate live attenuated virus vaccine candidates, it is highly applicable to gene therapy where recombinant viruses are created that deliver the genes. We have decided to commit to establishing an AAV gene therapy platform within Sanofi, from discovery to manufacturing, while we'll also tentatively explore other gene therapy approaches, such as the lentivirus platform that you heard about during the patient insight section. Now you may not be aware, but Sanofi actually has quite a bit of experience with the AAV platform going back to our Genzyme heritage. Several Sanofi AAV vectors were put into the clinic for ophthalmology and other indications. And a producer cell line technology was established for providing clinical supply of AAV product candidates. Over the past few years, we've been quietly establishing an internal pipeline of AAV candidates for rare and neurological disorders, relying heretofore on CMOs for manufacturing. To put it mildly, however, the reliance on external contract manufacturing organizations for GMP production of clinical material has been extremely frustrating and disappointing. We've decided, therefore, to create our own bioproduction capabilities. We've decided, therefore, to create our own bioproduction capabilities, leveraging the historical Genzyme experience and our vaccines manufacturing platforms to control the bioproduction ourselves. A fully dedicated CMC unit has been created in the Boston area and is being expanded now. Additionally, we have commandeered one of our manufacturing facilities in the Lyon area where Sanofi Pasteur is headquartered. And we'll have by the end of this year, our own GMP-grade manufacturing for clinical supply. Finally and importantly, we have reorganized our internal research to create a stand-alone genomic medicines unit with the full ensemble of capabilities to produce AAV vector design -- to pursue AAV vector design in preclinical development. Plus, the last year, we recruited an experienced gene therapy veteran to head this unit, Christian Mueller. So within the next 12 to 18 months, we should be in a position to provide more specific updates on our progress with establishing the AAV platform in-house and in generating a compelling gene therapy pipeline that aims to continue Sanofi's leadership role in providing therapeutic solutions for monogenic rare diseases and eventually, hopefully, expanding into complex diseases over time. All right. Now to wrap up. Let's move to Slide 72. I hope the previous presentations made clear what makes Sanofi R&D unique and how this is translating into transformative opportunities for patients through molecules like THOR707, venglustat, fitusiran, BIVV001 and our COVID vaccines. Each of these molecules has the potential to change the practice of medicine. And they're examples of our strategic commitment as the company delivered true innovation. Slide 73, please. I want to come back to the 7 priority molecules that Paul mentioned at the beginning of today's program. We expect multiple important readouts for these assets in the next several months. We remain fully committed to expanding the indications for DUPIXENT. In fact, even since the recent investor presentation devoted to DUPIXENT, we've received the approval by FDA for our auto-injector and, as Paul mentioned, approval in China for atopic dermatitis, opening an entirely new and large market for DUPIXENT. And we are intensely focused on accelerating development of our priority molecules with full vigor and pace. You can expect also some important results for those molecules over the coming months. Slide 74, please. Beyond those priority assets, Slide 74 shows that we also have a rich pipeline with exciting news flow coming across all our therapeutic areas over the next 24 to 30 months. And the fact that this is such a busy slide shows the remarkable progress we are making at Sanofi R&D. Given how slim the Sanofi pipeline was just a few years back, the density of clinical milestone readouts shown here clearly illustrates that our R&D organization is delivering with pace on our strategic framework. Next slide. To close, I'm confident that Sanofi is well positioned to deliver the next generation of medicines and vaccines. Summarizing what we communicated today, we have a broad toolbox of drug discovery technologies, including some truly unique platforms to fuel our next wave of potentially innovative medicines. Our deep understanding of disease pathways in immunoscience and monogenic disorders is helping us to identify drug candidates that could change the practice of medicine across the areas of high unmet need. Our focus on patient insights is helping us to aim our drug discovery development efforts on superior patient offerings that really matter in the day-to-day lives of those struggling with disease. We're driving innovative ways of working, including embedding digital into all of our processes and into our interactions with patients, with investigators and with the clinical study sites. And finally, our adaptive capabilities allowed us to launch clinical trials in record time while ensuring robust business continuity during these unprecedented times of the COVID-19 pandemic. Slide 76. On my final slide, I think it's important to remind ourselves of what is the real motivating force in Sanofi R&D, what it is that gets us out of bed every morning and keeps us working in the night. And that's simple: It really begins and ends with the patient. We have a responsibility to them, and that's what drives us every day. With that, I hand things over to Felix to start Q&A.

Thanks, John. And we would love to go straight into Q&A. Once again, we have a long list of analysts who are waiting to ask questions. [Operator Instructions] Natalie, can you remind everyone how to ask questions?

[Operator Instructions] Now we will take the first question of the second session from Jo Walton at Crédit Suisse.

I hope you can hear me. I've got a general one and just a very specific one on the COVID, if I could. I just wonder if you could tell us a little bit about what the regulators are looking for in terms of safety and efficacy. I can understand that by December, you may have some data on immunogenicity, but you won't have any long-term safety data. So will you be expecting an emergency use to be really narrow where there are people with high risk? So just a little bit more about that, please. And could I also ask and I guess this is one for Paul, a broader question about where you think you might be looking to reinvest the money that you got from selling your stake in Regeneron. And I think most people are assuming that, that is to fill up holes that may be apparent in the R&D pipeline. So where does he feel that, that would be best invested?

Well, thanks for your question, Jo. Let me turn the first one over to John Shiver to talk about the COVID vaccine. John?

Sure, John. So the regulatory agencies are going to have to determine what emergency use authorization guidances would be important and beneficial, right, by the end of the year when our data as well as other program data become available. Certainly because our Phase I/II trials, there were 400 subjects and concentrated at only 2 doses. We're going to have a substantial amount of safety and immunogenicity data across a wide range of ages. And so I think that plus supply can certainly support that use. But again, it's always risk benefit. And I think a lot will depend upon the quality, how the vaccine performs, how the other vaccines are intended to perform and the status of the COVID pandemic at that point. If it's really on the rise and the threat is continuing to increase, it may become more urgent to implement vaccines for that emergency use. If it is dissipating, as we might all hope at that time, but may not happen, then perhaps it might make emergency use more applicable.

All right. Thanks, John. Paul, about the proceeds from the Regeneron stock sale.

So thanks, Jo. Great question. So just to answer as brief as I can, the target of filling in the gaps, I think, is actually the legitimate one. The first step of that was understanding what we had in our hands, and think we're doing much better at that right now. And you've seen that from the series of R&D events. We're excited about things that can amplify what we already have in the pipeline. It's what we loved about Synthorx, about the use in combination. The moment to exit the stake was good for both parties, like I said earlier. And so we took it because it worked. We will deploy it, that's for sure. And the plan we have in place, the time line on that didn't change. So we know what's on our mind and how we're going to proceed, but it wasn't driven by that time line specifically. So we feel comfortable that over the coming months, you'll start to see us deploy the proceeds in ways that will make sense from the science that we've shared.

Next question is from Mark Purcell at Morgan Stanley.

Yes. Thank you very much for an interesting session. My one question is on the vaccine manufacturing buildout and the legacy you're creating here. Clearly, you're scaling an existing platform with a new target in COVID on the back of our site, and then you're establishing proof-of-concept on a new platform on MRA. So could you help us understand your ability to repurpose here, in terms of -- you obviously signed a partnership, an expanded partnership for respiratory vaccines on the mRNA side. Sort of which targets are you looking at, and how quickly can you repurpose? And then on the baculovirus side, how quickly can you repurpose into flu? And just related to that, clearly [ finish ] is one of the challenges with flu at the moment. So could you help us understand where you are intermittently expanding on the fit and finish side and the opportunities therefore to touch other geographies with your 3 vaccine franchise, such as China?

Mark, thanks for those questions, all related to the COVID vaccine. I guess, I'll ask John to start, but we have Thomas Triomphe here with us as well, who recently took the helm at Sanofi Pasteur, and I suspect he'd like to offer a comment or 2 as well. So John, do you want to kick us off? And then I'd love for Thomas to also get into the discussion.

Sure John, that would be perfect. So with the baculovirus-based manufacturing footprint we have for our flu block, we actually have the capability to use that infrastructure, that manufacturing infrastructure with various shifts and the greater Sanofi network of manufacturing that's available to reach the targeted number of doses in the time frames that we talked about, without impairing our flu product supply. And that's really critical, because we mustn't forget how important flu is as a disease as well. And certainly, the mix of cold and flu are very -- would be extremely bad in itself. So we do think we can meet those. We also have some networks of CMOs to assist us as well, and is part of a greater plan for how to make the baculovirus-based production available. Recall that the flu is not a full-time year of production to begin with, so that implies some inherent capability. For the mRNA, Translate Bio and we are working together. And again, with the capacity that they've developed, have the ability to produce what we said already in the projected doses there, the $90 million to $360 million, depending upon what the dose level turns out to be. And certainly, we can do a -- further expand our network and other means to expand that further, depending on what need turns out to be. So perhaps I'll pause there and turn it over to Tom.

Thank you very much, John. So you said pretty much, many things already. So there were different elements in the question. So on the flu side, you understood very clearly that our goal is to be able to do COVID-19 and flu vaccines, so both are extremely important for obvious reasons. COVID-19 vaccines for the pandemic threat that we are facing right now, and the flu vaccines are as important in the sense that, of course, the most fragile people against flu are the ones that are also more severely attacked by COVID-19. So definitely, we expect a strong influenza season, and we expect to meet the demand with a strong supply, and that's very important for us. Now when it comes to mRNA, just to complement a little bit what you said, John. I think the question was alluding to also what we are going to do the expansion of the mRNA deal with our partner. [ Here ] we do not disclose for obvious reasons the target after which we are going. I think we've disclosed in the past that we are already working on the flu candidate. That's of interest to us when we think about the next-generation of flu vaccines. We are also working on a different viral target and a different bacterial target where we are hoping to go very soon into chemic. But for the expansion, we foresee a lot of potential opportunities, very, very interesting targets all over the infectious disease space. But for confidentiality, we don't disclose the targets we're going after.

Good. Thank you, Thomas and John. And let's move on the next question, Felix.

Next question is from Geoff Porges at Leerink. Okay, so maybe we move to Florent Cespedes at Societe Generale.

Florent Cespedes from Societe Generale. And a quick one for Yong-Jun. Please, could you elaborate on the potential side effect profile of the 3 specific antibodies or also the nanobodies that you are developing? Because we understand that you expect better efficacy, but what about of the side effect profile?

Agreed [indiscernible]

[indiscernible] Thanks for your question. Yes, let me turn it over to Yong-Jun, and I don't know how much he's able to reveal in some -- in terms of some of the nuances of the design of those antibodies with respect to their -- the affinities of the relative binding units to different target antigens. But Yong-Jun, do your best to try to explain that.

Yes. So let me first comment on the safety of nanobodies. Sanofi Ablynx, we have the first nanobody product in the market. So this basically derisks the nanobody technology. We can have a safe drug, so the rest of the risk in will be more, depends on targets. So we have to do the experiment, we have to move the molecule into the clinic. Regarding the trispecific antibody platform, we have one trispecific antibody, as I introduced, against HIV. This is a broad neutralizing antibody against HIV in the clinical study. So in terms of manufacturing, safety, antibody drug effect, we derisk it -- all that in terms of trispecific platform. So the key, again, will be the target-related safety. So this will apply to all antibodies, right? You have to do and derisk the target's relative safety one by one by experiment, by preclinical study and then by clinical study.

Okay, Yong-Jun, thank you. Perhaps some more discussion could also occur off-line around the nuances of that. Good, let's go to the next question.

Next question comes from Keyur Parekh from Goldman Sachs.

[indiscernible], wonder for on -- just ask, if you can talk a bit about kind of what do you expect the therapeutic window of these trispecifics and kind of the multi-targeted nanobodies to be kind of how much of in-house expertise do you think you have as it relates to kind of getting the balance between efficacy and safety right for those agents, please?

Okay, Keyur. Thanks for your question. It's along those same lines as Jerome's question, I guess. Maybe I can try to start and then Yong-Jun can kick in from there. I think this is -- obviously, the opportunity and the challenge with the T-cell bispecifics is to thread that needle between efficacy versus safety. I like the fact that we often are putting 2 binding elements to latch on to the tumor within our constructs because that will probably allow us to go with lower doses and achieve more selectivity than a conventional 2 by 2 bispecific format. We, like many others, dialed down the affinity for the T-cell antigen receptor as a way of trying to make sure that the T-cell activation is occurring predominantly in the tumor microenvironment. And I would also say that you'll soon be seeing a number of NK cell engagers emerging from our pipeline. And we find that also an attractive area to pursue, because NK cells don't make some of the same cytokines that are problematic in terms of T-cells. So that will give another way to try to tackle the problem. And all these are very synergistic with the THOR707 as well. So all together, I feel like we're well poised to take this journey. It certainly will be a journey with its share of challenges along the way, but I feel like we're poised to do it, and then we can do it in a differentiated way. Yong-Jun, anything to add?

So good point, John. So I just want to emphasize one point. Actually, we believe scientifically, by targeting 2 tumor antigen can provide a better safety and better therapeutic window because our translation science really looking for 2 antigen expressed by the same tumor cells and most like -- most of the time, the normal tissue, if they express tumor antigen, they only express one. So in this case, our bispecific antibody can differentiate much, much better, binding to tumor cells versus binding to normal cells.

We'll try again with Geoff Porges at Leerink. Let's move on to Steve Scala at Cowen.

Paul and John, your former employers also talk a lot about digital, believing their strategies are a competitive advantage. Novartis talks about the ability to monitor 500 studies in real time. Roche obviously made a couple of acquisitions and owns the diagnostics business they think is important. How is Sanofi's digital strategy fundamentally different, if at all, from those 2 companies?

Yes. Thanks for your question. I'm going to let Paul start that, and then perhaps I can supplement. Jean-Baptiste may be able to supplement, et cetera. We just onboarded our new Chief Digital Officer, Arnaud Robert. I don't know if he's available, but Paul, why don't you kick us off?

Well, I think it is day 8 or something for our new CDO, so we'll give him a break, at least for another week. It's a really, really important question. So let me just take the Sanofi comparison first, and the other company comparison. The first thing is, that our emphasis on digital had been predominantly external collaboration. And while it starts to be applauded in many aspects, I think it left us a little under-resourced in terms of delivering our own master data management, architecture, accessibility and the requisite tools of machine learning, AI, automation to do something both from a targeting perspective that John may have mentioned, but also for us to be able to establish insights and take directive action. I think many companies have taken more of a vanity approach, big external collaborations or huge big data monitoring installations. What really matters is data that you can use to get insights to take action. And I think most of the industry has been pretty woeful at that. The good news, as with many things at Sanofi, we -- we're not hanging onto something desperately that we have to unlearn. We start quickly and with agility, and we'll move right across the board. It can be financial data, led by Jean-Baptiste, can be research and development data, led by John. But bottom line is, I think we're taking a slightly different approach, which allow us to action more actually in real time the data that we get. And I think it will put us ahead of the pack in the industry, but it's going to take us a year, maybe slightly longer.

Thanks, Paul. It's -- I think all the companies are going through this digital transformation journey. I feel good about much of the progress that is underway. If I can maybe even just cite one example is in -- our regulatory environment. Sanofi has had a history of providing 3,500 products in 80 countries around the world. We historically had that regulatory data, all those documents and the supporting information, pharmacovigilance, et cetera, spread over more than 300 systems around the world that didn't talk to each other. Thanks to a journey we've been on, which will be completed this year, we've now brought all those data together in a single relational cloud-based database that is -- where the data are formatted in ways that you can really manipulate them. We can apply natural language processing. We can use machine learning and AI techniques. We can automate the production of various regulatory dossiers. So that's just an example of one of the areas where we've been investing. There are several others where I feel very good about where we stand. I might even dare say in some of those, we might be industry-leading or certainly at the head of the pack. But there's far more to do certainly and particularly having data from different elements, being able to talk to each other and bringing it all together in a very powerful way. So that's what Arnaud Robert will be helping us to figure out over the next several months. Let's go to the next question.

Hey John, Geoff Porges was able to send his questions to the Q&A box. There's 2 questions. Does Sanofi expect to make a profit on COVID vaccines? Why should it be any different to influenza or other vaccines? And the other question is, John did not include complement in his immune system overview. Does that reflect his view of lack of activity, interest or opportunity in complement inhibition?

Well, thanks for those questions, Geoff. I think I'm going to take them in reverse order, starting with complement, to emphasize that no, we are very excited about the complement pathway. We're very excited about sutimlimab as our first entrée into that, but it won't be the last. We have a very robust discovery program under Yong-Jun and colleagues underway now. And in fact, we just nominated another development candidate that was moving into IND-enabling studies now. We do see the complement system as another branch of the immune system, the innate immune system. We just didn't have time to squeeze everything we would have liked to into this presentation. It was originally part of the presentation, actually, but we ended up having to trim some things to not make this too long an event. So that's where are with complements. So stay tuned. We're -- we like that pathway, and it's also, I think, an exciting area because the biology takes you in multiple different therapeutic areas. We started in hematology but expanding into other areas as well. On the COVID vaccine, I think I'm going to ask Thomas to take that.

Thank you, John. So as we said before, for us, it's very important to make this vaccine accessible to the largest population and to make it affordable. That's the spirit with which we went into this. We think we have great assets to contribute to this fight against COVID-19. We believe we have great technological abilities, that's why we also went with 2 candidates. We believe it's a race that's very important against the virus, not against each other. So we're really all in. Now I guess the question was related also to our financially, investors look about it. It's clearly way too early to think about that right now. We're really focused, as you've seen from John before, focused on actually making sure that we go as fast as possible to provide vaccines for the world against COVID-19. We are very excited to be in nonclinical stage and entering into Phase I September. As you've also seen from one of the slides from John, there are still many uncertainties to be looked at. For example, we look at [ this ]. We look at very different elements that will bring us to the finish line first at the end of December, when we see the key results from our Phase I/II study. And that's where, at that point, we'll know more about the product and where we can move forward with. So really, you understand first, speed execution being flawless, moving forward as fast as possible on both vaccines, that's priority #1. And then, of course, in the spirit of making it accessible to the largest population, and an affordable vaccine.

All right. Great. I think we have only a few minutes left, John. [Operator Instructions]

And the next question is from Luisa Hector at Berenberg.

So I just wondered, how do you see patients choosing between the 2 very strong profiles offered by BIVV001 and fitusiran? Will it come down to less frequent dosing versus a known safety profile? And then if I may, I just want to ask, John, given that we can see the positive effects of the R&D transformation emerging already, could you comment on the metrics you're using to assess your return on R&D spend, please?

Sure. Thanks for your questions, Rita. Vanessa, do you want to take the fitusiran versus BIVV001 with that patient-centric view?

Sure. Thank you, John, and regards the question, so as you've seen, today's treatment option has limitation. We think that the patients have to make a trade-off if they want to choose between treatment burden and activity restriction. And we do believe that the 2 products are offering the best for each needs. If you think about patients who are really looking for improving their treatment burden, fitusiran would really be the true high-efficacy monthly subcu therapy. So those patients should definitely like move to fitusiran. Now for patients who are really looking for activity first and want to raise the level of activity, as you've seen on the factor levels, BIVV001 will be the treatment of choice, bringing patients to like normal levels. So that's how we believe we can really address the remaining unmet needs in this area by providing the best option to address those 2 main needs.

Good. Thanks, Vanessa. And to really address your question more generally about the R&D transformation, I think the metrics we look at are, ultimately, how many enemies do we generate that really transform the practice of medicine. Along the way, of course, there are [ bracings ] to gauge, one of which is productivity from our own internal laboratories. We've been on a journey there. Yong-Jun came in, I think, in 2016, I think it was and began to rebuild the research teams there. We've been on a steady course of improvement. Just last year, we reached and surpassed the industry benchmarks on what it costs us to generate a development candidate. We're now slightly better than the industry, and that's the first time that's happened in anybody's recent memory around Sanofi. So we're very excited about the progress we're seeing in terms of the productivity from our own laboratories. With all of our candidates, we are really setting the first-in-class or truly differentiated best-in-class bar. So these are no longer to be me-too drugs or that kind of a fast follower sort of approach, but really molecules that, going forward will be quite differentiated. Another metric we put a lot of stock in is, what we refer to as not just proof of clinical concept, but proof of clinical and commercial concept, it's a higher bar. It means that the asset has been sufficiently derisked and looks sufficiently promising that we're going to invest as a company in pivotal studies. We've now set this POCC, proof of clinical and commercial concept, as our chief metric for the research and early development group. It's a higher bar but one that really, I think, matters in terms of what molecules are going to be worthy of the investment to take them forward into the market. We've also done things to try to incent the right behaviors. For example, when I came here, one of our metrics that we provided to the research team was how many new projects they started. We said going forward, it's not about starting projects. It's about ending projects. A fewer different projects, you have to start to end up with and meet at the other end, the better. So we took that away as a bonusable endpoint and then put in others that we think matter more. So I think those kind of KPIs around the pipeline are certainly elements of it that we'll speak to having a sustainable pipeline, and one that delivers innovation. So that's what it's really all about. But underlying that, I think, fundamentally, is evolving the culture of the organization that really adopts this, what Paul's been calling the play-to-win mindset and has that deep commitment to innovation and doing what's really going to matter for patients and doing that within the pace and urgency that patients will be proud of.

Great. John, I think that's concluded well. At that point, we have to come to an end of the Q&A session. Obviously, IR team is available for our analysts to take questions in the afternoon, U.S. time. And with that, I would like to hand it over to Paul for some concluding remarks.

Maybe just the last few seconds. Firstly, on John's last point about R&D productivity. I think we've made incredible progress. I've said upfront, I thought we had, I really believe that we genuinely have. I think we're definitely playing to win for sure. I just want to connect it to the overall expectations and guidance. Jean-Baptiste and I laid out at the Capital Markets Day that we have commitments in 2022 and 2025. We intend to deliver on those commitments without sacrificing super cool science, which means that we're happy to put the organization into a little bit more pressure to redeploy resources to finance science, if we think it's going to be best-in-class, first-in-class. We think that's the right level of tension in the organization, not disconnecting the incredible works going on in R&D. We have to balance that. Where we sit today, that's a really healthy tension I think we developed. So I'm delighted with that. Secondly, and well, finally, I want to thank all of the presenters and the people who have put a ton of work into putting this together for us. It's virtual. It's not easy, even face-to-face. Even harder virtually. I think it's been an extraordinary series of events that our comms team and others have put together. And you start to see the quality of the bench. You start to see our people authentically and open to debate the science with all those that are curious about whether we believe in it or not. I'm very pleased and proud of the team that showed up today. I think we've just started. While the work is underway, I think we really are going to surprise a lot of people, and we're doing things that we think will seriously change the practice of medicine. Some of you will take a bit more convincing. But I'm thrilled with how far we've come and the time we've had. And I'm excited about up and coming R&D events and days in the future. And thanks again, John, and everybody on the team and everybody that's put the meet together. And thank you for all those that joined us. Thank you.