Sanofi (SAN) Earnings Call Transcript & Summary

This meeting is being recorded, Dupixent R&D Investor event. [Operator Instructions] I would now like to turn it over to Felix Lauscher from Sanofi Investor Relations.

Thank you, Natalie. Good morning, and afternoon to everyone, and welcome to our R&D webinar. Thank you for joining us on the third of our 5-part series of interactive webcast events to highlight Sanofi's progress in R&D. Let me remind you Sanofi's virtual R&D event is scheduled for Tuesday, June 23. Now returning to today's event dedicated to Dupixent, our priority asset. If you are unable to view the presentation during the webinar, you can find the slides to this event on the Investors page of our website, sanofi.com. Moving to the second slide, Slide 2. I would like to remind you that information presented during this event contains forward-looking statements that involve known and unknown risks, uncertainties and other factors that may cause actual results to differ materially. I refer you to our Form 20-F document on file with the SEC and also our Document d'Enregistrement Universel for description of these risk factors. With that, please advance to the third slide, Slide 3, and let me introduce our speakers today. With me on this webinar are Brian Foard, Global Head, Dupixent Franchise; Frank Nestle, Global Head of Research, Immunology and Inflammation; Naimish Patel, Global Head Development, Immunology and Inflammation; and John Reed, Global Head of Research and Development. Joining later for Q&A will be Paul Hudson, our Chief Executive Officer; and Jean-Baptiste de Chatillon, Chief Financial Officer; as well as Bill Sibold, Global Head of Specialty Care. Brian will discuss how we are driving Dupixent's success in atopic dermatitis and asthma, after which Frank will provide a deep dive on type 2 inflammation. Naimish will update on our Dupixent line extension plans and John will wrap up with concluding comments. After the presentation, as usual, we will open for the Q&A session. With that, I'd like to turn it over to Brian, please.

Thank you so much, Felix. Good morning, good afternoon to everyone on the call. It's my distinct pleasure to kick off the R&D event on Dupixent. You had an opportunity to hear a lot about this really innovative practice-changing medicine during our Capital Market Day event. And really more specifically, we spent time on how we believe that by uniquely targeting IL-4 and IL-13, we can build a $10 billion-plus mega blockbuster brand across a whole host of type 2 inflammatory diseases. And you're going to hear more about that today. Our clinical and our in-market experience continues to grow, and so does our belief in DUPIXENT's ability to not only lead, but to truly transform the treatment of type 2 inflammatory diseases. But the reality is we're really at the beginning of this exciting journey. And as an example, even just over the past month alone, we achieved several important milestones. We received certainly, first and foremost, an important FDA approval for atopic dermatitis patients between the age of 6 and 11 years of age, which really speaks to the continued efficacy and safety in this younger patient population. And we also reported impressive preliminary data in eosinophilic esophagitis. And again, this is another one of those diseases with extremely high unmet medical need with very limited treatment options and is another type 2 inflammatory disease. But as we also shared at Capital Market Day, the foundation of our success really begins with atopic dermatitis and asthma. So over the next few slides, I'm going to spend more time on those 2 therapeutic areas. So if you would, please advance to the next slide. So the next slide really speaks to Dupixent being the first biologic approved in moderate-to-severe atopic dermatitis patients in the U.S. between the age of 6 and 11. And really, for us, I think certainly, there's the approval, but this really speaks to the hope of these patients. This population has dealt with this chronic condition. It's a high disease burden and as you can imagine, with an age group of 6 to 11, that burden also, a lot of that falls upon the parents or the caregivers. And so then we're really excited, and we're very hopeful that we can help transform the lives, not only of these patients, but also of their family members. Now with this latest approval, we've also extended, if you look at the right-hand side of the slide, we could also extend the patient population that we'll be targeting to about 90,000 additional patients in the U.S. And just to put some context around this, this is really represents the most in-need patient population. These patients, and I'll describe them a bit more in the next slide, but these patients are -- have commonly been on oral corticosteroids, injectable steroids or immunosuppressants. And so as you can imagine, the disease is quite significant. But you also see that we're at the very beginning of the journey and the fact that we are about 4.4% penetrated into the biologic eligible population thus far. So we're excited about this new patient population. So as you move to Slide 6, what you'll see is this really speaks to the strong efficacy and safety in this 6 to 11-year-old population. But I first want to describe the patient population, and just as a reminder, these patients, on average, they're about 8.5 years old, between ages 6 and 11. These patients, about 60% of their body surface was involved with lesions. And they've suffered from the condition for most of their lives, about 7.5 years of that 8.5 years of their lives on average. They also -- these patients had a severe itch score upwards of 7.5 to 8, on a scale of 10. So as you can imagine, quite a significant condition for these patients to live with for most of their lives. So we're really pleased to see the incredible efficacy that we saw in these patient groups. So what you see is on the left-hand side, when you look at Investigator Global Assessment of 0 or 1, we saw that -- actually, we saw a 2x or 4x greater improvement whenever these patients were on a Dupixent plus TCS versus TCS alone. As you move to the middle part of your chart, which you'll see is the improvement, 4-grade improvement in peak pruritus score, and you saw a 5x greater improvement on the Dupixent arms. But then also what you saw, which was quite impressive is you continue to see a very nice safety profile. In fact, Dupixent arms are associated with numerically lower overall rates of adverse events than those on topical corticosteroids alone. And now if you'll transition to the next slide, that adverse events -- and really positive adverse event profile that we have really has contributed to our growing safety, robust safety database and in-practice experience as well. Today, we have about 150,000 patients treated globally across indications, but also what you see is, you see that today, we have no black box warning, no evidence of immunosuppression and no requirement for lab monitoring. So again, as you can imagine, this level of safety profile is very important as we go into this younger patient population. Now on the right-hand side of the screen, you see, as we intend to go into younger patient populations, this is also supported by the FDA in our breakthrough designation, as you saw for 6 to 11-year-olds and also the breakthrough designation that we also have for the below the age of 6. So obviously, as we now continue to advance, this is going to be very important for prescribers as they make their choices for these advanced therapies for these patients and really does support that, no matter of the age group, really the strong safety profile that Dupixent has, it helps support Dupixent selection for these patients moving forward. Now as you'll hear from Frank in a bit, the uniqueness of Dupixent really is unlike potential entrants as well and also potential therapy for therapies that are on market because it selectively blocks IL-4 and IL-13, 2 key essential drivers of type 2 inflammation. And we believe this specific MoA contributes to the strong safety profile that we have and proven track record for Dupixent. So now to advance to Slide 8, please. Moving to Slide 8, what you see is, again, further support of this rapid and sustained efficacy in atopic dermatitis patients. And again, this goes back to the adult patient population. And on the left-hand side, what you'll see here, is that rapid effect was seen really after the first dose. So these patients, we look at a couple of different metrics that were very important. So EASI score, NRx score and also Quality of Life score. And these patients achieved at least one of those after that first dose, and we sustained it over a 16-week period. And this trial actually goes out to 52 weeks as well, and we continue to see that sustained effect. Now -- but if you look at the right-hand side, this is some new information as well that we've recently put out, which is, it actually shows our continued efficacy over a 3-year period. So up to 148 weeks, we see a continued reduction in EASI. But what's also very important is that continued -- the 3-year safety profile shows no change from previous studies. And as you can imagine, as we said before, in treating these chronic conditions, it's going to be very important for physicians to have not only a rapid and sustained efficacy, but also a proven safety profile over a long-term treatment horizon. So if you please advance to the next slide. Slide 9 provides another very recent piece of information that we just put out. It was recently published in JAMA, and it speaks to flares, and these are also known as exacerbations for atopic dermatitis patients. And this is normally a sign that the disease is uncontrolled. And certainly one of the most long-term important treatment goals in atopic dermatitis is to prevent flares, which can potentially result in hospitalizations and associated health care costs. Now what you saw in this trial was actually the patients on TCS alone actually had a 4.5x greater chance of experiencing a flare over the treatment course. And what was also quite impressive is if you looked at the patients that had previously had at least one flare, those patients that were treated with Dupixent, about 84% of those patients didn't experience a flare over the remainder of the treatment period so for the remainder of the year. So as we said, long-term disease control is one the most important drivers of therapy selection, and it will be for physicians moving forward. And therefore, this data will be very important for clinicians and their patients, reinforcing the unique profile of Dupixent. So now if you advance to Slide 10. Slide 10, you see an exciting brand-new piece of data as well, and this is also over a 3- year period, but this makes the transition to asthma. And so as we look at these type 2 asthma patients, they also achieved a rapid and sustained improvement in lung function. Lung function is really important to understand because it is -- for asthma sufferers, it's commonly associated with feeling better, that immediate feeling of feeling better. And so what you saw here is really after the first dose, you saw an improvement in lung function, upwards of 220 mL improvement, and that improvement was sustained over a 3-year period. As you look at the right-hand side of the screen, we're actually showing exacerbations here. And exacerbations are really the things that patients -- is a symptom that patients really live in fear most of. They worry that these exacerbations will send them into the emergency room. And as you look at the results of the data here, what you see is not only a reduction in exacerbations where they had historical of at least 2 per year, you see a continued reduction in exacerbation over time, and actually, about a little greater than 60% of the type 2 patients had no exacerbations over a 3-year period. And what's really interesting is, again, you look at the parallels in these clinical outcomes with Dupixent between 2 very different type 2 inflammatory diseases, both AD and asthma, but the parallels are quite remarkable and it really speaks to the potent effect of Dupixent on certain type 2 inflammatory diseases. And this is important as we move to the final slide. So as you look at the final slide here for me on Slide 11. Slide 11 really illustrates that approximately 80% to 90% of patients who have type 2 disease also suffer from another type 2 disease concurrently. Highlighting the fact that type 2 inflammation is systemic in nature and can affect multiple barrier sites in the body, not just the skin or the lungs or the GI tract in isolation. And since Dupixent is the only therapy selectively targeting 2 key essential drivers of type 2 inflammation, both IL-4 and IL-13, it's no surprise to us that Dupixent has been shown in Phase III trials to control type 2 inflammation systemically across different type of sites, such as the skin for atopic dermatitis, the upper and lower airways as in nasal polyps and asthma, and also, we aim to show this in the GI tract for eosinophilic esophagitis. So in closing, we're -- as I said before, we're really at the beginning of this journey. We have great expectations for the success of Dupixent, driven by our belief in its unique MoA and proven clinical profile in the areas of high unmet medical need. I certainly hope that this data, along with the other data that we will be sharing with you, help you also have the same confidence that we do in building, and the ambition that we have to build this drug to $10 billion plus in the years to come over a whole host of type 2 inflammatory diseases. So with that, it's my pleasure to shift over to Frank, and I'll share with him as he will deal -- he will dive deeper into type 2 inflammation and the deep science behind Dupixent.

Thank you, Brian. I would like to start by diving deeper into the biology of type 2 inflammatory diseases and answer the important question, why we believe blocking both IL-4 and IL-13 is important. Remember, our mantra here is that it takes 2 to tackle type 2 inflammation, and this dual pharmacology approach is delivered by Dupixent. We believe other mechanisms of action, including mono-targeted agents as well as JAK inhibitors, might be either too narrow or too broad. Slide 13 describes what type 2 inflammation defines. Type 2 inflammation is a connected underlying pathology of several chronic systemic diseases that you can see listed here. The historically termed atopic conditions include diseases such as allergic rhinitis, hay fever, asthma, atopic dermatitis and food allergy. The more contemporary term type 2 inflammatory diseases applies a molecular classification approach, focusing on key type 2 hallmarks and includes not only atopic, but also additional type 2 diseases such as chronic rhinosinusitis with nasal polyposis, eosinophilic esophagitis, eosinophilic or type 2 COPD and several pruritic dermatologic disorders. Type 2 immunity evolved as a now largely redundant immune response at body surfaces, primarily to protect us from parasites or toxins. In our modern civilization, the type 2 immune pathway has been now adapted to react against harmless environmental agents such as plant or animal macro molecules, including potentially your own cat. When type 2 inflammation becomes activated, it displays typical molecular hallmarks, including increased type 2 cytokines and chemokines, inflammatory eosinophils, IgE and barrier disruption. Slide 14 describes the details of the type of inflammatory cascade we see in type 2 inflammation. Starting on the left, inflammation begins with an upstream initiation event with allergens penetrating a disrupted barrier and IL-4 dependent priming of the T helper 2 cells. This leads in turn to an amplification event in tissues with IL-4, driving Th2 and mast cell amplification, IL-13 dependent mucus secretion and the combined effect of IL-4 and IL-13 resulting in inflammatory chemokine and IgE production and importantly, neuronal itch sensitization. Finally, on the right side of the slide, the type 2 inflammatory cascade results in downstream effects with maladaptation across the skin with inflammatory thickening and itch, airways with obstruction and mucus production, and esophagus with narrowing and dysphagia. Moving to Slide 15. This shows the various ways to intervene pharmacologically in the type 2 inflammatory cascade. There are 3 potential approaches. You can take an immunosuppressive approach that targets multiple types of inflammation by attempting broad blockade of T cells and/or cytokines, for example, with cyclosporine or JAK inhibitors. You can block single cytokines in the tissue, which potentially can result in an incomplete pharmacological effect. Or you can block downstream elements of the type 2 inflammatory cascade, such as mast cell degranulation with antihistamines or try to sequester all the IgE with biologics such as omalizumab. What makes Dupixent so unique is that by binding to its target receptors, it is the only agent that neutralizes the activity of not only one, but of 2 of the key type 2 inflammatory master regulators, namely IL-4 and IL-13. Slide 16 shows how Dupixent selectively inhibits type 2 effector biology by first preventing upstream initiation and priming of the type 2 inflammatory response, [ managed ] by IL-4; and second, by blocking the amplification effects of IL-4 and IL-13 in tissues, including the T helper 2 cell and mast cell amplification, inflammatory cell trafficking and neuronal itch sensitization. Thus, in aggregate, managing and preventing a whole range of type 2 inflammation associated signs and symptoms. Dupixent achieves this dual pharmacology by blocking a key receptor subunit, shared only by the IL-4 and IL-13 receptors. So the cytokines cannot activate their physiological target receptors. Developing this theme further, now moving to Slide 17, please. The type 2 inflammatory signaling cascade is mediated by 2 receptor types that present in distinct expression patterns across key immune and non-immune cell types. Dupixent binds to the IL-4 receptor alpha chain and that blocks both the type I IL-4 receptor, exclusively involved in IL-4 signaling and the type II IL-4 and IL-13 receptors involved in both IL-4 and IL-13 signaling. Please don't confuse the type I and II receptor nomenclature with the type 1 and 2 inflammation terminology. The right-hand chart shows a single cell view of IL-4/IL-13 receptor expression in atopic dermatitis samples. Please note that key effector T cells express predominantly the type I IL-4 receptor shown in blue, while non-immune cells express both IL-4 and IL-13 receptors. Dupixent is the only approved medicine that can block both receptor types mediating IL-4 and IL-13 signaling. So again, the message here is that it takes 2 to block type 2 inflammation. And if you attempt to intervene in this pathway by individually neutralizing cytokines, you might get a less favorable efficacy profile. Slide 18 speaks to the specificity. Please move to Slide 18. It speaks to the specificity of Dupixent compared with other therapeutic approaches. Some of you might remember the slide from Capital Markets Day showing a variety of lymphokine and cytokine receptors that exist in the body. When bound by their respective lymphokines, these receptors signal inside the cell and activate signal transducers such as JAK family kinases. If you want to target the type 2 inflammatory mast cell regulators IL-4 and IL-13 with a JAK kinase inhibitor, you would have to inhibit JAK1, JAK2 and JAK3. Let me walk you through what might be the unintended consequences of blocking all those JAK kinases. If you block, for example, JAK1, you interfere with IL-2 and interferon signaling, which you need for T cell activation and proliferation to protect from cancer and viruses. If you block JAK2, you risk interfering with key hematologic growth factors such as G-CSF, EPO and TPO, which you need for the body's production of leukocytes, red cells and platelets. We note that medicines blocking JAK kinases typically require regular blood monitoring and may contain black box warnings. I would like to remind you in this context what Brian said about the importance of safety in the management of chronic, lifelong type 2 inflammatory conditions we aspire to treat. On Slide 19, I want to introduce powerful additional players in type 2 inflammation, the epithelial barrier and the gut microbiome. Patients with atopic dermatitis are often prone to bacterial infections, with Staphylococcus aureus leading to abscesses requiring antibiotic treatments or viral infections with herpesviruses, often leading to hospitalizations. This is not only due to an imbalanced immune surveillance with predominant type 2 inflammation, but also due to an altered skin barrier. Dupixent treatment not only rebalances the immune system, but also helps restore the skin barrier function and a normal microbiome to enable return to healthy skin. On Slide 20, you can see data across atopic dermatitis, asthma and a specific study on Staphylococcus aureus infection that, in aggregate, support our belief that Dupixent can reduce infection risk. On the left, in a large data set of patients with atopic dermatitis, the risk of serious infections is reduced by close to 60%. And the risk of eczema herpeticum, a severe herpes infection often leading to hospitalizations, or herpes zoster, a blistering skin infection often leaving lasting pain, by around 70%. In the investigational skin microbiome study, the absolute abundance of Staphylococcus aureus in skin lesions was substantially reduced over time. In asthma, overall infections were reduced with roughly 15% to 25% reductions observed in upper and lower respiratory tract infections. This remarkable profile is in marked contrast to other immune suppressive medications that can often increase the risk of infections. On Slide 21, turning to eosinophilic esophagitis, we recently reported positive clinical data, which Naimish will detail later. The excellent clinical responses we are seeing in this indication reflect the ability of Dupixent to decrease eosinophils in tissues in addition to acting on multiple other components of type 2 inflammation. What you can see here is that the impressive changes in gene expression from baseline to treatment with Dupixent at week 12 actually mirrored the major improvements in endoscopy findings, histology scores and moderation of dysphagia. It shows that in addition to atopic dermatitis, also here in eosinophilic esophagitis, we find up-regulation of epithelial barrier genes indicating repair of the esophageal barrier. We also find reduction of genes involved in eosinophil trafficking, type 2 inflammation and tissue remodeling, indicating a rebalancing and normalization of the esophageal immune system. On my last slide, 22, I want to reiterate that Dupixent's unique dual pharmacology not only confers high efficacy with specific systemic inhibition of key upstream and tissue master regulators IL-4 and IL-13 of the type 2 pathway, but also accomplishes this with a strong safety profile that is based on rebalancing of the immune system and restoration of normal barrier function. I hope after seeing all these data, you will share some of our excitement. I hope you also get a sense that we are just getting started to take advantage of the unique molecular and clinical profile of Dupixent to make major inroads in a whole range of established and emerging type 2 inflammatory conditions. I would now like to hand over to Naimish Patel to update you on where we believe we can build on this science and take Dupixent to the next level in type 2 inflammation.

Thank you, Frank, for setting the stage for our line extension strategy. As mentioned, we are just at the beginning of the expansion of Dupixent. We're really excited about where we're going to take it. So let's go to Slide 24. So based on the deep understanding of the biology Frank just explained to you, we recognized the potential for patient benefit and additional type 2-mediated inflammatory diseases by applying a molecular classification approach, focusing on key type 2 hallmarks. This includes diseases such as EoE or prurigo nodularis, which are overall driven by type 2 inflammation or other diseases such as COPD, where a subset of patients have type 2 inflammation. Consequently, we've been systematically exploring potential opportunities for Dupixent using precision medicine and machine learning, mining public data and leveraging our real-world evidence database, which we call Darwin, which gives us access to around 450 million live medical records. We have prioritized our findings based upon additional key input from external experts and evidence from investigator studies as well. On Slide 25, through our prioritization process, we've identified 3 new dermatology indications: prurigo nodularis, chronic spontaneous urticaria and bullous pemphigoid, where we see strong biologic rationale for testing Dupixent. Each is a type 2 inflammatory skin disorder that severely impacts quality of life for patients, and each has reports of striking benefits of Dupixent from investigator studies, as I'll outline later. In total, we estimate there are over 400,000 patients with these conditions in the U.S. who would be eligible to receive a biologic, with chronic spontaneous urticaria being the most prevalent. Beyond dermatology, we have prioritized eosinophilic esophagitis, where we already had strong Phase II data and recently reported compelling results from Part A of the Phase III trial. And, of course, in respiratory diseases, where we have prioritized COPD. Regarding COPD, given the risk of this indication, we did not include COPD in our Dupixent peak sales forecast greater than $10 billion. So it should be a potential upside to our expectations if approved. Moreover, we have reason to be more optimistic on COPD, as I will outline later. I will now go into the key line extensions next. Please advance to Slide 24 -- 26, excuse me. With eosinophilic esophagitis, which is a chronic and progressive type 2 inflammatory disease characterized by typical molecular hallmarks, including up-regulation of type 2 genes, inflammatory eosinophils, high IgE and barrier dysfunction. This disease is triggered by a complex interplay of genetics, food and environmental allergens that damage the esophagus and lead to difficulties swallowing and eating. If untreated, symptoms and inflammation can cause constriction of the esophagus, food impaction leading to medical emergencies and invasive procedures. Importantly, no therapies are approved in the U.S. and surgical dilation is often the only option for these patients. In terms of prevalence, around 160,000 patients in the U.S. are receiving treatment for EoE, of which around 50,000 have failed multiple treatments and would be eligible for a biologic. On Slide 27, we've reported positive results last month from Part A portion of the pivotal Phase III trial evaluating Dupixent in patients aged 12 years and older with eosinophilic esophagitis. This trial met both co-primary endpoints as well as all key secondary endpoints with a high degree of statistical significance. The results are shown here. On the left, the first co-primary endpoint, patients reported a 69% reduction in dysphagia symptoms, and this is by far, the most important system -- symptom for patients with this disease. In the middle, on the second co-primary endpoint, 60% of patients experienced a profound reduction in type 2 inflammation as measured by esophageal eosinophil count compared to 5% for placebo. Finally, on the right, the key secondary endpoint, a 39% reduction was observed in abnormal endoscopic findings compared to a slight worsening for the placebo arm. This is the first time a biologic has shown clinically meaningful results in this disease as part of a Phase III trial and really suggest that Dupixent has the potential to be practice-changing for these patients. Advancing to Slide 28 and looking at COPD, we break down the large unmet medical need in this disease and the potential upside to our peak revenue target, if we are successful in this indication. Given the heterogeneity of COPD, we are targeting a large potential pool, around 300,000 eligible COPD patients in the U.S. who have underlying type 2 pathology and who continue to suffer exacerbations despite available treatment options. These patients have type 2 gene expression in the epithelium, a high eosinophil level in the blood or sputum, and they appear to be at increased risk for exacerbations and have reduced lung function among other clinical symptoms. We are testing the hypothesis in a Phase III clinical trial that Dupixent can improve lung function and exacerbation in patients with COPD who have type 2 inflammation as identified by a blood eosinophil count of greater than 300. Importantly, we would like to announce today that the interim analysis of this study has passed a prespecified decision criteria, which will result now in the initiation of a second confirmatory study. If successful, we would aim to be making a regulatory submission in the 2024 time frame. It's a very exciting news for us. So on Slide 29, we show some data that we already had on the potential utility of Dupixent in COPD. Here, we show data from our pivotal Phase III chronic rhinosinusitis with nasal polyposis, or CRS with NP studies on a subset of patients who had smoking history and clinical features of COPD. As you can see from the right-hand side chart, patients on placebo experienced a deterioration in lung function as measured at week 16 and 24 in the study. However, those on Dupixent were observed to have significant improvements in lung function. Although encouraging, we await the results of our randomized Phase III clinical trials of type 2 COPD. On Slide 30, I want to move now to prurigo nodularis. Prurigo nodularis is a skin disease characterized by local type 2 inflammation and multiple nodules with unremitting itch, which can cause sleep problems and depression. Multiple clinical approaches have been taken with limited success in this disease, including antihistamines, topical and systemic corticosteroids as well as phototherapy and cryotherapy. No systemic therapies are currently approved for prurigo nodularis, which represents a significant unmet medical need with approximately 74,000 patients eligible for a biologic in the U.S. And why we're excited about this indication? We advance to Slide 31 that shows the benefit of Dupixent treatment in prurigo nodularis from investigator studies, as I referenced earlier, as an input to our line extension strategy. Across 6 studies shown here, a total of 30 patients had dramatic improvements in itch, resolution of nodules and improved sleep. The level of benefit was broadly comparable across these studies, and the treatment was sustained for up to 1 year in one study. It is particularly important to note that these patients across these studies all had previously failed multiple therapies. Based upon this promising efficacy signal, we are running two 150-patient Phase III studies in prurigo nodularis, which we expect we will read out in the second half of 2021. If successful, we would expect to make regulatory filings before the end of next year. Moving to Slide 32, I want to finish my presentation with a large opportunity, chronic spontaneous urticaria, or CSU. This condition is characterized by typical type 2 hallmarks, manifested by swollen skin lesions or hives with extreme itch. It has a potentially severe impact on quality of life and is relatively common, affecting 1.5 million people in the U.S., of whom around 308,000 would be eligible for biologic treatment. The disease biology of CSU is complex. It involves the release of multiple cytokines as well as histamine and proteases and hyperactive mast cells together with an autoimmune component involving IgE and IgG. At present, patients typically receive antihistamines or the biologic Xolair, a monoclonal antibody against IgE. However, up to half -- half of the patients do not respond well to Xolair. Against this backdrop, we believe Dupixent has the potential to provide patient benefit by reducing mast cell activation in addition to reducing IgE levels. And this takes us back to Frank's mechanism of action slide for Dupixent in type 2 biology. And on Slide 33, my final slide, these are the results of a small case series of 6 severely affected patients with CSU, who had previously failed both antihistamines and Xolair. After 3 months, each reported dramatic improvements in disease activity scores, averaging 94% improvement. In some cases, patients reported no urticaria at all following Dupixent treatment. Based on these striking investigator findings and our belief in the biologic hypothesis, we have began a roughly 230-patient registrational study of Dupixent in CSU earlier this year and we expect results in time to file in 2022. And so to conclude my section, we have used a precision medicine approach, making use of genomic data, real-world evidence and investigator case studies to explore novel places where type 2 biology manifests with a goal toward identifying type 2 inflammatory diseases with high unmet need as potential line extensions for Dupixent. Across various line extensions I have spoken about today, Dupixent may provide a benefit in aggregate for over 700,000 patients in the U.S. and, of course, proportionately higher number of patients on a global basis. So thank you for your attention, and I would like now to hand it over to John.

Thank you, Naimish, Brian, Frank for explaining why all of us are so confident in the potential of Dupixent across a range of type 2 inflammatory diseases. I'll now wrap up with some brief concluding thoughts. And let's now move to Slide 35. We're really just at the beginning of our journey with Dupixent, as my colleagues have explained with the potential of this medicine to become the standard of care across multiple diseases where type 2 inflammation plays an essential role. This slide reiterates the reasons to believe in the line extensions that we currently have in development. I won't repeat what Naimish said, but will simply point out that the supporting evidence base across various indications is extremely consistent. In addition to our approved respiratory and dermatological indications for Dupixent, we're particularly proud of the remarkable recent data in a gastroenterology indication, namely eosinophilic esophagitis. We're excited about the data we've seen to date and what those data possibly mean to tens of thousands of patients whose quality of life is severely impacted by that disease. We're really looking forward to getting our hands on the full data set next year. Let's move to Slide 36. This slide shows what you can expect to hear on our journey with Dupixent's expansion into younger age groups and into new indications in the coming 2 years. In the second half of this year, we expect to report the pivotal results of our pediatric asthma study in 6 to 11-year-olds. In addition, we expect to receive the European approval for atopic dermatitis in children, 6 to 11-year-old. We're eager later this year to start Part B of our pivotal atopic dermatitis study in still younger children, including infants, which is supported by the increasing body of safety data with Dupixent that you've heard about today. Looking to 2021, next year, we will submit in asthma for children ages 6 to 11-year-old, and we will start an asthma study in infants and younger children, again supported by the pristine safety profile of Dupixent. We also expect to receive results from our pivotal studies in prurigo nodularis and in chronic spontaneous urticaria. And then finally, in 2021, we expect the Part B data from our Phase III in eosinophilic esophagitis to read out. And then looking to 2022, for our pivotal trial readouts should be occurring then, we expect to submit in the new indications of chronic urticaria and prurigo nodularis. Let's move to Slide 37. Our ambition with Dupixent is to maximize patient benefits across a spectrum of type 2 diseases. As a reminder of the key take-home points today, type 2 inflammation is a maladaptive immune response that leads to systemic barrier dysfunction and drive several chronic, often co-occurring diseases. IL-4 and IL-13 are 2 key components of the type 2 cascade, and Dupixent is the only medicine that was designed to specifically block both of these lymphokines by receptor blockade. This unique profile leads to a best-in-class efficacy and safety profile. The evidence base continues to build in favor of Dupixent, with our first pediatric approval, namely for atopic dermatitis, the long-term extension results in adults with AD and most recently, the compelling Phase III results in eosinophilic esophagitis, we are seeing a clinical profile that is consistent across diverse disease states making the benefit of Dupixent difficult to match by other mechanisms of action or other drugs in development. Though we're making great progress, we still have a way to go to address all the potential unmet need that patients have across the type 2 spectrum. The clinical data and real-world evidence give us great confidence in our line extensions with still much, much more to come. On Slide 38, my final slide emphasizes that when it comes to type 2 chronic inflammatory diseases, Dupixent is the only medicine that checks all the boxes. Dupixent's best-in-disease efficacy has been demonstrated in atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyps and now in eosinophilic esophagitis. No other therapeutic has such broad efficacy against the landscape of type 2 inflammatory diseases. This goes back to what I said at the Capital Markets Day in December last year. It takes 2, as we point out today, it takes the right 2 to address type 2 inflammatory diseases. Dupixent's unique dual mechanism of action, blocking not 1 but 2 lymphokines, IL-4 and IL-13, makes it stand out among the other treatment options. Furthermore, the safety profile of Dupixent is remarkable. Dupixent doesn't interfere with immune defense against cancer or pathogens unlike some types of medicines in this space. And our long-term safety data and the emerging profile -- emerging approvals for treatment of children speak volumes to the safety profile of Dupixent, making it the medicine of choice. With that, I hand over to Felix to start the Q&A.

Thank you. Thank you, John, and the other speakers. We will now open the event to your questions. We have already a number of questions in the line. Natalie, would you kindly remind everyone, the participants, of the options of how to ask questions.

[Operator Instructions] And now we will take the first question from Peter Verdult at Citi.

Pete Verdult from Citi. Two questions, please. A development one for Naimish and a commercial one for Brian or Bill. Naimish, when you look at some of the academic literature out there, it suggests up to 40% of COPD patients display type 2 inflammation. It looks from the slide decks you provided that you're assuming maybe less than 20%. Is that conservatism on the part of Sanofi? Or am I missing a step in how you arrive at the addressable U.S. patient population? And if I could squeeze one on Part B into that question. Are you able to share anything about the data that you saw of the interim analysis, be it lung function or exacerbation data that gives you this increased confidence in utility in COPD? And then one, I'm sure you're expecting Brian or Bill, anything you're willing to say about recent trends you're seeing for Dupixent in the U.S. as it relates to new starts, continuation of therapy and latest thoughts on how you're sizing up the opportunity in China?

Naimish, do you want to take the first question there? Naimish is trained as a pulmonologist, so I think it's a perfect question for Naimish.

Thank you for the question, Peter. It is a great question. I think there's a bit of a difficulty in how we define the type 2 population. There's patients who have -- because we're using a blood test, the blood eosinophil count, and a certain segment of patients have high eosinophils all the time and a certain segment of patients have somewhat fluctuating eosinophilic count. And depending on the patient population you study, you can get slightly different numbers. We are being a little conservative with the 20% figure because we know those are the patients who are reliably type 2, and those are the patients we're focusing on in terms of the studies we're carrying out. With respect to your question on the interim analysis, I would -- the interim analysis was a part of a very strict prespecified criteria around efficacy involving both efficacy and lung function and was -- the analysis involved an external DMC that reviewed the data. We're unable to say much more around the specifics of it, but we know that we're quite excited by the decision criteria and moving forward with the second study.

Yes. Thanks, Naimish. And Brian, do you want to take the question on the commercial part?

Yes. Thanks, Pete. Yes. We fully expected some questions in reference to performance and certainly on China as well. So really, despite COVID, actually, we've seen a really nice resiliency in the U.S. as it relates to Dupixent in the treatment of the patients there. As we've shared in the past, obviously, our TRx is holding up very robustly. And a lot of that has really contributed to the uniqueness of our molecule, really the fact that it's not immunosuppressant, the fact that it doesn't require monitoring. It really allows for physicians to feel comfortable both initiating as well as maintaining patients on therapy. Now as it goes to the initiation part, obviously, we've shared with you in the past that certainly practices, in many cases, we saw a decreased patient volume of upwards of 60%. So naturally, as you can imagine, that's hard to make up for completely with telemedicine, although they've done a very nice job. So many have come on and really started using telemedicine. And we have seen them initiating patients there. But we have seen our NRx decline a bit up to about 35% but we do see that rebounding as the year goes on. And we're already starting to see practices opening back up now and having more access to patients. So we're bullish on the fact that, that will recover shortly, and we'll continue to maintain patients from a TRx standpoint. We're quite excited about China. Obviously, we fully expect later this year -- second half of this year, to be launching in China. They're an important part of our growth trajectory. We actually are seeing somewhere in the range of -- over the next 5 years, somewhere in the range of 7 new indications potentially in China as well for Dupixent. So we're excited about the opportunity there. The patient population represents about 900,000 we calculated out approximately of those patients that would qualify for biologics. And the team is doing really an exceptional job there getting ready for launch.

The next question comes from Wimal Kapadia at Bernstein.

Wimal Kapadia from Bernstein. So firstly, just on CSU. I'm aware that you're testing Dupi post Xolair. Could Dupi compete with Xolair for the antihistamine refractory patients due to the superior safety profile? Just trying to get a sense of opportunity earlier in the paradigm. My second question is just on the strategy in place to extend the patent life beyond the end of the decade. Dupi will clearly be quite significant patent expiry. All that said, I appreciate it's some time away, what life cycle management plans do you have? And then if I can just get in a third one, across CSU, PN and BP, what is the overlap to atopic dermatitis and asthma for each? I appreciate you've given the patient numbers, but I'm trying to get a true sense of incremental population without double counting.

All right. Thanks for your question. I'm going to ask Frank, who is trained as a dermatologist, to take your questions because they mostly concerned derm indications. So Frank, can you lead us off with this?

Yes, absolutely, John. I mean in terms of chronic spontaneous urticaria, I think it's a huge opportunity out there. I think the indication has just been discovered and the unmet need now established. And I think what really -- what it does need is a differentiated approach, which is number one, safe. And I think we really convinced you, hopefully, about the safety aspect of Dupixent. But also in terms of its mechanism, I think the role of IL-4 and IL-13, especially in the mast cell pathology, is just beginning to be established. And I refer you to a really nice preclinical paper on, for example, asthma in this case, but it shows the role of mast cells in regards to IL-4 and IL-13. There are really interesting case reports emerging. So really I think CSU is a fantastic opportunity for a safe drug, for a drug you can essentially apply to long-term management. This is exactly what patients with chronic spontaneous urticaria need. And Dupixent is a perfect example where we add an additional mechanistic approach to urticaria.

Good. And then on the patent extension, I don't know that we'll be able to share much with you here today. But of course, it's on our radar, let's say, though that's about all I can share today, probably. Good. Should we -- next question. Did we get to -- did we cover everything you wanted to?

Actually, just on the overlapping population for CSU, PN and BP with respect to atopic dermatitis and asthma.

Yes. Frank, can you speak to that?

Yes. I mean there is some overlap, I would say, between prurigo nodularis and atopy in general, I wouldn't call it always atopic dermatitis there. A lot of patients with prurigo nodularis have some degree of atopy, I would say, about 50%. But then if you look at CSU and BP, they are really quite distinct diseases. And I think it's really not like you're treating atopic dermatitis, you're capturing that automatically. These are really distinct populations, where not necessarily you'll see a lot of overlap, clearly not between atopic dermatitis and bullous pemphigoid, also not a lot of overlap between CSU and atopic dermatitis.

And maybe I could just add to that, Frank. I mean keep in mind that -- so we're labeled for severe -- moderate-to-severe asthma, moderate-to-severe AD. And although there's overlap, there's rarely overlap on the severity. So relatively few patients have moderate-to-severe asthma and moderate-to-severe CSU. So it's not necessarily the same [ label of population. ]

Yes, good point, Naimish. Thanks.

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

So first one is on the COPD second trial, just help us understand exactly what the specific recruitment criteria for patients. Are you just using is eosinophil high or are you screening for or at least randomizing by the other markers of type 2 inflammation that you highlighted on Slide 28 that might allow you to better identify the more niche target patient population on the back of the results of that trial? Secondly, on CSU, obviously, Xolair, as you highlight, is well penetrated into that market. And we hear from physicians that they have to give Xolair to patients who are already on Dupixent for asthma, for example, for their CSU, which indicates that there could be perhaps discrete subpopulations that just respond differently to the 2 different drugs. How much credence would you give to that view? And what biomarkers are you using in your studies to try and identify those patients commercially? Or are you just going to go for Xolair failures? And then the last question I'll ask on behalf of everyone who e-mailed us after the last call. As we got Paul on the line, just a quick question on thoughts on how to build in M&A. You got $11 billion extra in your pocket now. Has that changed your thinking on M&A? Are you still looking at early stage augmenting of the pipeline? Or any change in thought process on what you might need in commercial spaces and/or gene therapy?

Well, thanks for all those questions, Graham. You asked some very good ones. So let's -- I'll let Naimish handle the COPD question first about the eligibility criteria for the patients in the studies, eos greater than or equal to 300 is the main eligibility. But anything else to add on that, Naimish?

Yes. The studies are replicated studies, so very identical in terms of the inclusion criteria. Of course, we are doing a thorough biomarker profile and looking at other type 2 biomarkers as exploratory examinations during the study. But overall, the enrollment criteria are really replicated, I should say.

Great. And then on the CSU, Frank, why don't you take that one. I know one of the questions was whether we're going to focus on the Xolair failures. And the answer to that is no. We're going to go out for patients who are naive to a biologic as well as Xolair failures. So we do have a broader ambition, but I think there were some questions more around the overlap. I guess that -- whether they're heterogeneous populations of patients that might respond to one, not the other is what I gathered. Frank, can you take that?

I think you're still on mute, Frank.

You are on mute, Frank.

Okay. This is typically what we are seeing when we are bringing these targeted therapies to patients that we're exploring really new biology. And I think the proof will be in the pudding when we bring in Dupixent to the chronic spontaneous urticaria. I think we clearly have seen Dupixent decrease levels of IgE. So clearly, an impact on that. And then also the role of IL-4 in activating mast cells is very differentiated from, for example, what omalizumab is doing. I think we have to do the clinical experiment, and then build it on there. We clearly have a variety of biomarkers in our trials, which are related to IgE and also the IL-4, IL-13 pathway. We know very well, for example, TARC. So we will be able to really disentangle them in a superior responder population. It's a good question. We're very keen on that precision medicine type of approach where we go into patient subsets, but that's something which the clinical experiment and the clinical trials need to establish.

Thanks, Frank. And Paul, do you want to explain what Sanofi is going to do with the $11 billion of -- we acquired through the Regeneron stock sale?

Paul, I think you are on mute and have to unmute.

Yes. Paul maybe saying about as much as he can. It's just probably not very much, but...

Maybe we will come back to this question, and in the meantime...

Yes, we can, but Graham, you would understand there's not a lot we can say. I think we've talked about with -- that we are open to exploring ways to supplement the pipeline, and we've shown some evidence of that earlier this year with the acquisition of Synthorx and excited about that synthetic biology platform and the pipeline that it brings on engineered lymphokines, actually one of which is going into this space here with an engineered version of IL-2 that increases regulatory T cells. And so Frank and Naimish are going to have fun with that molecule. So we'll -- more to come. Good work, Frank and Naimish.

Yes, maybe we'll take the questions here on the Q&A chain, which was sent to us by Mark Purcell from Morgan Stanley. And maybe that's a question in the same context. How does Sanofi seek to build a portfolio of medicines around Dupixent? Whether it is complementary mechanisms or mechanisms to help Dupixent refractory patients in atopic dermatitis, complementary mechanisms in asthma and other type 2 indications? Are there assets in the Ablynx pipeline, which could build on Dupixent? Or indeed, are there any potential Dupixent 2.0s. John, can you?

Felix, can you hear me? It's Paul.

Yes, now we can hear you.

All right. Sorry about that. I was giving you a beautifully put together answer, but you couldn't hear, and so more training required for me on the audiovisual. I think John was spot on as always. I think it's worth saying a couple of quick things. We did the sale because it was right for both companies right at that moment. And it was perhaps a perfect moment to do it, both the companies aligned. And so now we go into our planned approach of what to do with the proceeds. So news to follow. I think what we should add, because I think it's quite important. I don't think it's a surprise, but where we have a world-class development -- drug-development expertise and commercial expertise in areas that we already participate in, it would make sense to add assets because they become accretive faster and because we think we can get to unmet need faster. So you should look to us trying to add to areas we are first, and then beyond that, only if we think it makes sense, and news to follow. Sorry about that, Felix.

No worry.

Yes. And then maybe from the Q&A chain, let's -- I think that's an important question about where do we go from here. And I'll provide kind of an outline, but then I would encourage Frank and Naimish to jump in. So there are several dimensions to it. One is in terms of understanding how patients respond to Dupixent. Frank has established a precision immunology capability with single-cell RNA sequencing and other advanced technologies using machine learning and AI to really try to understand when you have an occasional patient who doesn't respond to Dupixent, what might be going on, what might be alternative targets that we could go for. And so that has helped inform our thinking around some next-generation therapeutics. And Frank had been using the Ablynx platform and the ability to produce multi-specific biologics to tackle that and has put 3 molecules this year into our development -- preclinical -- our development. We're finishing the IND-enabling studies and hope to bring those in the clinic probably early next year, given the delays from COVID. And then the pipeline does now have some assets with -- that are in the clinic, early in their journeys, CD40 ligand antibody that interrupts T/B collaboration in a number of -- which we think is important in a number of indications, a small molecule oral RIP kinase inhibitor. RIP kinase, to remind you, works downstream of TNF receptors. So an opportunity to intervene in some of the same pathways as TNF, but with an oral. And then I mentioned very briefly a minute ago, the Synthorx acquisition has given us access to a molecule, THOR-809, that is an engineered version of IL-2 that preferentially stimulates the proliferation of regulatory T cells to try to dial up one of mother nature's ways of putting the brakes on the immune system. So those are some of the pillars of our effort. But Frank, anything you'd like to add?

Yes. Thank you very much. I have to say and the reason why I joined Sanofi was -- as Head of Immunology Research was to kind of open their textbook chapter of type 2 inflammation and be a category leader in the type 2 space, definitely. And I'm happy to report that after 3 years, we've assembled the team with incredible talent. We have a type 2 inflammation cluster led by Paul Bryce, a professor we hired from Northwestern in Chicago. And we build sort of the tools to really understand, number one, patient biology much better in terms of potential inadequate responder long term -- what it takes for long-term responses to really go at the single-cell level. As John said, we put just some data in there to -- as a little teaser, where we can now actually go at a single-cell level. Remember, 5 to 10-micron per cell and get 2,000 genes per cell. This gives us a whole new way to understand best-in-class approaches, first-in-class approaches in terms of target biology and understanding patient journeys. And I think the other really key element is combining real-world elements with genomic algorithm-based AI approaches where we can really leverage genetic and genomic data, all this comes together to kind of get a completely new understanding not only on type 2 inflammation, what it is as a biology, it gives us new targets. And then really the two to tango is the modality. And I think bringing Ablynx gave us this multimodal biologic toolkit where we can take these single-chain essentially nanobodies and put them on like a -- on a string of beads, and we can dial in, for example, tissue targeting conditional activation, we can modulate half-lives, coming back to some of your questions. So this is really like this biologic 2.0 toolkit, which we match with our sort of target [ ID ] efforts and understanding patient biology better. And we are already in a record time are bringing molecules into the clinic, and this is for another R&D Day when John feels it's the right time.

Good. We should probably move on. We can spend quite a bit of time on that topic.

Natalie, we can go back to the audio questions. And -- but we will take care of all the other questions in the Q&A chat room. So I will try to handle them all. Thank you. And Natalie, please go ahead.

Yes. We will now take the questions from Jo Walton at Crédit Suisse. Jo, please make sure that you unmute your mic.

If she is not around, then we'll go to the next question. I think it was Peter, right?

Yes. So we can now take the question from Peter Welford at Jefferies.

Hopefully you can hear me. I've got 3 really brief questions, please. Firstly, I wonder if you could just talk about atopic dermatitis, specifically, what the potential advantages could be of blocking IL-4 and IL-13 versus IL-13 alone, focusing particularly on the efficacy angle, if you could. And secondly, I wonder if you could talk a little bit about the non-proportionate patients you think who are on more frequent doses of Dupixent? We heard numbers as high as 1/5 or 1/4 of patients require more frequent than biweekly dosing. I wonder if you could comment on that. And then finally, I wonder if you've done any work on the cases of facial rashes and conjunctivitis, which seems to be the most troubling from our physician conversations. It's for a small minority of patients. And to what could be causing that? Whether there's potential, I guess, mechanistic [ rote grand? ] And how that could potentially be improved upon?

Well, thank you for your questions, Peter. Frank, why don't you take the first one about atopic dermatitis, IL-13 monotherapy versus IL-4? I think you tried to cover that in your slides around the basic biology and talking about IL-4 playing a role, both upstream and downstream. IL-13 being more of a -- more in the middle of slides, more downstream, but let's touch on that. And then I'd like Naimish to pick up the issue around the schedule, how frequently Dupixent is dosed as well as the topic of the conjunctivitis, which is seen in some patients with AD.

Thanks, John. Exactly as you say, I mean, it takes 2 -- we believe, it takes the right 2 in type 2 inflammation. And maybe a lot has been said and is presented on IL-13. Maybe let's start with IL-4. IL-4 is such an important molecule. Number one, it's like it primes the immune system, the type 2 immune system. If you think about type 2 immunity going wrong, it's like an orchestra going rogue. And IL-4 is really the director, which sets essentially a tone for that kind of type 2 rogue orchestra. And if you block that, you can actually go to the very causal origins of what type 2 inflammation is all about. So IL-4 is really key, but it also plays an important role, like John said, in the tissues. It amplifies not only TH2 effector cells. And I hope you remember the single-cell data from atopic dermatitis, where you saw that all the blue was on the T cells. So really, those T cells in there, we know on a single cell level, they respond to IL-4. So you have to block it. And then there's another player we didn't even talk about is the mast cell. Mast cells explicitly express this, what we call Type I IL-4 receptor. So you're actually getting into the mast cell biology. And we had a lot of interest about CSU. That's -- that actually contributes to our confidence that Dupixent is a great player in there. Now IL-13 especially can work in combination with IL-4, everything from class switching, IgE production to really mucus production in the asthmatic lung and has a lot of synergies with IL-4. But I think there's an IL-4-specific component we're specifically leveraging, and that's why quite potentially some of those single-cytokine approaches are what we feel incomplete. If you look at our clinical footprint now across 4 type 2 inflammatory diseases, a lot of the other ones are just in an individual indication. For example, only in AD, but not in asthma, for example, only in certain indications. So there is this kind of notion that if you're blocking one, it might be an incomplete kind of approach to type 2 inflammation.

Yes. It could be very important for that restoration of barrier function too, which is really what begins to create the opportunity for more long-term disease modification. Let's ask Naimish. Can you tackle the issue of the Dupixent schedule and the conjunctivitis that's seen in some patients with AD, but interestingly not in -- typically in patients with asthma or esophageal or eosinophilic esophagitis, some of the other indications. So Naimish, over to you.

Sure. John, that's exactly right. Maybe I might pass over to Brian after I'm done. Just because the question is also about real-world use. But in terms of the dosing schedule, in our Phase III program, we did extensively compare the efficacy of QW and Q2W dosing of Dupixent. And over a broad population, there wasn't really much difference in efficacy. Whether there are subpopulations within the AD sphere that might benefit more from QW dosing is -- and I would say an unanswered question, an unproven question, but we -- at this point, we haven't been able to rule that out either. So -- and just about the conjunctivitis piece, exactly right, relatively uncommon in atopic dermatitis and actually not seen at all in, for example, asthma or EoE. What we do understand about conjunctivitis is, as I mentioned, relatively uncommon, but it actually is -- frequently occurs in AD patients who are not treated with Dupixent. So something about atopic dermatitis specifically with conjunctivitis. We also know that, in general, the reactions with conjunctivitis are relatively mild, they can be treated conservatively with eye drops. And very rarely does it ever lead to the requirement to stop dosing Dupixent. So usually it gets better over time with continued Dupixent therapy. And maybe you can hand it over to Brian to address the other question.

Yes. Brian, anything to add?

Yes, absolutely. I think that in reference to the question about the dosing, right, 2 week, maybe Q week. What we tend to see is -- we don't have a quantification of how and what is the percentage of that. But what we tend to see is we -- or we tend to hear is we hear that very infrequently. And when we do hear it, it's normally from the KOLs, those individuals that have maybe been involved in the previous trials and they're trying, in some cases, the higher dose of going with a more frequent dose. But it's a very low percentage, most of what we see is within the label, which is every 2 weeks.

Yes. And I guess, no matter what the frequency is, we're working on an auto-injector, which we hope to be able to provide soon to make the experience of taking your Dupixent even more convenient for the patients going forward. Shall we go to the next question?

The next question is from Geoff Porges at Leerink.

First, perhaps I'll ask one to Bill Sibold who's looking very serious in front of his beautiful painting. First, could you -- Bill, comment on what effects you think payer mix is going to have on your revenue trajectory for Dupixent in the second half of the year? Obviously, we've had a huge surge in unemployment, and presumably, patients might transition over to Medicaid. So can you just give us a sense of what sort of headwind that might be? And then secondly, could you talk a little bit about, perhaps, Brian, about JAK inhibitor competition. Like it or not, JAK inhibitors seem destined for approval in atopic dermatitis. So we'd love to hear what your market research is telling you about how JAK inhibitors might slot into the landscape that you're competing in. And then lastly, perhaps Naimish could talk a little bit about bullous pemphigoid. You didn't give us any information there about the relative size, timing, and indeed, the current clinical evidence for efficacy in that indication.

Okay. Several good questions. So Bill, you want to kick us off?

Okay, Jeff, thanks for the questions. I'll look a little bit less serious. Look, thanks for the question. It's a little premature to know what, if any, impact there is going to be as we look to the second half of the year. The way we've approached this is we've made sure that we have the appropriate patient assistance programs in place to help patients, first of all, go in uninterrupted if they have any kind of change in status. So that's where we've been focusing. I think overall, the message that I would give is that we're starting to see more practices that are opening. So more patients are going to get to practices to be prescribed. And we see the growth growing through any of these changes that may or may not happen from a payer shift perspective. But until we know what that ultimately looks like, Goal #1, make sure that we've got the programs in place, patients stay on therapy, uninterrupted access. And we've got at least 3 or 4 good programs in place. So I think we'll be in a better position to report out on that as we get to the Q2 call, we'll have our first sign, and then certainly after that as we get more back to fully open practices to give you an update on it. But it's certainly on our mind, we're monitoring, and I'll turn it over to Brian.

Yes, Brian, do you want to tackle the class of medicines with the black box warnings? Maybe say a few words about them.

Yes. Absolutely. I think that, obviously, it's a really interesting time for the development of these agents. And as we've expressed in the past, I think, in Capital Market Day, the JAK class, what we're seeing is pretty consistently with what we've seen with previous JAK therapies, really the broad immunosuppressant-type approach is creating a profile that you see that you're going to have to go up in strength to get the efficacy required in this particular patient population, and with that, comes some side effects. And I think in the Capital Market Day, we clearly laid this out that in this particular community, in the dermatology community, when you have that type of profile, our research is really suggesting that this is going to be a second-line therapy that would be really reserved for patients that have really potentially no other options at that particular point, but after they would have considered Dupixent. So we'll see how it continues to develop. I think we have to see the remaining data for each of them and see what the labels are that they actually get. But for the time being, obviously, we feel incredibly bullish about our profile remaining the best-in-class profile for the foreseeable future.

All right. And there was a question about bullous pemphigoid, which I think, Naimish, can you tackle that?

Sure. So I mean this gets back a little bit to our theme about Dupixent, where I think we're just scratching the surface. We're just beginning the journey in all the indications where Dupixent can be, and we prioritized a few of the larger ones for discussion today. Bullous pemphigoid is one of those very important indications that we are advancing Dupixent, and the Phase III program has already commenced. And it is an important disease. It's a relatively smaller indication than the others, about 27,000 patients biologics eligible in the U.S., and it's a very type 2 disease similar to the others we've discussed with the same hallmarks, characterized by eosinophilia, high Ig levels and autoreactive IgE to skin causing blistering. And it's really a quite severe disease with a high mortality for these patients. And we believe that Dupixent can really make a difference for these patients. It's a disease primarily of the elderly, and we're very interested in advancing the study in this area. We just haven't discussed it extensively in this presentation, but...

So -- and just to chime in from a dermatology perspective. I think it's really -- it's a paradigmatic example how we are now establishing type 2 inflammation as a connected pathology with these type 2 hallmarks and actually bringing diseases in which in the textbooks I was reading, it didn't feature under type 2 inflammation. But clearly, with high IgE eosinophils, the IgE probably [ even ] involved in the blister formation, a very interesting indication we have in our case reports lined up to basically support the mechanistic hypothesis. But also think about the patient populations, typically elderly patients. They need chronic treatment, they can't be on steroid, which is the only other -- all the steroids are now -- the only other really therapy we often have for these patients. If you have a safe drug, which is on mechanism, and can be given on a chronic treatment paradigm, I think Dupixent is right up for the game as a potential breakthrough therapy.

Okay. Thank you. So let's move on to the next question.

Yes. We may go back to the Q&A line. It's getting increasingly difficult to find and to make sure that we address every question, which has not been addressed before. There's a question from Richard Vosser, which is in line with what we had before, but there was one additional element. Richard Vosser from JPMorgan. In terms of your $10 billion peak sales ambition, how much of a contribution are you factoring in for AD and asthma? I think the other question was already addressed.

All right. Brian, do you want to take that? I don't know how much of the detail you've been revealing on the mix of indications contributing to that $10 billion aspiration, but over to you.

Yes, absolutely. I think we -- as we said at Capital Markets Day as well, there's multiple ways to get to the $10 billion and beyond, quite frankly. We -- the foundation of that, however, atopic dermatitis and asthma are 2 really foundational indications. So we don't really kind of share what the split -- what we think the split will be. All we really share is that we think that, I mean, first, think atopic dermatitis, that's the best way to think about it. First, think about atopic dermatitis, big population, high unmet medical need, very low penetration rate today. And then think asthma as well, obviously a big population, still pretty low penetration rate, and even in spite of having 5 competitors now in the marketplace. So those are really our 2 foundational indications. I think the other way you should think about it is why it's multiple ways to get there. As you see the indications that are now coming, these are adjacent indications and further strengthen our dermatology and respiratory plays. So they're -- as Naimish laid up, bullous pemphigoid and prurigo nodularis and others, they share some characteristics, which further strengthen your AD profile and further strengthen your asthma profile on the respiratory side. So that will help, I think, in further defending ourselves in both the AD and the asthma space as well, but multiple ways to get there.

All right. Thank you, Brian.

The next question is from Luisa Hector at Berenberg.

So 2 questions really linking to atopic dermatitis. The first question is on the patients who do respond really well to the drug. I wanted to check that you feel comfortable that you're well positioned for long-term persistency of therapy. I'm wondering whether there might be a temptation over time to dose taper. And then secondly, as kind of a flip side to that, the patients who are not the super responders, maybe they don't respond so well or not at all. The question there is really, why don't they respond so well? Do you think there is a mixture of misdiagnosis, they were never truly AD to start with or a mixture of diseases or perhaps some underdosing, if they are, let's say, heavier patients, some kind of weight element or any other reasons?

Thanks for the questions, Luisa. Naimish, why don't you start with the dose, the long-term dosing, whether patients will be tempted to taper dosing, et cetera. Brian, you may also have some insights into that from your work in the field. So let me ask Naimish to start, and then Brian to follow. Then Frank, I'll have you take the nonresponder question because that's an area of science I know you're very passionate about. So Naimish?

Sure. So I could start with -- Luisa, thanks for the question. I could start with the data we've accrued. So the SOLO-Continue study in AD, which has been published is a study in which we took patients who responded really well to dupilumab, IgA-01, and tapered their doses to a Q4 regimen, Q8 regimen. And what we did know from that study is there's definitely loss of efficacy if you go to a less frequent dosing regimen. So -- and I think the strongest sort of incentive for patients to stay on Q dosing is the superior efficacy of Dupixent. But Q2 dosing, as we've seen with the long-term extension trials, is very effective for years on end, and then with even increasing -- or continued dosing, which has even increasing efficacy over the long term. So that's one of the really strong sort of incentives of staying on Q2 dosing. And Brian, I don't know if you have anything to add to that.

Yes. We've seen very strong persistency rates. I think we've shared in the past, upwards of 70%, 75% at a year. And again, this really speaks to, I think it's really important to understand the disease state. These patients didn't have a lot of therapies beforehand. Obviously, they came onto the therapy and they saw, in many cases, obviously, in most cases, very positive results from Dupixent. So these patients are really quite persistent with their treatment. So we have no reason to believe that, that will change over time, and we're quite confident in that from this.

All right. Thanks, Brian and Naimish. Frank, on the nonresponders? Share your thoughts.

Yes, first, when I came, I said where are the nonresponders? And there weren't actually many because it's really interesting how, basically, every patient responds to Dupixent, with some degree of response, which is often satisfactory. But then if you're on a chronic disease journey over 20 or 30 years, there might be patients who are coming off Dupixent, and that might be for a variety of reasons, maybe not injecting regularly anymore, taking a drug holiday or any other possibilities out there. And we're studying these patients very, very intimately, I would say. And we're understanding what these -- what molecular sort of underpinnings are. And we're using that to kind of design our next-generation therapeutics, which is not the topic of today's discussion. But obviously, as John was alluding to, we are very passionate about establishing a whole portfolio of medicines around Dupixent to establish that type 2 leadership and that's [ playful now there. ]

Good. Okay. Thanks, Luisa.

Thank you. We want to go back to the Q&A room. There's a long list of questions from Jo Walton at Crédit Suisse. Maybe some of those questions have already been addressed. I will read them -- all of them. What do you expect to see from tralokinumab this week and then the AAD, and later, perhaps on lebrikizumab? Given they are only going after AD and with derm-focused companies, do you feel them coming in with limited indications, but much cheaper? In particular, how important is speed of onset in treating itch? How do you expect to see pricing in Europe as you keep adding indications in this? Is this an issue? You have presumably less flexibility on pricing in any one indication, given the breadth of your sales. Can you help us on the most recent patient split in scripts? So we can assess the level of penetration today in AD and asthma. Potentially, some of the questions have been addressed before, but John, you may want to...

Yes. No, there are some new ones here. So on the competitor molecule coming up at the dermatology meeting. Frank, are you familiar with that molecule? Do you want to make any comments about that?

Yes. Actually, probably -- I mean, number one, it's always -- to predict anything, especially if it's the future. But -- and we don't have any particular insights into those datasets. But maybe -- I mean, I talked a little bit about the kind of incomplete elements based on the science, I already alluded to that. Maybe Brian wants to kind of take this and talk about the positioning where he sees Dupixent versus the IL-13 class on a commercial success, if that's okay, John?

Sure. Yes.

Yes. Very good. Yes, absolutely. There was a lot of questions in there, Jo. So I'll try and tease them apart.

Actually, while you have the floor and you can maybe take the issue about the pricing for different indications in Europe or what that means as well as the -- there's a question around the relative proportion of prescriptions being scribed to different indications and sort of a follow-on, I guess, to what you said previously. So maybe you can take all of those, and well -- and then the other question was about speed of onset, which I know is a topic that's near and dear to your heart, Brian. So I think you can take all of these.

Yes. Yes, I'll try to remember all of this. But yes, speed is absolutely very important. And I think as you saw in the presentation, we really -- we've been very pleased. And I think -- we hear in the real-world as well, the physician audience is very pleased as well as are the patients with the onset of action really after the first dose. We see this across atopic dermatitis, and we see it as well in asthma, very impressive results. Really after that very first dose, patients started to feel the effect immediately and see the effect in some cases like in dermatology. But as you look at the -- and I think, Frank, you started it off, as you look at the new products -- the new potential entrants, IL-13s. I think the word incomplete is something that comes to mind. That we actually -- we've shared with you today, really the importance of the role of IL-4 and IL-13, and we're seeing this really in the data. Now while we haven't seen the Phase III data yet for tralo or for lebri, either one of those. What we have seen is, obviously, we've seen our Phase II data. And while there are some interesting results in there, one of the things that we do see is that in both cases, we haven't seen them work across type 2 diseases. So in both cases, we've seen -- or excuse me, lebrikizumab has not tried that there at least to our knowledge, but tralokinumab obviously did not work in asthma previously. So again, getting back to the importance in type 2 inflammatory diseases of both 4 and 13. So I expect -- I'm interested to see the results this weekend, but our market research really suggests as well much like the JAKs that these will be reserved for second-line therapy behind Dupixent. Now as you think about the future -- the additional questions, obviously, atopic dermatitis, we've said, is a big part of our success. We've actually said as well that the penetration rate, however, and I think this is one of the questions about the splits. Penetration rate is still extremely low. So we're in about, if you look at the U.S. alone, about 4.4% penetrated. We see this marketplace growing like what we saw in the psoriasis marketplace. So we still have enormous growth potential ahead of us. And we're really excited about that. Asthma has just recently launched, of course. I mean we're still relatively recent and still there's a lot of market still to launch. So we should see asthma continue to come on and contributing a higher portion of the growth in the future. Now last one in reference to price. Price is very important, but it really begins with payers, ex U.S., especially, really helping them understand the burden of these diseases. And I think the teams have done really an exceptional job of sharing the information about the burden of these diseases, the cost to the systems and really making sure that we establish our product as an effective and safe therapy that provides value to their patients. And we've seen that. We've secured nice positions, nice pricing ex U.S., really very strongly competitive versus what we've seen actually across psoriasis marketplace, and certainly, in other markets. And we believe we can sustain that over time because we thought about the other indications as we went in to speak with the payers. And that was an important part of our ex U.S. pricing strategy. But a lot more work to come. First and foremost, it begins with innovative treatment for patients with high unmet medical need.

Thank you, Brian. Felix, any questions?

Yes. We have only very few minutes left, but still a long list of people with one last question. So we'll go back to audio. And please try to reduce your questions to only one, in order to allow for another 2 or 3 questions. Thank you. Natalie, please go ahead.

The next question is from Tim Anderson at Wolfe Research.

I look at how the psoriasis market evolved over the course of a decade. Initial biologic agents like the TNF were clearly much better than standard of care at the time, but their absolute levels of efficacy on things like PASI-90 weren't that high. And sure enough over time, you have other classes like IL-17s and 23s that came in, they're really going to do a step change. So when I look at atopic derm, it makes me wonder if the same might occur because if I look at EASI 90 scores with Dupi, their absolute levels really aren't that high. It's 25% to 30% or so, which are certainly better than what's been out there. But I tally up all the companies and different mechanisms going after atopic derm, and it's a really long list. I know we don't have Phase III on a lot of these or really in any of them. In a lot of cases, we're going to have Phase II, but could that psoriasis precedent be worrisome?

Yes. Thanks for your question, Tim. I think that's a great one. I'm going to ask Frank to -- as our dermatology expert, to start and then we can maybe ask -- and maybe Brian -- and maybe if we can then -- maybe even our CEO, Paul, has something to say about that because I think he knows a little bit about the psoriasis space.

So should I kick off or...

Yes, go ahead, Frank.

So I think it's a great analogy. And when I started off my career on the academic clinical side, we first started to use biologics. And actually, my first patient was a patient on infliximab, and I still remember a psoriasis patient that came home, and at next visit, was with a lot of shopping bags. For the first time, she could wear clothes she never dreamt about wearing. And I have to say when you come into the type 2 space and you try to kind of put this into perspective versus the type 1. I think, number one, the type 2 space seems to be much more interesting into many, many diseases where we're moving in, and connected pathology is like much wider in terms of where the pathological net captures patients and establishes disease pathologies, also many different organ systems can be involved. And in terms of therapeutic success, I have to say I was there when Enbrel, the early anti-TNFs were there. And you're right. I mean, they obviously were eclipsed now by the IL-23s and then anti-IL-17s. But I would say we're much closer to the pathology to the real master regulators, IL-4, IL-13. I haven't seen as a scientist and as a clinician scientist, not a better master regulator. I was involved in discovering IL-23. And I knew immediately, that's the master regulator in psoriasis with IL-17 as downstream and TNF is all over the place. So clearly, Dupixent is not this all over the place anti-inflammatory. It really acts at these master regulators of IL-4 and IL-13. So we'll wait and see. I mean there might be always something coming, and we certainly work on some next-generation drugs. But we're pretty close to the causal mechanisms of that type 2 inflammatory disease with 2 master regulators combined. So it's a pretty good start.

Yes. Paul, do you want to contribute to anything given your history of...

John, can you hear me okay?

Yes. Yes.

All right, great. So the beginning part of the question was a little faint. But -- so if you want to repeat it for me, it would be great. Otherwise, and I think Frank just said it, I mean, we're probably right at the limit of efficacy and tolerability in a single medicine we're ever going to see in these disease areas. I think we have set an efficacy and safety bar that it's going to be almost impossible for many of the entrants to reach in almost all of the indications. They will play around the edges will try and carve out a position, I am sure. But fundamentally, derms, [ palms ], everybody that's using the medicines knows, we have set such a high bar. It's very difficult because of the reasons Frank and the team have outlined to imagine anybody considering something else. I think while we're on, I just want to say thanks to the team because I think as we start to broaden the impact of this medicine and really start to get under, I hear the enthusiasm. I see it every day, but I think thank you to them for how they've shared it. We are really -- and I think, Brian said it, like 4% penetrated of patients that could benefit from a medicine that is probably going to be the standard of care for a decade plus. I think we just have to recognize where we're at and say we haven't even started yet. And that's incredible for patients, and indeed, to create value for the company and those that invest in us.

Thank you, Paul. Brian, did you have anything you wanted to add? I saw you trying to answer.

Yes. Of course, obviously, I've been in the space for a long time in dermatology. So we're -- and the truth is we're really going to benefit. And I think that's the way to look at this, right? We're going to benefit in atopic dermatitis from the way in which the psoriasis market developed. So if you think about it, the psoriasis, a lot of the physicians, as Frank indicated, the same type of thing, they didn't have these advanced therapies at the beginning more than 15 years ago. And their first -- the number of them, one of the big issues was safety. There were some struggles with safety. And this particular community, I think, as Paul very nicely laid it out, safety is of utmost importance. So I think as you think about how the profile has changed over time, it wasn't just on efficacy, the profile has changed over time in psoriasis on their balance of efficacy and safety. And that was a big transition point, I think, for the psoriasis space as it grew, and I think what you see for us is just as Paul is laying out. We really have a nice balance of both efficacy -- we don't give up anything on the efficacy side, but certainly, that safety profile is going to be incredibly important for the physicians certainly in an atopic dermatitis space. So -- but we will benefit from the lessons learned in psoriasis, for sure.

Great question, Tim. Felix, do we have time for another 1 or 2?

Yes. I think we'll take 2 more questions. So please one question each. We have many more, but we will handle these after the call. Natalie, please go ahead with the 2 last questions.

So the next question is from Seamus Fernandez at Guggenheim.

Okay. I'm [ managing ] you from multiple different screens. So just a quick one. Really wanted to understand a little bit better the dynamics of eosinophil counts, the interaction from that perspective in COPD, in particular. I think you've emphasized the importance of eosinophils there. Can you just help us understand what was the choice to advance that program? Today, I think the announcement was just made with regard to advancing into a broader COPD program. And is it related to sort of the pneumonia and bronchitis dynamics around ICS, is that an opportunity to see a real meaningful improvement in the treatment of COPD? Or is it simply just the eosinophil counts? Because when we look at some of the other programs, in particular, the benralizumab program, which actually knocks down eosinophils very quickly and very effectively, we didn't see that big of an effect. So this feels a little bit like a trial design benefit more so than a molecule, but please just correct me if I'm wrong.

Seamus, thanks for your question. I'm going to ask Naimish to kick us off in terms of trying to answer that. I would clarify though that the second study is essentially the same as the first. We're not broadening to a low eosinophil population or something, it's really for purposes of having 2 studies, one of which will be confirmatory for purposes of registration. But Naimish, can you handle the detail there again?

Sure. Sure. Seamus, thanks for the question. I guess one way to say it is sort of eosinophils are important, but eosinophils are team players. The team they play on is actually type 2 inflammation, and they are just a marker for type 2 inflammation. We are identifying a subset of patients with COPD who have active type 2 inflammation. We're using the eosinophil count as sort of a biomarker to identify that, but it's much more than just eosinophils is what's going on. As Frank alluded to extensively in his presentation, IL-4, 13 have effects on airway mucus production, airway hyperplasia, all these things are very important aspects of what we think is the pathogenesis of COPD. And that's why we think Dupixent has a real chance to be different than what we've seen with benra or mepolizumab in terms of efficacy and COPD. And the data we had from CRS-NP study really outlines patients who had COPD in that study had a lung function benefit from Dupixent, and that hasn't been seen previously with any of the biologics in COPD, and that's what gives us confidence. In terms of the other big confidence driver is the interim analysis that we had that was, as I mentioned, had a strict go/no-go criteria based on efficacy conducted by an independent DMC and that figured prominently into the decision criteria of launching the second study. I hope that answers the question.

Yes. Great, Naimish. Thank you for the good question, Seamus.

All right. Natalie, a last one from the line.

Yes. So the last question is from Jean-Jacques Le Fur at Bryan Garnier.

A question regarding -- a commercial question regarding the market share in atopic dermatitis. When you reach the $10 billion mark in sales or so, what could be -- or what do you expect as a market share level you will reach at the same time? I know you will not give me a precise figure, but could it be in the low double-digit level -- or range, 20%, much more than 20%? So just to understand where you will be in market share for AD since you have quite very strong dynamic right now.

Brian, do you want to take that, and then Bill could supplement if he cares to.

I think Jean-Jacques is right. It's really hard to share a number there because, as we said, there's multiple ways to get there. So it's -- we don't have a formula, like I said, that it says, okay, at that particular point, we'll be AD this much and asthma this much and some of the others. But I think the best way to think about it is that you should think about that market, the dynamic of the penetration rate into the atopic dermatitis. So if you think about the big contributors to the ability to reach $10 billion, as we mentioned, and to exceed it, quite frankly, it's -- first starts with atopic dermatitis and really the growth of that marketplace. So as we said a bit earlier, we're only about 4.4% penetrated into that patient population as we speak today. And so that will certainly be in the double digits for sure as far as penetration rate goes. Now our share of that, obviously, will be determined based upon, obviously, the competitors and how we continue to maintain our leadership position. But I would say -- I'd sum it up by saying, based on the market growth there without a specific number, we will still be the leaders in market share significantly within what's in that particular marketplace. And there will be other contributors like asthma and other indications by that particular point.

Maybe John, I can...

Bill, yes. Bill, yes, please.

Force that a little bit. As you think about AD and you think about what's the bio penetration look like, and you've seen where psoriasis that we talked about earlier in the call, being in that over 20% range finally after a lot of years, we see that Dupixent and AD -- or pardon me, that biologics and AD get over that 20%, 20% to 25%. The question is what's going to be the time. Not sure of what the timing looks like because the specialty is getting used to still treating atopic dermatitis. But what I will tell you and what I believe very strongly is that we will be the leading player in the space. Brian mentioned it, but we don't see anything that displaces Dupixent. We've said from the start, we're just getting started. There's still this enormous breadth potential based on the mechanism of action. We're going to go to other places where the type 2 inflammation takes us. The enormous depth, we're just getting started with all the penetration rates that Brian referred to when we talked to you about the -- during the call. And there's just not any other profile there that we think displaces it. So I mean, we are -- still remain bullish on this and believe in the potential of this product. It is a once in a career product, and we're excited.

Thanks, Bill. Good. Thanks for the question, Seamus. What next Felix, one more maybe?

I think we have come to the point we're already 15 minutes over time. If you want to maybe take a couple of minutes to conclude, and then we'll let people call us, again. We tried our best to address as many questions that we had on the line as possible, both on the phone as well as in the Q&A room. So please forgive us, we will do this separately and individually.

Good. Well, let me start by thanking all who joined us today to give an update on Dupixent. Dupixent really is a flagship product of the Sanofi portfolio. I think my colleagues hopefully did an outstanding job of really explaining the fundamental biology behind type 2 inflammatory diseases, the diversity of those diseases in terms of how they manifest. It's fundamentally a systemic problem with how the immune system is regulated, but manifests in different organs. And you've seen already with the approvals in 4 indications, and hopefully soon, another with moving into the eosinophilic esophagitis, which takes us then in from respiratory and dermatology into even gastroenterology. You've seen how the manifestations of these type 2 diseases in different organ systems can be very effectively and safely addressed by Dupixent. It is really a remarkable, very special medicine that is beginning to address enormous unmet patient need. The stories of these patients who had suffered all their lives with these conditions are heart-wrenching. And so to be in a position to address those needs is about as good as it gets for physician scientists like me and my colleagues. So thank you for your attention. We look forward to further update. So a lot of news flow, obviously, ahead of us with the broad program that we're investing in for Dupixent and trying to make the most of this medicine because there are so many patients that are really -- urgently need Dupixent. So thank you, again, and we'll look forward to further updates.

Thank you.

Thank you.

Thanks.

Goodbye.