Roche Holding AG (ROG) Earnings Call Transcript

Ladies and gentlemen, welcome to the Roche Pharma Day. My name is Henrik, and I'm the technical operator for today's call. Kindly note that the webinar is being recorded. [Operator Instructions] At this time, it's my pleasure to introduce you to Karl Mahler, Head of Investor Relations and Group Planning. Karl, the stage is yours.

Yes. Thanks a lot, Henrik. Welcome from our side here for our Roche Pharma Day this year. So we have around 3 hours -- a bit over 3 hours ahead of us and very much looking forward that you joined us through this webinar, that you can make yourself -- that we can make you familiar with our pipeline and progress, which we have done since the last update in September last year. So we will have Bill Anderson with us. He -- his presentation is on sustainable growth, so more patient benefits. So basically, he will talk about strategy. He'll talk about translation, transmission we are in -- transition we are in and the progress on the pipeline which we have done. Then we have Teresa Graham, our Head of Global Product Strategy. She will give us an update on the late-stage pipeline but also on progress which we have done for products which was recently launched. Then we have planned for a very short break of about maybe 5 minutes just to give us a bit of a mental break. Then Levi Garraway, our Head of Development, will focus on the broad pipeline but also highlight certain assets like the BTK, the SERD and PI3 kinase inhibitors. The third -- we have in neuroscience Paulo Fontoura with us, Global Head of Neuroscience and Rare Diseases, talking about maybe the best pipeline in CNS in the industry. Cristin Hubbard, she is responsible for the immunology and ophthalmology pipeline. She will basically focus on ophthalmology in the first part. Then we have John Young, he's the Global Head of Infectious Diseases or pRED. He will do a case study on the HPV pipeline. Now this is a kind of an experiment or a case study. And you can see that Roche is also focusing on things where, I believe, the other companies are not focusing on but where we have great hopes that we can make a difference for patients in the end. And then we will close with Cristin Hubbard again. She will talk about our contribution to manage the COVID crisis. The next one. So we have as Roche 36 breakthrough therapy designation received already since 2013. So this is the largest number of breakthrough therapy designation of any company in the industry. And basically, the formula here is very easy. It's -- the breakthrough therapy designations plus new market entities should end up in growth. So we have a strong pipeline, maybe the strongest ever, with a good balance in terms of risk-taking and therapeutic diversity. And on top of the 15 blockbusters in the market, we have 23 by additional large stage -- late-stage assets, which are already in launch phase or in late-stage clinical development. So as for every pharmaceutical company, our long-term success depends on the success in research and development. And we expect, in that sense, 16 new market entities to reach out -- being filed within the next 2 years with additional many important line extensions, in particular but only -- not only Tecentriq. So with this one, we have an exciting journey ahead of us. For the next 2.5 hours, you will have plenty of time to ask your questions. We have reserved about 70 minutes for this one. Henrik can explain you on how you can manage your contribution here to this webinar. With this one, I would like to hand over to Bill. Bill, please.

All right. Thanks. Thanks, everyone. Uh-oh, it seems like -- here we go. Thanks, everyone, for joining us on our first all-virtual Roche Pharma Day. Obviously, we'd like to see you in person, but events have made that impossible. I know you're thinking, "Wow, look at that great Zoom background that Bill has." But I promise you, this is actually not a Zoom background. It's one of our offices, so I'm actually in Basel in person. So you get to have a piece of Roche with you. And in fact, to underscore the point, just out these windows that I'm looking out is the Rhine River. And yesterday, my wife and I were doing what's probably our last float down the Rhine River in our -- if you haven't been to Basel, you actually float down the Rhine River swimming. So it's one of the many fun things about working at Roche, is you get to come to work in the office and then on the weekend, you get to float by your office with thousands of your closest friends. So anyway, we know -- let's face it. 2020 is a year that has brought a lot of not great news. And we hope that we can infect you with our optimism and encourage you when you see what we've got going on at Roche in terms of our pipeline, in terms of the progress that we're making in personalized health care and in the way we're transforming our company so that our people can have a bigger impact and we can assure the world patients a brighter future. So that's what we're going to try to cover today, and we hope that you'll find it encouraging as well as informative. So next slide, please. So we have a track record of innovation. And if you look at our list of medicines approved over the years, what you find is not only a lot of medicines and a lot of medicines that are doing great things for patients, but a lot of unique MoAs, a lot of really breakthrough science. And we hope to continue that tradition, and we're going to talk about that a lot today. Next slide. This is the progress we've made with our newer products. Our newer launch products are up to 38% in the first half of 2020 of our total portfolio. And you can see by 2024, we should be at 60%, whereas Avastin, Herceptin, Rituxan will be down to about 10%. So this really is the kind of peak years of transition for us as a company. And that's why that pipeline is so important to us. Next slide. This is the so-called gap and the gap slide, and we've been showing this for several years now. And you can see the gap to fill has been CHF 9.6 billion. If we take your numbers, the consensus numbers from The Street, it adds up to almost CHF 18 billion. And this is why we're increasingly confident that we will grow through biosimilars. Next slide. So this is the evolution over the last year. And what you can see is we've added an additional CHF 1.4 billion on to that estimate so that by 2024, we could overshoot the gap by over CHF 8 billion. And it's -- again, it's a testament, I think, to the breakthrough science that's happening in the world and how much of that we're able to advance at Roche into medicines. Next slide. As Karl mentioned, in addition to 15 blockbusters that we already have available for patients, we have 23 late-stage medicines that have large sales potential. So we haven't even counted some of our smaller medicines in this list, and I think this is part of why we're so excited. And as you can imagine, I talked about an CHF 8 billion increase over the gap by 2024. But many of these medicines will only be launching in 2022, 2023, and so the growth potential for them beyond 2024 is immense. Next slide. Well, I've also talked about our transformation in the past, and this just kind of gives you the context. We've been transforming the company since 2016. And I hope you'll agree with me, this means this is not a flavor of the month. We're now in year 5 of the transformation. And the move here really is to get away from the old traditional ways of doing things in a large organization, in silos, heavy emphasis on functions and heavy emphasis on really top-down management and replacing that with an organization that everywhere in the company is focused on customers, focused on patients, focused on the science or the molecule, putting the org chart and the department kind of behind them and really having that -- the prize in front of them. It means leadership is very different. We get away from a command-and-control mentality, that -- some illusion that at the top we're controlling things, but rather building discipline in at the ground level so that each person is able to have a bigger impact and each team is able to have a bigger impact over time. Next slide, please. So here's one example of what I mean by building discipline in at the ground level. So I shared last year about the sort of experiments we had done of getting rid of conventional budgets. And in fact, we've now eliminated traditional budgets from a majority of our operations around the world. And what we -- now when you get rid of budgets, you can imagine, you could end up with sort of chaos. So you have to replace the formal sort of static, top-down budget model with something else. And what you want is a model that's dynamic, that allows every person, including individual contributors, to understand where their work fits in the mission and what decision they should make each day to deliver. And so this model we call the vital model. The components, for example, the vision, it means do things that make a clear difference for patients and stop any activities that don't improve performance. This means, if you have a team, let's say, of 10 people doing a task this year and next year, you need the same task, you'd assume that you can do that with 8 people. Why is that? Because people are tremendously adaptable. They figure things out. They learn. And so why would you have a static model or a static assumption? Talent flow is really at the heart of our new dynamic leadership model. So often, people are locked up in places based on what they were doing yesterday, based on affiliations with a manager or a department. You have to have a system that allows talent to seamlessly flow to the most important mission opportunity. We replaced top-down accountability, which is so subject to gaming and sort of managing up, to accountability to peers. And believe me, you might be able to fool your boss, but you can't fool your peers. And we just think this is a much healthier approach to great progress and great mission progress. And then finally, lucidity and making things clear to everyone in the organization. We try to treat everyone who works at Roche as an owner, and owners deserve to understand what is the plan, where are things going and what is their part in it. So you'll hear more about this in the future, but I want to just give you a sample of the things we're doing. Next slide. So these are some of the results and some updates on our productivity. Again, the focus for us hasn't been on financial productivity, but rather really unleashing the power of the individuals and small teams across the company. But when you do that well, you deliver tremendous productivity gains. And this metric is arranged in order of when the transformation ways was adopted in these various groups. So for example, in pharma technical, they started in 2016. In that time, they've delivered 55% increase in volume with 1% increase in spend and 19% reduction in head count. I mean that's really amazing. If you look in the U.S. organization, 34% sales growth, head count is down by 19% over that same period. In pharma international, 14% sales growth, head count is down a lesser amount, but they're gearing up for big changes in how they engage with customers that they believe will make every member of their organization more effective. In China, 110% sales growth with a much smaller increase in head count. And then in pharma development, where we're sort of entering a second stage of transformation, they've managed a much grown portfolio, but now we're looking forward and saying, wow, we've got to be able to do a lot more and deliver a lot more. And so more to come on that. Next slide. So through this productivity, we've been able to deliver really solid profitability despite tremendous changes in our portfolio, the arrival of biosimilars, entry into new therapy areas. And I remember people ask for a number of years, "Like how are you going to keep margins up with these new therapy areas requiring new sales forces and things?" Well, the answer is we've been able to take on new therapy areas without just adding additional sales forces. And again, we'll talk more about what we're going to do to continue that work. Next slide. So this is our vision for 2030. I talked about this some last year at a high level, but I want to be more concrete about this. This is something that is, I'd say, tremendously energizing across Roche, across the whole enterprise. Our people are really motivated to deliver this. Roche people do not come to work to be #1 in sales or to deliver a bigger profit. That's just not the thing we get up for. What we're up for is changing the world for patients. And we thought that this is a vision for 2030 that matches kind of where our hearts are and also where we believe -- what we believe is possible and necessary for the world. So we want to double medical advances, defined as doubling our output of new medicines. We want to deliver a bunch of other important progress for patients, and we want to do that at a much lower cost to society. And I hope you'll agree with me that, that is really what the world needs. I mean patients desperately need better medicines. They need new hope. But we need to find how to do that and the life science industry needs to figure out how to do that at a much lower cost. And so this is really what drives us, what energizes us as we come up with new ways of working and new ways of driving benefits. Next slide, please. Let me just talk a little bit about each of these in turn. Next. So in terms of doubling the output of new medicines, you can see here a little bit of historical trends. So we've typically had around 10 new molecules, new medicines in the pipeline. I'm not talking about new indications but NMEs. In the last year or so, we bumped that up to 14, 13 at half year. Look at the outlook for the end of 2020. So this is our best estimate of how many molecules that we'll have either in filing stage or in Phase III where patients are actually being dosed in Phase III studies. We've actually -- we're planning to add 10 NMEs, a number of these have already happened, but 10 by the year-end. So we're taking a rate -- basically doubling our rate of new medicines in late stage. We've got to continue to do this, but I just wanted to give you a taste of what our vision is driving. Next slide, please. What is this going to take? Well, it's going to take new ways of working. It's going to take increased productivity, but it's also going to take a major shift of our investment from areas like manufacturing, M&D, G&A to R&D. We -- again, we think this is the way of the future for the life science industry. I think the -- we have to make the most of each investment dollar if we're really going to drive many new advances for patients at a much lower cost to society. We also have to get more productive at R&D. So it's not one or the other, it's both. Next slide. We also need to continue to focus on external innovation. And I think we've done a really good job of that. In fact, in the last 12 months since our last pharma day, we've brought in 4 new late-stage assets, and this compares historically with between 0 and 1 in most years. So I think excellent progress in terms of bringing in new medicines from the outside. I'm focused here on the late-stage assets, but we've also done the same in early-stage assets, research technologies. And we're continuing to drive digital and personalized health care solutions. Next slide. Now I mentioned other benefits for patients. And this includes things like how do we approach the customers so that we can make sure they are able to deliver the maximum benefit for their patients, but also things like disease management. Next slide. This is basically a long-term shift in how we approach customers. And we began this a couple of years ago in earnest, but I think we're really accelerating now from an idea of a push model where we have lots of people in the field and they're basically kind of on a product-by-product basis to having fewer folks in the field that are much more empowered to deliver what the customers need right across the spectrum of customer needs. Also bringing a lot more digital content and services to bear, that can be updated more in real time, supported by advanced analytics. And we just want to deliver a much better experience for customers. And we've been making progress on this. On the next slide, I'll show you an example. So the customer engagement model in the U.S. is undergoing a profound change. In the past, we had separate teams that were focused on pharmacies, on providers, on payers, on patients. We've now implemented a new structure. Last year, we started with so-called pioneer areas that were about 25% of the nation. Now we have adopted this model across the whole nation. It brings tremendous new power in the local environment to deliver exactly what the patients, what the customers need sort of city by city, region by region. But it also brings a much more cohesive face to the customer so that we can meet their needs sort of on one stop instead of with multiple calls or multiple efforts. And we're the first large pharmaceutical company in the U.S. to really develop this full ecosystem approach. Next slide. We also want to deliver integrated solutions. So it's not just a different way of sort of approaching selling or medical education but also bringing new tools into clinics. And so for example, in oncology, we've been driving this really hard in partnership with companies like Flatiron Health and Foundation Medicine. It starts with access to comprehensive genomic profiling. It's so important, especially for new medicines like Gavreto, like Rozlytrek, that require early personalized diagnosis. Also supporting molecular tumor boards, new clinical decision support platforms that allow physicians and other health care providers to see a comprehensive view of the patient and to make the best possible decisions. It's also vital to have access to molecularly guided treatment options. So we have to make sure that health care systems and payers around the world understand the value of personalized medicine and that these therapies are available in -- yes, in rapid succession from the approvals, which hasn't been the case in the past. And then capturing the clinical outcomes in rural databases so that those can feed back into both R&D and to the next decision for the next patient. Next slide. So finally, I mentioned less cost to society. And this may seem a little counterintuitive, but we actually believe, as a mission-driven company, that we're here to deliver more than just sort of what's good for our company or what's good for patients, but we also need to have a focus on what society needs. And I want to talk about a couple of those. Next slide. So first, we try to always engage in a responsible approach of pricing. We've done this for many years. We have the WHO fair pricing dimension kind of at the heart of how we look at pricing. Next slide. This has resulted in decisions like our decision to price OCREVUS 25% below other therapies in the market, Hemlibra at about a 50% discount, Rozlytrek also at 50% discount. You can also see in terms of price increase behavior in the U.S., on the middle chart, over the last 5 years, we've been basically at or below 0 in terms of net price increases per year. And then most recently, in August, we launched Evrysdi, our new medicine for SMA, we priced at what amounts to a 25% discount to Spinraza in the U.S. over the first 5 years. Next slide. But it's not just about pricing. There's a lot of other ways that we can reduce cost to society. So for example, Actemra and COVID-19, in our Phase III study, we had a trend towards an 8-day reduction in time in hospital for patients treated with Actemra. And we've got a number of ongoing studies to examine this benefit or potential benefit. And I think you could see that reducing hospital stays by over a week could deliver major cost reductions for society. In the case of Venclexta in CLL, Venclexta plus Gazyva, this is a relatively short treatment period that leads to long-term remissions. Again, a great savings to the health care system, not only from a shorter cost of therapy but also less additional care required. And then OCREVUS in MS, really leading the world in reducing disability progression for people with MS. And that disability leads to long-term cost for society. Next slide. So I hope I've given you a flavor of why we're confident that we can deliver on such a bold vision. Bringing it right back to today, this is what our pipeline looks like, sort of one snapshot of it. If you look at what are the readouts that we will have of major medicines and new indications over the next about 2 years, there's actually 27 of these with significant population, significant unmet needs, real opportunities to drive benefits for patients, a lot more benefits for patients and, in many cases, a much lower cost to society. Next slide. So this is the chart that we've used in the past looking at how we move beyond our historical base. And I just want to share with you new pivotal trial starts in 2020. I shared before how many more medicines we will have in Phase III, and this is basically what makes it up. You can see a number of really important oncology medicines but also important medicines for COVID-19, for autoimmune diseases, for neurologic disorders and our port delivery system for ranibizumab with a new indication for diabetic retinopathy. So really exciting stuff, and this is kind of what fuels our confidence in the pipeline. Next slide. So over the course of our sessions today, you're going to see a number of themes. And this is sort of a map to the topics we want to cover. There's actually 21 topics, but you'll find, hopefully, this will be helpful to help you kind of navigate the day as we go through it. Next slide. So this is my last slide. And I just wanted to remind everyone, in July, we reiterated our positive growth outlook for 2020. As you can imagine, that's a heavy lift in a year where we have not only the high impact of biosimilars but also this unanticipated and unprecedented COVID epidemic. And so we're working incredibly hard to deliver on that guidance, but what gives us confidence is that continued uptake of our new medicines, of our launch medicines, continued regulatory progress. And so we look forward to more opportunities to present our results in the future. And with that, I'd like to turn it over to our Head of Global Product Strategy, Teresa Graham.

Great. Thank you so much, Bill. I think we always find it very inspiring to have you walk us through the mission. So thank you. As Bill mentioned, my name is Teresa Graham, and I'm the Head of Global Product Strategy. And it's my pleasure to walk through with you today what I believe to be one of the largest and most diverse portfolios in the pharmaceutical industry today. We can go to the next slide, please. Before we jump in, I just wanted to start with a question that we're frequently getting these days, which is how are we actually working within our local ecosystems and with local health systems to help ensure continuity of care for patients during this really unusual time. These are 3 examples of things that our affiliates around the world are doing in order to make sure that patients continue to get the medicines that they need and have access to the diagnostics that will actually help inform their quality of care. Bill talked about how, as part of our transformation, we're really leaning in to empowering our people to deliver innovative solutions for our patients. And I think there are a couple of great examples on this slide. It's indicative of the kinds of things we want to continue to do and to do more of in the coming years. So next slide, please. Next slide, please, yes. Okay. So as Bill mentioned, we've got a lot to get through today. So why don't we go ahead and jump right in, and we can go ahead to Tecentriq. So Tecentriq has CHF 2 billion in annualized sales with a number of significant growth opportunities ahead. The short- and midterm growth of Tecentriq will largely be driven by the launch of HCC, along with continued growth from the small-cell TNBC and the first-line non-small cell cancer indications outside of the U.S. We are also expecting our neoadjuvant and adjuvant trials to start reading out at the end of the year. But we're also particularly interested in looking at places where CIT combinations might be more effective even though we may already have strong PD-1, PD-L1 products already in place. So for example, think about first-line non-small cell lung cancer. We still only see about a less than 2-year overall survival rate in that patient population. So the question is whether or not a combination of Tecentriq with something like tiragolumab will actually be able to reassess the standard of care in those markets. And we'll talk a little bit more about that later. We go to the next slide, please. And one of the first places we are resetting that standard of care is with HCC. HCC is a global health issue. As you can see, it is the fourth largest cancer in China. And what that means in real terms is that every day, about 1,000 people in China are actually diagnosed with HCC. It's also the fastest rising cause of cancer death in the U.S. So this is clearly a place where a new innovation is needed. And Tecentriq plus Avastin did demonstrate strong survival benefit versus sorafenib in its Phase III trial. As a result of that, all major global guidelines now recommend Tecentriq plus Avastin as the new standard of care in HCC, and it was our first product to receive concomitant registrational review by the U.S., Europe and China. The initial launch is going quite well. Tecentriq and Avastin is now approved in 25 countries, and we're expecting our China and EU approvals in early Q4. HCC overall represents about a $1 billion opportunity for us, and we have a number of ongoing development trials in earlier lines and new combinations to try and see how far we can push the benefit that we can bring to patients with liver cancer. Next slide, please. Tecentriq in early disease is another area of particular focus for us because this is the place where we have the potential to be curative for the largest number of patients. As you know, early line also represents a significant commercial opportunity as it's often a place where you have the largest number of patients and patients do tend to stay on therapy for much longer than they do in the metastatic setting. We have a number of trials across all tumor types with Tecentriq, and we are also investing heavily in technology for future clinical development programs, including ctDNA and digital pathology. Our next data to read out here will be the adjuvant non-small cell lung cancer data, which is expected at the end of this year. To the next slide, please. Now you'll hear a lot more about tiragolumab from Levi in his section, but I did want to start with just giving you a little bit of an overview of where we think this molecule may fit in. This tira program is the first program with randomized data showing benefit on top of a PD-L1 therapy. It's based on the strength of our Phase II data in non-small cell lung cancer as well as our Phase I basket trials that we've initiated, 6 randomized trials of tira plus Tecentriq. Now SKYSCRAPER-01, 02 and 04 probably look quite familiar to you. But what may look less familiar is the 3 trials with the orange arrows next to those. Those are new trials. SKYSCAPER-03 is looking at stage 3 unresectable non-small cell lung cancer versus -- head-to-head against durva. And SKYSCRAPER-08 is looking at esophageal cancer in the first line, specifically looking at how that disease is treated in China. And SKYSCRAPER-07 is looking to go into locally advanced esophageal cancer. We also have a number of exploratory Phase Ibs in several other tumor types, such as liver and bladder. What I do want to leave you with before you hear from Levi is that we believe we have a very strong strategy for TIGIT that we are very diligently following the science but that we are acting with a lot of urgency here. We believe there could potentially be some great benefit with Tecentriq-tira combinations, and we want to get that to patients as quickly as we possibly can. So if we go to the next slide, please. Another evolving area for us is the area of oncogenic driver mutations. As we all know, cancer therapy is moving to a biology-driven approach. And we've invested broadly into several mutations in the lung and pan-tumor space. You can see here that's primarily ALK, MET, ROS1 and NTRK. We're following the path that we established with Alecensa, which has turned into a $1 billion opportunity for us. These trials typically have high overall response rates and a very durable benefit of therapy. You can see that Alecensa has almost 3 years worth of durable efficacy compared to just about 8 months in the same setting for PD-1 and PD-L1 drugs. Obviously, the NGS testing rate is quite important to realizing the full breadth of this opportunity. And we are happy to see that those testing rates do appear to be on the rise. Right now, in the U.S., about 60% of patients with lung disease currently get NGS tested. But we would expect that to expand as we see new technologies and therapeutics coming on to the market. Just to give you a little bit of perspective, currently, there are 10 targeted mutations that actually have a therapy that makes them actionable. And we would expect that to grow to 20 by 2024. So the more actionable mutations you have, the more likely a physician is to actually test looking for them to provide benefit to their patients. In addition, things like the FML liquid biopsy, which was just FDA approved, will allow us to test patients that historically have not been able to be tested due to lack of tissue. These trials are typically lean and often involve innovative uses of real-world data. And we are committed to exploring this opportunity in pan-tumor across multiple programs. Just calling out one. TAPISTRY is a basket trial, where we will NSG screen over 40,000 patients, dividing them into biomarker-defined arms to be treated with 8 Roche therapies. We believe that we as Roche are very uniquely positioned to take advantage of the driver mutation opportunity given our long-standing commitment and experience in R&D, our commitment to PHC. This really is a one Roche opportunity involving Foundation Medicine, Flatiron and Navify as well as the pharmaceutical group and our commercial experience and footprint, which allows us to very economically market these products going forward. This is certainly not an area where we would expect to see fast growth, but it is one that we think is very important and worth doing over the long term to bring very impressive, very impressive returns to patients. So I'd like to go to the next slide, please. So just to talk about Alecensa in a little bit more detail. I have to admit that I'm a little partial to Alecensa only because, over the last couple of years, I've had the opportunity to meet a number of patients whose lives have been really changed by this drug. We have about CHF 1 billion in annualized sales for Alecensa, and we are firmly the market leader in ALK-positive mutations with over 70% market share in the U.S., EU and Japan. China is driving significant further growth in Alecensa, following its NRDL reimbursement. Just, again, to put that in a little bit of perspective, in the first half of this year, we saw 5,000 patients go on to Alecensa in China. We are very interested in exploring Alecensa in early disease, seeing how we can expand testing to more patients and looking at tumor-agnostic development. And so we're looking forward to see how we can continue to address the unmet need for these patients. Go to the next slide, please. Switching gears into breast. We have recently received the Phesgo approval in the U.S. This is our Herceptin plus Perjeta fixed-dose combination. This brings the administration time for H+P down from as high as 7.5 hours down to 20 to 38 minutes. This is not only a great efficiency benefit for our customers, it also is a great convenience benefit for our patients. So it's quite unsurprising that 85% of patients do prefer the subdermal route of administration versus standard IV. It's still quite early days for the launch, but we are encouraged by what we're seeing and particularly encouraged that some of our early adopting customers are beginning to see an acceleration in conversion. So more to come on that in Levi's section. Next slide. So sticking in breast cancer, we are -- again, you'll see a lot more about both the SERD and PI3 kinase programs from Levi in his section, but this is an area of significant high unmet need in a very large patient population. As many of you know, 65% of breast cancer patients HER2 -- are HR-positive, HER2-negative, about 3x the size of the HER2 population. Currently, these patients are treated with endocrine therapy, including fulvestrant and aromatase inhibitors. Until -- that's standard of care until patients have develop resistance. Based on our well-tolerated safety profile, the strong efficacy that we saw with our SERD program in early trials, we are seeking to replace endocrine therapy as the standard of care across all lines, moving into monotherapy in later lines. Our PI3 kinase program is aiming to help the 40% of patients who have a positive PI3K mutation. And again, it is highly differentiated by its abilities to combine at full doses and at Phase III has been initiated in combination with standard of care. I want to leave you with the fact that the high potency and high combinability of both of these molecules make them potentially very compelling and best in class and could be truly transformational for some of these patients. So we're very eager to see how these play out in the clinic. Switching gears over to hematology on the next slide. Hematology is another place where there is a tremendous amount of market activity and where we are well positioned to build on our leadership. We currently have 5 marketed molecules in hematology and about another 12 in the clinic. We'll start here with Polivy. As you know, Polivy had rapid uptake in relapsing/remitting DLBCL, being the only therapy to show strong overall survival benefit relative to standard of care. Compared to 2 CAR-Ts, it was well tolerated. And the fact that it is off the shelf is incredibly important because you can deliver a very efficacious medicine to patients very quickly, which is important in this very aggressive disease. We are currently awaiting the POLARIX data readout in first-line DLBCL, which is expected to happen in 2021. First-line DLBCL is a very large population, 3x the size of second line, but more importantly, it's an opportunity that we have to actually be curative for these patients. When you look at the historical data, our early data in first-line DLBCL with Polivy compares very favorably from a complete response perspective. So we're encouraged in what we might see with this trial. And I think it's also important to note that POLARIX is the only Phase III trial in this patient population that is non-biomarker driven. So it gives us an opportunity to help an awful lot of patients. Moving on to our bispecific portfolio. Mosun and glofit, very well-known to all of you. Both of these molecules are differentiated by structure as well as their clinical properties. And so we've taken this opportunity to actually really follow the science and see where we believe each one of these molecules might have the greatest impact to patients. And it also gives us multiple first-in-class bispecific potential. So in relapsing and remitting follicular, where the reduction of chemo is really the most important thing to patients, based on its well-tolerated safety profile, we have chosen to put mosun into this area. We have received breakthrough designation in third-line-plus follicular, and we are actively talking to the FDA about options for accelerated approval. We have also started a Phase III safety run-in in second-line -- second-line plus follicular. Within relapsing/remitting DLBCL, which is a highly aggressive disease, the increased response rate and durable efficacy that we saw with glofit we think makes this a very good option for these patients. A Phase III safety run-in has also been initiated in this area in combination with GemOx. When it comes to first-line DLBCL, where we already have a very high efficacy bar established, we actually haven't picked a molecule here yet. We have chemo-free regimens being explored in Phase Ibs for both molecules and in combination with drugs like Polivy. So while this is a rapidly evolving space, we do believe that we are the furthest advanced in our bispecific portfolio with over 1,000 patients dosed, a number of Phase III randomized trials being initiated in the largest patient population. And we are furthest ahead in our combination work. So you will hear more about this from Levi, but I think a couple of very exciting options for patients. Moving on to Venclexta on the next slide. Venclexta is a drug that we don't talk a whole bunch about usually, but we really should because it's a pretty tremendous therapy with over $1 billion in annualized sales, primarily driven by CLL and AML. The Ven plus Gazyva combination in first-line CLL, as Bill was mentioning earlier, has that fixed-dose chemo-free regimen with that high MRD-negative response, which, as Bill pointed out, actually means that patients don't have to be on therapy long term, which prevents them from potential exposure to long-term side effects but also provide savings to health systems who only have to pay for 1 year of treatment versus 5. We've also seen strong uptake in our first-line AML indication where Venclexta was the first treatment approved in over 20 years. We currently have about 40% market share in first-line unfit patients. And we're also looking forward to see the results of our multiple myeloma trial, which is currently underway in the 20% of patients with t11:14 translocation. So more to come shortly on Venclexta. And finally, no conversation about hematology would be complete without talking about Hemlibra. So if we could go to the next slide. Hemlibra continues to be a transformational advance for hemophilia patients, regardless of inhibitor status, age or dosing regimen. It's currently used in over 70% of inhibitor patients at all major markets. The WFH guidelines recognize the benefit that Hemlibra has brought to patients. We continue to see an increase in patients with zero bleeds in our HAVEN long-term extension studies, going from 60% at 24 weeks to over 85% at 72 weeks. With these kinds of results, it's unsurprising that in the U.S., we currently have nearly 25% of total market share of both inhibitors and non-inhibitors. In addition to the clinical efficacy and safety profile, we are also very encouraged by the fact that the vast majority of the patients are actually very happy with the Hemlibra therapy. Our EmiPref study asked patients what they thought of their current and former treatment. And I'm very pleased to say that 95% of patients surveyed preferred Hemlibra to their prior therapy. Of the 5% who didn't, they actually had no preference. No patients actually preferred their prior treatment. We believe that Hemlibra is relevant for about 85% of the hemophilia population. These are patients who are using prophylaxis or who regularly have bleeds that they treat on demand. The remaining 15% of the hemophilia population is too mild for prophylaxis treatment. Looking forward into the future, we're eager to see what gene therapy might bring to patients, particularly our 2 Spark programs. Based on what we know today, we believe that about 20% of the hemophilia population will be eligible for gene therapy. And we know from recent communications from the FDA that reliability, predictability and durability are going to be very important in considering bringing these therapies to market. So when you look at the totality of the data that we have in Hemlibra, in addition to the patient experience that we provide, we believe that we will be the cornerstone of hemophilia treatment for many, many years to come. So lots of great things happening with Hemlibra. So moving on to our next segment. We're going to spend a little bit of time here in ophthalmology. Now Cristin will go over ophthalmology in a lot more detail in her section, but I did want to share with you some additional information on port delivery system. So if we can go to the next slide. So port delivery has the potential to improve real-world outcomes with its innovative twice-yearly dosing regimen. And I think all of us know that despite the advances that have been made in IVT treatment, patients just simply aren't going back regularly for their injections. And that means in the real world, we see vision loss. In fact, only 50% of patients can be extended to Q3M dosing with current IVT therapies. However, with PDS, we can see that nearly all patients can be maintained on twice-yearly dosing, which dramatically improves patient compliance and importantly, real-world outcomes in the preservation of sight. The PDS implant is a onetime 30-minute inpatient -- outpatient procedure to implant a permanent refillable ocular implant, which is about the size of a grain of rice. And the refill exchange happens twice yearly in office and is very, very similar to what happens with the typical IVT injection. It's important to note that the needle assembly and the port delivery device can only be refilled with the proprietary formulation of Lucentis. No other molecules or biosimilars can be used in this treatment. Moving forward, next slide. In ARCHWAY, we saw that, that 2-year dosing -- every 6-month dosing with PDS was not only non-inferior to Lucentis but also showed equivalent vision. We saw strong treatment durability and, unsurprisingly, a high degree of patient preference as well, over 90% of patients preferring PDS to regular intravitreal injections. The insertion and refill exchange were well tolerated and have a favorable risk-benefit profile. So moving to the next slide. We are now currently -- all gears are rolling for a purposeful launch with PDS globally. Important to us is making sure that we have a safe and consistent experience, both with implantation and with refill. And so we're investing quite a bit in training. And here's where Bill talked about sort of the advances that we hope to bring with technology. And I think there are a couple of really interesting things that the PDS team is doing here. First, we've invested in virtual reality training, which will help prepare physicians for actually doing the PDS implant and the refills. We are investing in a very targeted surgical device liaison team globally to support on-site training and facilitate education and discussion. And we have a great example here of an integrated solution with myVision tracker, which is actually a remote vision monitoring application. So this is right on someone's smartphone, and it involves a series of tests that they can take to actually test to see whether or not they're having vision loss in between their injections. If they do experience degradation in vision, an alert is sent to their doctor, and they can be called back in for treatment. So this is a really great way to make sure that we're ensuring that patients are getting the right level of care in real time. In fact, this is such a neat application that during the height of the COVID-19 crisis where we had a number of institutions who were looking to keep people out of hospitals who didn't need to be there, they actually asked to use the myVision tracker software in order to ensure that only the patients who truly needed to come in for their injections were coming in. So looking very much forward to the PDS launch, and I'm sure Cristin will have more to tell us in a little bit. Moving on to the next slide. So last but not least, we'll talk about neuroscience. Paulo will talk in more detail about all of these programs, but I wanted to give you a quick heads up on where we are with some of our in-market assets. So first things first, let's start with OCREVUS in multiple sclerosis. MS is a progressive disease, and that progression starts early and can lead to long-term disability. This is particularly impactful when you think about the fact that most people diagnosed with MS are relatively young, and MS is one of the leading causes of disability among young adults. So from the moment of diagnosis, the chief goal of any physician and patient is to prevent progression. OCREVUS is the first and only disease-modifying therapy proven to impact disease activity in both RMS and PPMs with consistent impact on progression across a broad range of endpoints and biomarkers. This has resulted in having the broadest label in the U.S., including the only therapy that is approved in PPMS, which does represent about 35% of our U.S. sales. Today, we have over 170,000 patients who have been treated with OCREVUS, which continues to demonstrate a consistent and favorable risk-benefit profile, with more than 7 years of safety data on hand. So with a profile like this, it's quite unsurprising that even though there are more than 15 available therapies in the U.S., OCREVUS remains #1 for patients who are seeking to either start or switch their disease-modifying therapy. We can go to the next slide, please. One of the things that patients actually like most about OCREVUS is the extremely convenient twice-yearly dosing regimen. And you can see here in a real-world claims analysis that OCREVUS patients actually have consistently better persistence and adherence after a year. For someone who spent most of their career in the chronic therapy space, this is pretty amazing persistence and compliance when you look at it. And it's 4 to 7x better than what we see with our injectables in our world in the same category. So it's clear that there's a strong patient preference for a regimen that is administered just twice a year. If you go to the next slide. We continue to invest to improve the patient experience for patients on OCREVUS. Shorter infusion has been launched in the EMA, and we are expecting FDA approval before the end of the year. That will reduce the infusion time down to 2 hours. We also have really made it a point to protect access for OCREVUS and make sure that the most number of patients can benefit from this extraordinary therapy. I think that our commitment to that was illustrated with our launch price of OCREVUS at $65,000 a year. And we have not taken any price increases since we launched OCREVUS. We are currently priced at about 32% below the market average in the U.S. And it's that responsible approach to pricing as well as the overall clinical profile of OCREVUS that has allowed us to both -- to achieve and maintain broad access for OCREVUS, including in first line. And finally, we continue to invest in expansion of infusion options for patients, and as of today, more than 50% of our infusions actually are occurring outside of the hospital. Go to the next slide, please. So Enspryng is one of our most recently approved molecules. It is the first and only subcutaneous treatment for NMO. NMO is a very progressive disease, very aggressive. Over half of patients are blind or require a wheelchair within 5 years of diagnosis. And despite the fact that we've had a number of new therapies approved over the last year, the unmet need for NMO patients for an efficacious and convenient therapy remains quite high. And Enspryng delivers a highly effective, best-in-class clinical profile that demonstrates a reduction in relapses, which are what drive progression in this disease state. It also has a flexible and convenient dosing schedule and has been studied as both monotherapy and in combination with immunosuppressants. It's actually quite important because a lot of these patients, over 50% of them are treated with steroids and immunosuppressants, and so being able to add a therapy on top of provides a great option for patients. We're still very much in the early days of our launch with Enspryng, but we're encouraged with what we see. We're currently approved in 4 countries and have filed in more than 50 others moving forward. So Evrysdi is another one of our very recently and long-awaited approved molecules. It really does have the potential to be the treatment of choice in SMA for a wide variety of reasons: first and foremost, best-in-class efficacy. The durability that we see -- the durable increases in SMN protein lead to best-in-class clinical outcomes. And we have a very good safety profile from all of our clinical trials. None withdrew treatment due -- I'm sorry, none withdrew from treatment due to treatment-related side effects. We have a trial that was -- a trial program that was designed to show meaningful benefit in a very broad population, and we are highly differentiated. It was a very simple, a very simple oral administration. And that means that it can be administered at home and could be used by all patients regardless of [ severity of disease ]. So if we move to the next slide. Prior to Evrysdi, therapies have really only been tested in a very limited patient population, including primarily younger patients and those without complications. The Evrysdi clinical trial program really sought to explore Evrysdi's efficacy in the widest possible patient populations to really make sure that we were bringing the potential of this amazing therapy to as many patients as possible. Our trials cover presymptomatic to older patients, treatment-naive and pretreated and those with broad disease severity and functional ability. So what are we seeing in the real world? So if we go to the next slide. While it is still early days, we were just approved on August 7, we are highly encouraged with what we're seeing from the initial results of the Evrysdi launch. We were able to get out to the market fast, enabled by a very well-executed, remote, digitally-driven education campaign by our field. And today, we see broad uptake against all segments in the first month of approval. We see patients with all types of SMA being prescribed Evrysdi. In fact, about 25% of those patients have type 1. We're seeing both treatment-naive and switch patients. We're seeing about 2/3 of our patients having prior experience with either Spinraza or Zolgensma. I think it is interesting to note that at least 2 payers in the U.S. have made provision for Zolgensma patients under certain circumstances to actually get Evrysdi. And we're seeing uptake in a broad range of patients, from infants as young as 5 months old to adults well over 70. We are supporting that access through responsible pricing. As Bill mentioned, we've priced Evrysdi with a 25% discount to current standard of care over 5 years. You'll recall that Evrysdi is a weight-based dosing, and so that is for patients who are over 20 kilograms, which is about 6 years old. Infants are considerably cheaper. It's early days, but I think, as I said, we're super encouraged in what we're seeing. And I think one of the things that I personally am proud of is that our first commercial patient only had to wait 9 days from prescription to actually having therapy ready to start at home. And that is just an incredible achievement when you think about how long these patients typically would have had to wait to start treatment. So just lots to be looking forward to here with Evrysdi and look forward to bringing you updates in the future. So before we hand it back to Karl and head to break, if we could go to the next slide. Just wanted to give you a little bit of further information about happen -- what is happening in China. We frequently talk about China in relation to our larger disease areas. But I think it is important to note that rare disease presents a very significant opportunity in China, and we are well established with our leading rare diseases there. China was the #1 enrolling country for FIREFISH, and we have completed regulatory submission with approval expected in the first half of next year. Enspryng was accepted in China with priority review. And the NRDL negotiations for the inhibitor population in China are expected to begin in 2020 for Hemlibra with the regulatory submissions completed for non-inhibitor already. And we expect that label expansion to happen for Hemlibra in the first half of 2021. If we can move to the next slide. We are also noticing that the Chinese approval processes are moving so much faster than they really ever had before. Back in the day, you would expect it to take a couple of years from the launch of an innovative therapy in the U.S. to actually reach China. But in the last 5 years, we've seen that shrink down to something more like 9 to 12 months from U.S. approval to Chinese approval. And in fact, we would expect that the HCC approval for Avastin plus Tecentriq happens within 5 to 6 months of U.S. approval. This means that our commercial teams are increasingly thinking about China in that first wave of launches and very actively considering what we need to do within our development and our commercialization programs to ensure that we are as successful as possible in the Chinese market. You can also see that the NRDL negotiations for 2020 have kicked off and will include Kadycla, Tecentriq and Hemlibra. In the past, when we have submitted other drugs for NRDL listing, we've seen between 3 and 5x volume growth within the first 2 years of listing. So potentially, there's opportunity to help a lot of patients in China with 3 new innovative therapies. And finally, my last slide. And Bill showed you this slide already, but this is what keeps us busy all day. Again, I think we have -- as Bill mentioned, we have one of the most active and robust pipelines in the industry today. And every time we look at this, we are consistently looking for opportunities to commercialize in ways that are more innovative and more efficient than we ever have before because we know our success is really hinging on making sure that we can fund our pipeline as aggressively as possible. So I'm going to hand it back over to Karl and look forward to hearing from Levi in a little bit.

Thanks a lot, Teresa. Thanks a lot, Bill. I mean there's really a lot of things ongoing at the moment in Roche in terms of strategy, in terms of pipeline. So keep tuned. And with this one, we planned on 5 minutes break before we go into the development part. So we reconvene here 7 past and looking forward to -- we have about 550 people online at the moment. So that is also -- thanks for your interest in that, and it's also a testimony of the strong interest in the Roche case. See you again in 6 past -- or 7 past. Thank you. [Break]

So welcome back. And we wanted to get into the second part of the Innovation Day with Levi. Levi, the floor is yours.

Thank you, Karl.

Joining us actually from San Francisco. What is your time now, Levi? I mean only that the people really see that you give everything for the company, waking up at 3:00, 4:00 in the night. What is your time now?

Well, it's 6 or 7 a.m. But you're right, we were up at 3 a.m.

Okay. Good. Please, the floor is yours.

Well, thank you, Karl. Hi, everybody. I'm very pleased to have the opportunity to kick off today's pipeline presentations. Next slide. So one key approach to achieving the ambitious vision that you heard about from Bill involves, of course, augmenting our pipeline, and we've taken a first step in that regard, as you heard from both Bill and Teresa. And for us, that's resulted in one of the most significant pipeline advances ever for a single year. But of course, the other key element is to ensure that our augmented pipeline contains some potentially transformative medicines. So next slide. So I'll provide a few examples of our progress in this area for oncology. And then I'll turn it over to Paulo and others to talk about the rest of the pipeline. So next slide. Great. So Teresa mentioned that we have moved 2 CD20/CD3 bispecific antibodies into late-stage development for non-Hodgkin's lymphoma. And so I'll tell you a little bit more detail about both of those. So the first one is called glofitamab. And what you can see here is some updated results from the Phase I dose-escalation study in relapsed/refractory aggressive non-Hodgkin's lymphoma. And in diffuse large B cell lymphoma patients who had received dosing of 10 milligrams or greater, the overall response rate was about 49%, and the complete response rate was just over 34%. And you can see the median duration of response was not reached after over 10 months of follow-up. So also, the cytokine release syndrome that was seen in these cohorts overall was manageable, really confined to the first cycle. And based on these data, we believe that there's potential for early filing of glofitamab for use in relapsed and refractory DLBCL in 2022. And in addition to the relapsed/refractory setting, our current program for glofitamab includes a Phase III trial with GemOx in the second-line setting. And as you heard, the safety run-in for that is currently ongoing. And we're also exploring various other potential DLBCL combinations, which include regimens like R-CHOP and Polivy. But also, on the next slide -- yes. So we're looking at several other options, both within and outside of our portfolio. And the data shown on this slide are really meant to be illustrative of the combinational -- combinatorial potential for glofitamab. It's still early days, so no conclusion should be drawn from these specific examples. But to our knowledge, we're the only company with 6 in-house hematology assets as well as multiple cancer immunotherapy assets, such as Tecentriq and tiragolumab. So we have numerous options that we're currently exploring. And ultimate goal here is to develop chemo-free regimens for these patients, but there's a lot more development work needed to get that done. Next slide. So our second bispecific antibody is called mosunetuzumab. And here, you can see pooled dosing data from third-line and greater follicular lymphoma. And in these patients, you can see that the overall response rate was 62.7%, and the complete response rate was just over 43%. And of those complete responders, nearly 83% remain in remission for up to 26 months now off treatment. And in this setting, mosunetuzumab produces a rather mild, if you will, CRS picture. It consisted predominantly of grade 1 fever, and this was seen in about 28.9% of patients. But only 1.1% of CRS events reached grade 3 or higher for mosunetuzumab. And in June, mosunetuzumab was granted breakthrough therapy designation by the FDA for relapse and refractory follicular lymphoma based on these data, which raises the possibility of an early filing in 2021. And we've also initiated a Phase III safety run-in for the combination of mosunetuzumab and lenalidomide in the relapsed/refractory follicular lymphoma setting. And as was the case with glofitamab, our program includes a number of additional exploratory combination studies. And finally, at ASH this year, we will present the first Phase I data of our subcutaneous formulation of mosunetuzumab. Next slide, please. So the other highlight I'll mention from our heme/onc franchise is Venclexta. And here, you can see the results from our VIALE-A trial of venetoclax plus azacitidine, and this was in first-line unfit AML setting. And the addition of venetoclax to azacitidine improved overall survival with a hazard ratio of 0.66. And so these results supported filing of this regimen in both the U.S. and the EU. And moreover, we've now initiated or plan to initiate several additional Phase III studies of Venclexta in various indications. And examples include the VIALE-M study, which is in first-line fit AML. And here, the hypothesis is that adding venetoclax to azacitidine compared to best supportive care could be beneficial as a maintenance therapy for patients who are in first remission after conventional chemotherapy. And also, we've kicked off the CristaLLo study in first-line fit CLL patients that started in Q2 of this year. And here, the primary endpoint will be the MRD response rate at month 15. And we're planning additional studies with Venclexta in myelodysplastic syndrome as well as in AML. So exciting times for Venclexta. Next slide, please. So now I'm going to shift gears to our solid tumor portfolio. And I'll start by talking about breast cancer. Next slide. Let me start with triple-negative breast cancer and Tecentriq. And here, I'll begin first by reiterating our confidence in the activity of Tecentriq in this setting. The combination of Tecentriq and nab-paclitaxel, which -- the data from which is shown on the left, remains a new standard of care in first-line PD-L1 positive triple-negative breast cancer. And that's based on the robust overall survival data that was seen in the IMpassion130 study. Now recently, we had a negative result in our IMpassion131 trial, which studied paclitaxel instead of nab-paclitaxel as the chemo backbone. And those data, of course, were disappointing. And it may turn out -- we're not exactly sure, but it may turn out that maybe it was concomitant steroid use which was done with paclitaxel, maybe that was problematic or maybe the chemo backbone itself could be important. We're still sorting that out. But we remain confident in Tecentriq's activity in this setting. And this confidence is, of course, buttressed by the positive neoadjuvant triple-negative breast cancer data for Tecentriq that we saw in our IMpassion031 study. And those results will be presented at ESMO as well the results of IMpassion131. So here, you can also see a summary of other TNBC studies of various types. The adjuvant -- the other adjuvant studies in this setting will read out after 2021. And I'll also note that we expect to present data for the triple-negative breast cancer arm of the IPATUnity130 study of our AKT inhibitor, ipatasertib, at a meeting later this year. Next slide. So now I'll turn to our efforts in hormone receptor-positive breast cancer. And here, I'm going to show 2 highlights. The first is that, as Teresa mentioned, we're very excited about our oral SERD, RG6171, which may have -- we think it may have best-in-class potential in this disease. Our SERD, from a biochemical standpoint is between 5 and 15-fold more potent than several well-known competitors. And the waterfall plots that you see on the right here shows some initial efficacy data, both as a single agent, which includes efficacy in the presence of ESR 1 mutations; as well as with palbociclib, the CDK4/6 inhibitor. And this is the first SERD to show this type of combo data. And our SERD was well tolerated at doses up to 100 milligrams per day. No patients withdrew or reduced their dose due to adverse effects. But our PK/PD data support dose expansion at a lower dose, so 30 milligrams per day. And that's important because at that dose, we've seen no bradycardia events. And even the events that we did see at the higher dose were all grade 1. So next slide. So we think of our SERD as a third-generation SERD, and that's compared to the first generation, which is exemplified by tamoxifen, which is confounded by its partial agonism. And then the second generation is exemplified by fulvestrant, and it's an ER degrader but it has known bioavailability challenges. And so our SERD, RG6171, is a third generation based on both improved bioavailability and a novel mechanism of action. It seems to work by both inhibiting and immobilizing the estrogen receptor when bound to DNA, and that's followed subsequently by degradation. And so together, that mechanism suppresses the estrogen receptor transcriptional output, which, of course, has long been postulated as needed for optimal efficacy against the estrogen receptor. So altogether, based on this aggregate scientific and clinical rationale, we've launched a robust development program for our SERD, and that includes -- as summarized on the right side, that include a combination with palbociclib in frontline metastatic ER-positive breast cancer, a Phase II neoadjuvant study; a Phase III adjuvant study, which is in the works; and finally, a pivotal Phase II study in later lines of metastatic HR-positive disease. And the results from that would be expected in 2022. Next slide. So the second highlight in hormone positive breast cancer is our PI3 kinase inhibitor, which Teresa also mentioned. And we believe here that this could as well have best-in-class properties. And so brief background, the alpha subunit of PI3 kinase is commonly mutated, oncogenic mutations in breast cancer. And this is, of course, now a clinically validated target. However, existing PI3 kinase inhibitors still have toxicity concerns, and that could be particularly problematic when pursuing combinations with other targeted agents of interest in breast cancer and other malignancies. So we have developed a next-generation PI3 kinase inhibitor. And that molecule has enhanced potency and selectivity towards the alpha subunit, and it has the ability to selectively degrade the mutant PI3 kinase isoform, and we've seen this in preclinical models. So these characteristics may yield an improved therapeutic window as evidenced by the waterfall plots that are shown on the right. And these data are from patients who were treated with full doses of GDC-0077, together with full dose palbociclib and letrozole. And so there was both good safety data from this combination, low discontinuation rate, which is important and actually noteworthy. And there was promising efficacy data in this heavily pretreated population. So based on these results, we've launched a Phase III trial of GDC-0077 together with palbociclib and fulvestrant, and we compare that to placebo plus palbo and fulvestrant in hormone receptor-positive, first-line metastatic breast cancer. And we started that study in the first quarter of this year. So together, there are some exciting developments in our pipeline for hormone receptor-positive breast cancer. Next slide, please. Great. So now I'm going to turn to our lung cancer programs. So as you know and as you heard from Teresa, lung cancer management has evolved towards what we like to call a personalized health care or PHC framework. And that's happened for lung cancer perhaps more rapidly than any other malignancy. So this is, of course, long been evident in the targeted therapy space where actionable driver mutations offer an increasingly complex array of therapeutic choices, but it's also relevant to cancer immunotherapy. So our lung cancer strategy is twofold: first of all, follow the science to develop rational therapeutics; and second, leverage our growing PHC investments to develop integrated solutions that direct our therapies to those patients most likely to benefit. Next slide. So first, let me start in the IO space by briefly updating you on the progress of our adjuvant studies. And as you can see, our adjuvant program spans multiple solid tumors, but I'll focus specifically on lung cancer shown in the middle here. Both IMpower010, which is our adjuvant study of Tecentriq; and IMpower030, which is our neoadjuvant study of the same, for both of those, we expect initial data some time in 2021. So next year will be an important one for Tecentriq in lung cancer. Next slide. But of course, one of the big questions in cancer immunotherapy in general is whether additional benefit can be gleaned through IO-IO combinations. And toward that end, we remain enthusiastic about the data we presented at ASCO on our TIGIT inhibitor, tiragolumab. And as shown on the right, we saw significant increases in both response rates and progression-free survival in the PD-L1-high subgroup of non-small cell lung cancer when tiragolumab was added to Tecentriq. So based on these results, we initiated 3 Phase III trials with tiragolumab and Tecentriq in lung cancer this year. And also, we'll see an update of the CITYSCAPE Phase II data, including overall survival in 2021. And during next year, we also plan to present biomarker data from CITYSCAPE at a meeting. Actually, that will be later this year. Next slide. Okay. So now we'll turn to targeted therapy and the expanding personalized health care platform we're assembling as part of our lung cancer franchise. And so here, I'll mention 2 recent additions. The first is Gavreto, our selective RET inhibitor, which was in-licensed from Blueprint and just approved in RET fusion-positive non-small cell lung cancer. And Gavreto is a potent, selective, oral and brain-penetrant small molecule inhibitor. RET fusions are detected in 1% to 2% of non-small cell lung cancer. And of those patients, 40% develop brain metastases. And as you can see on the right, Gavreto has achieved an overall response rate of 70% in the treatment-naive setting, which includes an 11% complete response rate. And the overall response rate in patients with brain -- with CNS disease is 56%. So we have a global confirmatory Phase III trial ongoing, and we filed these data in the EU as well. Next slide. The second addition to our targeted therapy repertoire in lung cancer is our KRAS G12C inhibitor. I'm sure many of you know that KRAS can be thought of as the godfather of all oncogenes. It's commonly activated in many cancer types, including lung cancer. But for a long time, of course, efforts to drug this oncoprotein failed. However, a few years ago, Kevan Shokat and others at UCSF showed that one form of mutant RAS, the G12C mutation, was amenable to inhibition through a covalent mechanism because of properties germane to the cysteine residue that's formed as a result of that mutation. So the KRAS G12C mutation, which is particularly prevalent in lung and colorectal cancers, has been pursued in terms of small molecule inhibitors by us and many others. So our molecule just called GDC-6036 really checks all the preclinical boxes. It's selectively potent against KRAS G12C mutant cell lines in vitro. And indeed, as you can see on the right here, it actually looks like it could even be superior to competitive molecule in this regard, at least in vitro. And it also induces regressions in mouse models of KRAS G12C mutant tumors. So Phase I studies of our molecule were initiated earlier this year. And ultimately, our goal is to determine the most optimal therapeutic combinations that should be anchored by a KRAS G12C inhibitor. And we feel that our overall portfolio is very well positioned for such investigations, not only in lung cancer, but elsewhere as well. Next slide. So I'll conclude the lung cancer portion by highlighting another PHC advance by the Roche group. And this particular advance is in the area of circulating tumor DNA, also known as liquid biopsies. It turns out that upwards of 30% of patients may have insufficient tumor tissue available for standard genomic studies. But recently, the FDA-approved the FoundationOne liquid companion diagnostics test from Foundation Medicine, which allows robust mutational profiling of the fragments of tumor DNA that circulate in the blood of cancer patients. So this test can be performed on a tube of blood without the need for tissue biopsy. But this also allows us to conduct pivotal trials that use liquid biopsies as the primary means of identifying patients amenable to various targeted therapies and immunotherapies. And one such study is BFAST, and this is essentially a Phase III platform study. And an initial cohort from the BFAST trial was used to successfully identify ALK rearrangements in the blood and show that those patients were suitable for treatment with Alecensa, our ALK inhibitor, which you heard about from Teresa. So ongoing cohorts are assessing mutational load in the blood to identify patients likely to benefit from Tecentriq as well as other settings. But overall, our lung cancer franchise remains an anchor for our portfolio overall, but also our personalized health care strategy. Next slide. So I'm going to provide a few brief notes from other areas of oncology before handing it off to Paulo. So next slide. First, let me give a mention of ipatasertib in metastatic castrate-resistant prostate cancer. So now this slide shows the Phase II data from this molecule because the Phase III results have not yet been presented. But our Phase III IPATential150 study met its co-primary endpoint of radiographic progression-free survival in metastatic castrate-resistant prostate cancer patients whose tumors harbor PTEN loss as assessed by IHC. So the overall survival follow-up now is continuing until the next planned interim analysis. So we'll present these results at an upcoming meeting. But certainly, this is an important result in the prostate cancer setting. Next slide. The second highlight is tiragolumab, our TIGIT inhibitor, now in esophageal cancer. So we have initiated 2 Phase III studies of our anti-TIGIT antibody in locally advanced esophageal cancer and esophageal squamous cancer. The preliminary safety and efficacy data from this indication and the rationale for it will be presented at an upcoming meeting. And global development here will have a heightened focus on Asia in general and China in particular. So this is an expansion of our tiragolumab program outside of lung cancer. Next slide. So the third brief highlight pertains to Gavreto again, but this time in thyroid cancer. So RET mutations are common in various types of thyroid cancers. So that includes 90% of patients with so-called medullary thyroid cancer, but also 10% to 20% of patients with a more common form of papillary thyroid cancer. So 10% to 20% of those patients have RET fusions, which are analogous to what's seen in lung cancer. But Gavreto shows a robust overall response rate, a 74% response rate in medullary thyroid cancer, 60% response rate in pretreated patients, but also a 91% response rate in papillary thyroid cancer. So additional registrational data for medullary thyroid cancer will be presented at ESMO. And a confirmatory Phase III trial will be starting soon. And these thyroid data for Gavreto are currently under priority review. Next slide, please. So finally, I'll just mention our combination of targeted therapy and immunotherapy in BRAF-mutant melanoma. Go back one slide. Can you go backward? Yes. Okay. So our Phase III study of Tecentriq in combination with Zelboraf and Cotellic met its primary endpoint of progression-free survival, and that resulted in FDA approval through project Orbis. Now the overall survival, which you can see on the right, is still immature, but it's leaning in the direction of the triplet. And so the next interim analysis of overall survival will be in the first half of 2021. Okay. So next slide. And so I'm going to give now 2 very brief highlights from the benign hematology space before concluding. Next slide. So the first is our gene therapy for hemophilia A, which is being developed by Spark. And the data that we've presented thus far underscores really 3 key points. The first is about the dose. Our AAV capsid can be dosed at anywhere from 10 to 100-fold lower concentrations than some competitor assets while still achieving robust efficacy. So this would presumably bode well for the overall safety profile. The second point is the durability of factor VIII expression. We are seeing stable factor VIII expression with good safety and efficacy after 2 to 3-plus years of follow-up thus far. And the third point is the clinical outcomes themselves. We've seen a 91% reduction in bleeding rates and a 96% reduction in factor VIII infusions. So after some additional optimization around dosing and immunomodulation, we expect to initiate the Phase III trial of our gene therapy at Spark in 2021. Next slide. So the second highlight is crovalimab, which is our anti-C5 monoclonal antibody. This asset comes to us from Chugai and uses the same recycling technology that was incorporated into Enspryng, which Teresa talked about for -- because of its recent approval for NMOSD. The data you're seeing here are from our Phase I/Phase II trials of crovalimab in paroxysmal nocturnal hemoglobinuria. And they illustrate 2 points. The first is a profound reduction of C5 levels, which is a complement factor, key pathophysiologic mechanism in PNH. And you see this in both treatment-naive and eculizumab-pretreated patients. And the second point is the normalization of LDH levels in both settings. And so this is indicative of sustained control of hemolysis. This, of course, is the key treatment endpoint for patients with PNH. So we're starting Phase III trials in both the treatment-naive setting and in the setting of switching from prior molecules. We're starting those this year. And we're also exploring potential uses of crovalimab in other indications where complement is a driver of pathophysiology as well. Next slide. So I'm almost done, but I'm just going to make one last big-picture point, which is our clinical development programs in oncology are increasingly benefiting from investments from across the Roche group. And one example is the database that we've constructed, which consists of both tumor genomic data from Foundation Medicine and real-world data from Flatiron. And this database is driving understanding that's guiding clinical trial design and patient selection sort of across R&D in multiple ways. This includes genomic profiles that correlate with rapidly progressive disease, natural history cohorts for genetically defined populations, mechanisms of resistance, improved prognostic classifiers. So overall, this is a rich set of tools to help us drive pipeline progress. Next slide. So finally, I'm going to conclude where we began, which is our vision, which you've heard from Bill, is to provide more patient benefit at much less cost to society. And in R&D, we're doing this first by augmenting our pipeline, not only numerically but also as shown here in diversity of innovation. And along these lines, our pipeline now contains an unprecedented diversity of modalities, therapeutic areas and indications. And we're also working to ensure that our augmented pipeline contains its full share of potentially transformative medicines. So I've described where we are with oncology, and now I'll turn it over to Paulo Fontoura, who will walk through our neuroscience pipeline. So Paulo, over to you.

Thank you, Levi. And hello, everyone. So I'm really happy to be here today to give you an update on the neuroscience pipeline. Can we have the next slide, please. The first point I'd like to make is that we continue with our strategy, our long-term strategy of building really the industry-leading pipeline in neuroscience by investing in either first-in-class or best-in-class medicines. And as you can see here, we have a very strong and differentiated pipeline that includes numerous assets at all stages of development, the large percentage of them being, again, either first-in-class, breakthrough therapy designations or PRIMEs and already with 3 assets being launched and on the market having an impact on patients worldwide. Next slide, please, and the next one. So the first medicine I will talk to you about is OCREVUS. And with OCREVUS, you heard it from Teresa before, this is really a medicine that's shifting the standard of care for people with MS at all stages, both in the relapsing disease and progressive disease as well. And the data that we keep showing, in this case here, the 6.5-year follow-up and the 7-year follow-up from our pivotal programs, again, is a great demonstration of that. OCREVUS, during this long duration of therapy, keeps providing benefit. Now importantly, the analysis you're looking at here is an analysis to 2 very critically important clinical milestones. On the left-hand side, time to EDSS 6, which is when patients start to have real disability in walking and, therefore, start accruing health care costs and lose the autonomy, the ability to hold a steady job. And on the right-hand side, for PPMS, the time to wheelchair placement. In both of these, you'd see about a 45% reduction in risk, which is really very, very significant, to think that these are very young people with very active lives, and therefore, keeping autonomy is critically important for them. Next slide, please. Of course, what's illustrated as well is not only the importance of early treatment to prevent that disability, that accumulation, and I need to point out that patients who were on the placebo or interferon arm never caught up, but also that in analysis of these trials, we've observed that there was a clear correlation with higher levels of B-cell depletion and higher levels of exposure to higher impact on disability progression. And therefore, our aim really here is to improve on the efficacy, which is already great for OCREVUS, but see if we can achieve something more for patients, especially for patients who progress with phenotypes. And these are not only the patients with PPMS because progression with phenotypes underlies all forms of MS. Next slide, please. So based on these analyses, we've decided to conduct what we're calling the higher-dose OCREVUS program. These are 2 new Phase III studies, double-blind and controlled against standard-dose OCREVUS, both in relapsing and patients as well as in primary progressive MS patients. This is a really first-in-class trial because we're trying to beat what is already a very, very highly effective drug. And very importantly as well, because we know that safety is key here as well, we've modeled the doses -- the higher doses that are going to be given, in this case, 1,200 milligrams for patients under 75 kilos or 1,800 milligrams for patients above 75 kilos, to optimize exposure, but at the same time, to optimize safety as well. These trials have already been filed and are going to start recruiting this year. Next slide, please. Now of course, OCREVUS was a really landmark therapy in being the first therapy to really address progressive forms of MS. But we want to see if we can do something better than this. And there -- this is why we've decided to start exploring our own BTK inhibitor, fenebrutinib, in MS in all forms, both relapsing as well as for progressive forms. Now of course, fenebrutinib is an oral, highly selective and very, very potent BTK inhibitor. Importantly, it's the only reversible non-covalent binder to the BTK enzyme. And this is important because of the safety concern. Now we do have a long time residency in the enzyme, which means that in terms of potency, it actually mimics other binders which are covalent. On the selectivity side, as you can see here, we feel that BTK is -- that fenebrutinib is actually probably the best-in-class and most selective BTK inhibitor at the therapeutic doses that need to be achieved in order to have robust suppression of BTK activity in B-cells, in mild doses. Now this is an important point because we feel that MS, especially progressive forms, are driven not just by the actions of B-cells, but also by the actions of myeloid cells, such as microglia and macrophages. And therefore, this new mode of action, this dual tackling of both B-cells and myeloid cells, we feel could really be an advancement for the treatment of progressive disease. Next slide, please. So based on this and on other data which exists and essentially proves the concept that BTK inhibitors can have an impact in MS, next slide, please, we've decided to launch 2 -- our Phase III program with 2 trials in relapsing patients and 1 trial in primary progressive patients. This -- our ability to move directly to Phase III is really based on the well-established safety for profile for fenebrutinib because we have studied this molecule across 13 clinical studies, over 1,200 patients, of which a significant proportion are exposed for over 1 year. So we feel we have enough understanding of the pharmacokinetic and safety profile of this molecule to move directly into Phase III. As I mentioned, these are 2 active comparator trials. In the relapsing trials, we're comparing fenebrutinib against teriflunomide, which is a -- which is an approved medicine and orally available medicine for MS that has a significant impact in both relapses and progression. And for PPMS, we are actually comparing fenebrutinib to OCREVUS, which is the standard of care for these patients now. Now importantly, because we feel that the advancement here is really to see if we can achieve higher levels of progression control, the primary endpoint for all of these studies is actually what we're calling the composite confirmed disability progression endpoint at 12 weeks, which is really a more sensitive and thorough approach to measure progression, which includes not only measuring the EDSS as usual, but also changes in the 9-hole peg test for hand function and a timed 25-foot walk for ambulation. For the relapsing trials, we have the co-primary endpoint of annualized relapse rate. So moving on to the next slide, please, and then the next. I'd like to turnover to Evrysdi. And Evrysdi, as you know, is risdiplam, which is recently approved in the U.S. It is really a first-in-class medicine, the only orally available splicing modifier that can be taken as a liquid form at home. And it is as well, we believe, the best-in-class medicine given its very, very robust efficacy profile and a very, very good safety profile. I'm showing you here on the right-hand side data from the FIREFISH part 2 study in type 1 SMA patients. And these were patients, just to give you an idea, which started treatment at a relatively late age. Considering the severity of this condition, the median age was 6 months. And by this time, the majority of these babies have already had some disability. Now despite that, setting a much higher bar for efficacy, we saw extremely encouraging efficacy. So not only almost 30% of them achieved the primary endpoint, which was sitting unassisted for 5 seconds at month 12, which is a clinical milestone that patients with SMA type 1 never achieve by natural history, we also saw that almost 95% of patients survived and were alive at 1 year. And 85% of them did not have an event such as loss of swallowing or respiratory assistance. But also the large majority of patients respond with on increasing motor milestones. Equally importantly, as I mentioned, the safety profile of Evrysdi in these patients was really very benign. And therefore, we really feel we have the best profile here, a molecule which is very efficacious, it's very safe, and it's conveniently dosed at home. Next slide, please. Now this doesn't stop here. As Teresa mentioned, we really went out to do the broadest possible clinical program in SMA, studying not only patients -- the younger patients with type 1 or young patients with type 2, but also going up to patients with type 2 and 3 up to 25 years old and in the JEWELFISH program, up to 60 years old. And the reason we wanted to do that was really to demonstrate the benefits of risdiplam in the broadest possible population of real-world patients as physicians actually see. Now for JEWELFISH, this is very that interesting study that we finished enrolling this year. Over -- about 174 patients that have switched over either from other splicing modifiers, olesoxime, Spinraza or Zolgensma. And we'll have efficacy data for these patients in about a year from now. At the same time, we were running our first neonatal screening program for patients who are presymptomatic and are treated as early as they're diagnosed, and this is called RAINBOWFISH. So based on really on all of these data, we believe we are really building here the treatment of choice that would benefit the large majority of patients worldwide. Next slide, please, and then next one. So moving on to Enspryng. You also heard from Teresa that we're very encouraged by the early progress of this molecule. This is an IL-6 receptor antibody that's being developed using the recycling technology from Chugai, which, therefore, is engineered to achieve maximal suppression of IL-6 signaling in NMOSD. Now NMOSD, as you heard, is a very severe condition, in which relapses are really the main driver of disability. After a relapse, a patient can essentially require wheelchair or blind. Therefore, prevention of relapses and the stability of prevention of relapses long term is really key for NMOSD. What we're showing you here is the 5-year follow-up data of aquaporin-4 patients in SAkura, a Phase III program. And you see a really robust reduction in relapse incidents, about 65% reduction. But also -- and importantly, we recently presented data that shows that the severity of these relapses were also reduced by about 75%. Now this is, as you can see, again, a highly efficacious medicine, but at the same time, a very, very safe one. And because it's a subcu given once a month, it actually is the most convenient for the therapy for these patients well. We are currently following up with plans to continue to do IL-6 inhibition in other diseases of the nervous system in which this mechanism may be effective. Next slide, please, and next one. Now turning over to our ongoing efforts in Alzheimer's disease. You probably heard a lot of times about gantenerumab, so I don't need to really remind you too much of this one. It's a fully human anti -- monoclonal antibody, anti-amyloid that has a really high affinity for neurotoxic oligomers and plaques. It's being studied right now in the Phase III program called GRADUATE in prodromal to mild patients, which is fully enrolled, and we hope to get results in the next couple of years. Now in the meantime, we continue to generate data from our open-label trials that were done earlier. And as you can see here in the middle panel, we see very robust reduction of amyloid with continuous dosing. And in 3 years, we have over 80% of patients being amyloid negative. And at the same time, from our recent DIAN-TU trial in familial Alzheimer's disease, we confirm the signal we have already seen that dosing with gantenerumab reduces biomarkers of neurodegeneration, in this case phospho tau and neurofilament light chain levels. Now importantly as well from these trials, we are continuing to see a really very favorable safety profile and high tolerance with long-term dosing of gantenerumab including low [ RR ] rates. This is important for a therapy which is believed to be -- to have to be taken chronically. And therefore, what we hope to achieve in the GRADUATE program is really an optimized exposure to the highest dose with a very simple titration regimen and a very favorable safety profile. Next slide, please. Of course, nowadays when one speaks about Alzheimer's, we need to mention tau. Tau is probably one of the key pathophysiological nodes in this condition. And we have a -- what we think is potentially the first-in-class and best-in-class monoclonal antibody being developed with this condition, semorinemab. And this is an antibody that targets the N-terminal epitope of tau and targets all known isoforms of tau really regardless of their phosphorylation status. The mode of action here, as you may have heard, is that we're trying to stop spreading of pathological tau in between neurons and, therefore, stop the cascade of neurodegeneration that happens in Alzheimer's patients. Now we have the Phase II trial in prodromal to mild Alzheimer's disease called TAURIEL, which we hope to have the results in this quarter. And we're targeting here a reduction in the primary endpoint of change in CDR Sum of Boxes. At the same time, we have a second Phase III trial called LAURIET in patients with moderate Alzheimer's disease, which is still ongoing. Next slide, please. Finally, I wanted to give you a little bit of a vision of the future. And as you know, one of the biggest challenges with monoclonal antibodies or biologics in general for neurological conditions is actually getting the drug to the site of action, so in this case, getting monoclonal antibodies across the blood-brain barrier. We've been working on a technology called a Brain Shuttle for a number of years now. We're really happy that this year, we had our first Brain Shuttle [ getting-around ] module going into the clinic, and we have the preliminary PK/PD data that we're looking at right now. And really, the idea here is that, on one hand, we'll be able to substantially increase the penetration of this antibody to the CNS tissue, into the site of action, but not only that, increasing in quantity, but also increasing the penetration to areas of the brain, including the deep brain, which usually are harder to target with a regular monoclonal antibody. We're very excited about this, not just because of the technology itself, and we look at this as a proof concept for this platform, which could potentially be useful for other biologics. But obviously, because a Brain Shuttle version of gantenerumab might presumably be more efficacious. Next slide, please, and next one. Continuing to look at our neurodegeneration pipeline, I'd like to speak a little bit about tominersen, which is our antisense oligonucleotide, which we partnered with Ionis in development for Huntington's disease. I wish -- I believe we've spoken about this numerous times. This is really the first time anyone has ever attempted to selectively suppress the production of mutant Huntington protein in the brain using an antisense. We've shown you data on numerous times that shows -- and this year, again, at CHDI, that with our open-label trial data at 15 months, we show substantial and sustained reduction of mutant Huntington CSF levels at the target we're aiming for, which is about 30% to 50% reduction in the CSF, which corresponds to about 80% reduction in the deep basal ganglia. Our Phase III pivotal program, GENERATION HD1, is fully enrolled in the second quarter of this year, and therefore, we hope to have the first result early 2022. Next slide, please, and the next one. Now I'd like to speak about the therapy, which I believe is the first time, and this is the partner program with Sarepta for micro-dystrophin gene therapy for Duchenne muscular dystrophy. Suffice it to say that Duchenne is an area of tremendous medical unmet need, and there's lots of hope that gene therapies might actually be the first disease-modifying therapies to really make a significant impact for these patients. Now what we're really excited about this particular therapy is the technology behind it. On one hand, we think that this is possibly the very best vector with the AAVrh74 vector that has very low likelihood of preexisting immunity and high tropism for muscles. Secondly, we think this is the best promoter with the MHCK7 promoter that really induces the expression of micro-dystrophin in cardiac and skeletal muscles. And finally, the construct itself is constructive to retain critical elements of dystrophin to -- that make it a functional protein. Now early data from the first 4 patients dosed, and this is the data you see here on the right-hand side, was very, very encouraging and made really everyone in the field super excited about this, where we saw a large proportion of muscle fibers, over 80% expressing micro-dystrophin by immunohistochemistry. And also at the same time, the same patients achieving really significant improvements on the North Star Ambulatory Assessment, which is a measure of motor function. And this is really, up until now, something that has never been seen before. So we're super excited about this one. It's early days. We're planning for 2 global Phase III trials in ambulatory, non-ambulatory Duchenne patients, which are -- and planning for -- these are ongoing, and we hope to add -- at the same time, to keep seeing data from the open-label Phase I trials. Next slide, please, and the next one. So the final program I'd like to speak a little bit about is prasinezumab in Parkinson's disease. This is the most advanced monoclonal antibody that targets alpha-synuclein, which is, as you know, one of the key pathologies in Parkinson's disease. The mode of action, similarly, is to prevent the spread of alpha-synuclein pathology between neurons. And the first study that we've conducted in patients was PASADENA. This was a study in early Parkinson's patients who were not taking [ levodopa ] so they were either on no therapy or monotherapy [indiscernible]. And the results here -- the 52-week result's here. As you probably heard, the primary endpoint, which is the MDS UPDRS part 2 score, was not met. And this is a functional score. But on the MDS UPDRS part 3, which I'm showing you here, which is the motor score, we did see a very interesting reduction of severity of this condition, about a 25% reduction in the MDS UPDRS score, which has seen -- both in the clinical endpoint, looking at it, as you see here, is a continuous variable. But also interestingly, on the right-hand side, when we do the time-to-event analysis to, let's say, an increase in severity of 5 points in UPDRS, which is a very significant decline for these patients, we saw, again, a very interesting reduction in the risk of this clinical milestone. At the same time, we saw the consensual changes on our digital endpoint, which I'll mention briefly afterwards, but also on other biomarkers. And therefore, what we see here is that there's really encouraging signs that prasinezumab is affecting the disease biology in Parkinson's disease. And this is a condition for which there hasn't really been any new therapeutic advances in the past 3 decades. Therefore, we are encouraged by these data. We are actively planning for next trials because we do believe that there's something here, there's science here that needs to be followed. Next slide, please. And this lets me talk a little bit about our efforts in digital endpoints. Now as you probably know, in neuroscience, one of the hardest things for us is to measure clinical change. And behavioral improvement, whether that is progression in MS, ambulation for Duchenne patients, tremor for Parkinson's patients, et cetera, is really something that's measured very roughly with clinical tools. What we hope to achieve by using wearables and digital platforms such as [ Lab Line ] is to really improve our sensitivity to change and our ability to detect clinical benefits. Next slide. And therefore, we're really applying this technology all across our pipeline because we think that we can only really develop better medicines and provide more value for society by improving our ability to track and measure changes and changes that matter to these patients. So we're very encouraged to see that this approach actually can be fruitful in our PASADENA trial, and we're hopeful to see similar changes in other trials for the future as well. So with that, I'll turn it over to, I believe, you, Karl or Cristin.

Over to me. Thank you so much, Paulo. And I am excited to be here today to share with you a few of the highlights from our late-stage immunology, ophthalmology and infectious diseases portfolio. And I do have the pleasure of sharing the floor as well with our Global Head of Infectious Diseases from pRED, John Young, in just a few moments to kick off our infectious diseases section. So next slide. What we'll do today in diving into immunology is I'd like to cover 3 distinct disease areas. And on the next slide, we'll start with the treatment of idiopathic pulmonary fibrosis or IPF with our recombinant human Pentraxin-2. Now for context, and this is on the next slide, we recently brought this asset into our late-stage portfolio through the acquisition of Promedior. Now we felt that it would be wonderful to kind of build on our established expertise in IPF, but also have the opportunity with this novel MoA to explore the potential treatment for other fibrosin diseases. Now Pentraxin-2 is a naturally occurring immune regulatory protein in our bodies that inhibits fibrosis by binding to monocytes and macrophages and effectively shifting the development of those cells into a fibrotic phenotype. Now IPF is a prototypical fibrotic disease. And what's known in IPF is that these patients often have lower levels of -- lower serum levels of Pentraxin-2, and this correlates with the severity of disease. So with this recombinant human Pentraxin 2, the idea is that with -- by adding that back to the body that we can, maybe on top of standard of care, further slow the declining lung function that these patients unfortunately experience. Now on the next slide, you can see here the data that really piqued our interest in Promedior, and that was also the basis upon which the FDA granted the BTD status. And what this shows is that in 116 IPF patients, what we saw was that on top of -- in some cases and in most cases, on top of standard of care or untreated, patients did see a significant decline in their loss of lung function and not to mention also preservation of exercise capacity that you can see over there on the right. So with these data, we were eager to get started on our Phase III that in this single Phase III should confirm what we saw in Phase II, and that will be starting here later this year. Not to mention, as I said, that this might be a more -- given that this is a novel MoA, we might be able to treat other fibrosin diseases. And so we're very eager to see the results of the ongoing myelofibrosis study in Phase II that we look to see later this year that will really help us to chart the path as to where we'll go in other fibrosin diseases. So moving on to our next area of immunology. We'll talk a little bit about lupus nephritis and other B-cell-mediated diseases. So on the next slide, we have Gazyva, which, to remind you, is a type 2 antibody, which really lends to its ability to induce greater B-cell depletion when compared to other type 1 antibodies, such as Rituxan and OCREVUS. Now what this means is that by really having a deeper and more sustained depletion of peripheral cells but also potentially tissue-based B-cells, these are thought to play a significant role in some immunology diseases such as lupus nephritis. And so what you can see over there on the right is that we are excited to get started in lupus nephritis, and we already have, but we're also exploring other areas where there still remains high unmet need and where this deeper B-cell depletion hypothesis would [ bring thrill ]. And so you can see there, for instance, the furthest advanced is membranous nephropathy, and we anticipate starting our Phase III study in the first half of next year. So on the next slide, what I wanted to talk a little bit was Gazyva specifically in lupus nephritis. Now just to remind us, lupus nephritis is a devastating disease. We have high mortality and morbidity rates, and it disproportionately affects women of color. And so there remains a very high unmet need, which is why we were so encouraged by our Phase II NOBILITY data. And not to mention, it was these data that was also what garnered the BTD status given by FDA. Now what you see here is at week 52, a significant proportion of patients achieved a complete renal response. Going further out at week 76, we also saw that we saw a continued clinical improvement, both in complete and overall renal response. And we're very excited to share with you even longer-term data that we have at 104 weeks that will be presented in upcoming congress this fall. Now what we did was we -- very quickly based on these results, we went into designing and implementing our single Phase III pivotal study that you can see over there on the right called REGENCY. And the idea, of course, is to replicate the Phase II. And should this be positive, this will be substantial for approval. And we've actually already started it, and I've learned that we already have our first 2 patients enrolled. So we are looking forward to building on that momentum. And now the last area on the next slide that I wanted to talk about was -- in immunology anyway, is inflammatory bowel disease. So if you'll move on to the etrolizumab -- or excuse me, the IBD slide, 2 slides away. And one more. We have there our overarching pipeline in inflammatory bowel disease. And you can see there based on the assets that we have on the left, we really are committed to bringing better medicines to patients that are still suffering with IBD. And you can see there that, of course, etrolizumab is our most advanced of the molecules. And to remind you, etrolizumab is a gut-selective, anti-integrin antibody that we have been studying moderate-to-severe patients with both ulcerative colitis, or UC, as well as with Crohn's disease. And now we recently did announce our top line results from our 5 pivotal UC studies, and what those showed was that we had mixed results in inducing remission but disappointing results in the maintenance setting. And now while you can imagine, this was one of the biggest IBD programs ever to be put forth. And so we're still digging through the data and mining through it, and we'll be presenting those at a near -- in a congress coming up in this fall. So -- but what's important to note on this, though, is that we still have a program going on in Crohn's disease. And you can see the Phase III BERGAMOT data here on the right, and these are interim results from our cohort 1. And what they show is that a proportion of patients achieved symptomatic remission as well as endoscopic improvement at week 14. And so it really -- and we're going to see the full results of this trial coming out in 2021, and it really is too early to tell kind of which direction this will go in Crohn's disease. And I say that because for one, ulcerative colitis and Crohn's disease are distinct diseases. They affect different parts of the GI tract. But not to mention, we also used a higher dose in the induction setting here in Crohn's disease, which could, of course, change the outcomes. But irrespective of what happens with etrolizumab, we are very eager to continue to learn on this journey and apply those learnings to our pipeline that, again, you see over there on the left, whether that be how we're conducting clinical trials, what measurements we're using that are relevant to patients but of course, navigating the evolving regulatory and commercial landscape in this space. So we do have a robust pipeline there with novel MOAs, all targeting non-immunosuppressive pathways. And the idea here is that we're looking for high-bar efficacy and enhanced safety because potentially, we could think about some of these as combination therapies in the future. So that rounds out our inflammation -- our immunology portfolio. So if you could move to the next slide, please. We'll flip over now to ophthalmology. So on the next slide, this is a disease area that really we've been pioneering for nearly the last 2 decades. And we've made significant inroads in the last several years, actually. And while there have been several new agents that have come and truly transformed the retinal space, and that started actually with the launch of our own Lucentis in 2006, about 15 years ago, these -- really, much of these therapies have been in the anti-VEGF space as monotherapies. And so what we aim to do, our near-term strategy anyway, is to develop 2 complementary but distinct, innovative products to the retina community that we hope can ultimately land to patient benefit. Now with faricimab, if the data are positive, of course, what we have there is the potential for a new standard of care IVT therapy. That brings together the VEGF pathway, but with the novel MOA. And we could potentially see improved efficacy as well as improved durability over current standard of care. And then with PDS, the port delivery system platform, as Teresa previously described, this innovation really does bring a continuous delivery of medicine. And in this case, initially, it will be with the specialized formulation of ranibizumab. But this really does provide unparalleled durability, and this fundamentally transforms the treatment burden that patients experience. So on the next slide, specific to PDS, what we want to do is build on the momentum from our ARCHWAY study. And you've already heard about Archway specifically from Teresa, and this should be on the next slide. There may be a lag here on my side. But really, we've started our Phase III PDS study in DME and are looking forward -- that's already enrolling and enrolling nicely, and so we're looking forward to our data come first half of 2022. And we've also kicked off our Phase III study in diabetic retinopathy. And so the idea, again, is to start off with PDS with the formulation of ranibizumab. But ultimately, what we want to do is we want to really break through that efficacy barrier by bringing in novel MOAs. And we plan to do that with the PDS platform by then using other technologies based on our own proprietary DutaFab platform that we can build bispecifics that can then be specially formulated to be used in the PDS platform. And so we currently have 3 DutaFabs with novel MOAs in development, and we'll look to accelerate those as quickly as possible. So moving on now. If you could skip 2 slides, we'll move right into faricimab. We really believe that we can raise the efficacy bar by bringing in a new era of treatment for patients. And the idea here would be to, again, use the VEGF pathway that is well known but then, of course, build on that with novel MOAs. And you can do this by virtue of bispecifics, which is precisely what faricimab is. And so what you can see there is that faricimab is the first bispecific antibody in ophthalmology. And what it does is it targets the VEGF pathway that we know while also simultaneously targeting angiopoietin-2, or Ang2. And Ang2 inhibition may improve response or improve anyway vascular stability as well as reduce retinal inflammation. And so what you can see there on the right is our Phase II results in neovascular AMD. And what we saw here was that we saw efficacy that was similar to Q4 weekly ranibizumab, but we saw a substantial improvement on the durability relative to Q4 weekly ranibizumab, where patients could have been extended all the way up to Q16 weekly dosing. So these data form the basis as well as the excitement for our Phase IIIs, which we already have the enrollment complete, and we are eagerly anticipating our results in the early part of next year. So moving on to faricimab in DME. You can see there are Phase II results in DME, which is our BOULEVARD study. And this here showed that faricimab had both statistically superior efficacy relative to Q4 weekly ranibizumab as well as enhanced durability. And so based on these results, we quickly designed our Phase III trial that you can see over there on the right in YOSEMITE and RHINE so that we really have 2 shots on goal here to show superiority. In arm A, we're comparing 8 weekly -- Q8 weekly faricimab to Q8 weekly aflibercept. And we have the potential there to show enhanced -- or superior, I should say, its power for superiority efficacy. And in the personalized treatment arm in arm B, we have the opportunity to prospectively bring patients out to Q16 weekly dosing. And so that means that we could really show superior durability with this molecule. So again, this has been a very fast-enrolling trial, and we eagerly await our results at the end of this year. So if you think about it, kind of by early next year, for faricimab, we will have our pivotal trial readouts in neovascular AMD, in DME, and we will have also kicked off our studies in RVO. So there's a lot of exciting data to come here in ophthalmology. And I just say that this really is an exciting time to be in ophthalmology when there's this new era of treatments that are being ushered in, and once again, we're really thrilled to be at the forefront of that at Roche. So with that, I'll hand it over to you, John, to kick us off in infectious diseases.

Okay. Thank you, Cristin. So here at Roche, we're addressing areas of high unmet medical need in infectious diseases with a focus on developing innovative drugs to cure chronic hepatitis B virus and respiratory virus infections. We're also aiming to develop game-changing antibiotics to treat drug-resistant bacterial infections. And today, I'm excited to share with you the progress on our HBV pipeline. Next slide, please. And the next one. So chronic HBV infection represents a huge unmet medical need with approximately 260 million people infected worldwide, 90 million patients in China. And these patients have an increased risk of developing advanced liver disease and hepatocellular carcinoma. 2 types of standard-of-care treatment are available today, pegylated interferon, a 1-year treatment option with low efficacy and tolerability issues; and nucleosides or nucleotides, so-called nucleics that can prevent disease progression and in some cases, can reverse some disease conditions, but these require long-term, most probably lifelong treatment. In both cases, these treatments are associated with very low cure rates, highlighting the need for new therapeutic options for patients. Next slide, please. It's a delay in my end, I think. The goal of new treatment options is with a finite treatment regimen to eliminate the viral protein HBS antigen or the surface antigen of the virus shown in the left panel and also to achieve undetectable viral DNA in the bloodstream of patients. This is a so-called functional cure, and HBS antigen loss is the ideal clinical endpoint because, as shown on the right panel, it's associated with reduced risk of developing advanced liver disease and paracellular carcinoma as demonstrated in this recently published retrospective meta-analysis of clinical data. Next slide, please. The Roche strategy is to achieve a best-in-disease combination therapy for hepatitis B virus infection, and our approach combines antivirals and immunomodulators. We currently have 4 clinical-stage assets in our portfolio, 2 antivirals and 2 immunomodulators. HBV siRNA is an oligonucleotide inhibitor of biogene expression, a program we're developing together with Dicerna. CpAM is a class 1 core protein allosteric modulator that was developed internally at Roche. TLR7 agonist is a liver-activated double prodrug, again, developed internally at Roche. And we also have a novel immunomodulator, which, again, is internal program from our discovery groups, that has entered into Phase I study, and we'll be disclosing the identity of this program in an upcoming scientific conference. Next slide, please. So the first antiviral agent we want to look at more closely is HBV siRNA. This is a subcutaneously injected, liver-targeted drug that was developed using Dicerna's proprietary GalXC platform. Shown on the left, the drug inhibits expression of multiple HBV genes by targeting the surface antigen open reading frame of the virus. Results presented recently as part of Dicerna's R&D Day demonstrated a durable and profound HBS antigen decline in the Phase I dose-finding study shown on the right, confirming the high potency of this molecule. Next slide, please. The second antiviral agent is an orally administered allosteric modulator that leads to the degradation of the virus core protein, which forms the capsid of the virus. This is a so-called class 1 CpAM. This mechanism of action differs from most other CpAMs that are in early clinical development today, the so-called class 2 CpAMs, that instead lead to the formation of genome-free capsids. As shown in the right panel, in Phase I dose-finding studies, treatment with our class 1 CpAM led to significant reductions in viral DNA on treatment, confirming the very strong antiviral activity of this molecule. This CpAM has now moved on to Phase II studies together with an immunomodulator that we'll look at on the next slide. Next slide, please. The most advanced immunomodulator in our portfolio is an orally administered TLR7 agonist that activates innate and adaptive immune responses. And the goal here, of course, is to restore antiviral immunity in patients with chronic hepatitis B virus infection. This molecule is a double pro-drug that is selectively activated in the liver. Phase I studies have demonstrated that this molecule can trigger pathway activation in all patients, as you can see in the right panel, and this molecule has now progressed to Phase II studies with the CpAM. Next slide, please. We're using a platform designed for our Phase II combination studies, and this is aimed up to a 48-week treatment period with a 6-month follow-up. This is a very nimble and adaptive design for clinical development, allowing us to seamlessly add or switch different drug combinations while leveraging the same or a common control arm. The design also allows us to act upon interim analysis data, as you can see in the graphic, to inform decisions on the efficacy of existing combinations as well as to inform our future combination plans. Next slide, please. So as I mentioned, our first combination to be tested is the CpAM and TLR7 combination. It recently moved into Phase II clinical study, and we expect the first interim results in Q2 of next year. By way of summary and from my presentation, the program overview on the right panel shows a totality of compounds that we have in our development pipeline, including the novel immunomodulator in Phase I. That concludes my presentation, and I'll now hand back to Cristin to cover our influenza and SARS-CoV-2 programs.

Thanks, John. So on the next slide, building on what John has said, Roche has a legacy in really transforming serious infectious diseases. And we've done so under difficult circumstances, which is no different today. If we look at what our response has been to this pandemic, it really has been about bringing the diagnostics and the pharma businesses together so that we can collaborate to quickly develop, manufacture and distribute solutions across the world as effectively and as quickly as possible. On the left there, you can see the numerous solutions that our colleagues in dia have generated in record time, and they have been really critical for the diagnosis and monitoring of COVID-19 as well as understanding how this coincides with other viruses. And of course, this list isn't exhaustive. There's more that they've been generating. And on the right-hand side, you can see Roche Pharma and the critical role that we play in bringing innovative therapies and advancing the science and understanding by building on that body of evidence. Not to mention, we and pharma have the world-leading biologics manufacturing capacity, which is important given the scale and the complexity that we're addressing here with regard to COVID-19. And then, of course, across both dia and pharma, we have strong partnerships with our affiliates in local health care ecosystems, which helps us to understand what's happening in various pockets of the world, but also then that helps us to quickly get any of these effective solutions out to the public as quickly as possible. So you can see there some of the therapies that we'll talk about on the pharma side that we've been working on as it relates to the pandemic. But I think what you can see here is net-net, we are all in, in terms of tackling this COVID-19 pandemic on all fronts. So moving on to the next slides. You can go straight to the Xofluza slide. We'll talk a little bit first about influenza. Now the reason we're talking about influenza here is because the flu season is fast approaching, and it is important more now than ever to ensure that we are really getting out ahead of this to try to mitigate the impact that the flu can have, especially when we think about patient safety as well as health care utilization. Now appropriately diagnosing and of course, treating patients is going to be very important during this flu season. And this is where we think Xofluza, which is a first-in-class and highly potent single-dose oral drug, can provide another option to what's out there in terms of standard of care. Now it's currently approved in 24 countries, and we still have filings underway looking at pediatrics and postexposure prophylaxis indications as well as other studies that are underway. And the one that I want to draw your attention to is CENTERSTONE, and we anticipate the readout of this study in 2022. And what's exciting about this is it's the first study of its kind, and what we're testing is that if the transmission of flu can be blocked from somebody to other individuals. And if this study reads out positive, this could truly transform the way we think about and treat the flu. Now one of the things I'd mention is that it is really important, especially in the midst of this pandemic, that we understand what patients are presenting with when they come to the hospital so that they can be appropriately treated and managed. And that's why we're so proud of our dia colleagues who recently garnered an FDA Emergency Use Authorization for their SARS-CoV-2 and influenza test that's on the cobas platform. So what this does is with a single swab that can be analyzed, we can understand if a patient has SARS-CoV-2, if they have influenza A or influenza B. And I know that the team is working very hard on making sure that we have approvals in other parts of the world as well. So moving on to the next slide, looking at our treatment specifically targeted for COVID-19. Now similar to our efforts in influenza, we've been on the front lines of really trying to develop treatments for COVID-19 directly. And what we learned early on, of course, is that infection with SARS-CoV-2 leads to COVID-19-associated pneumonia in a lot of cases. And for some patients, they advanced to a pro-inflammatory state, even extensive as what's called a cytokine storm. And there were early data that were emerging that suggested that patients with high IL-6 levels were actually what was correlated with severity. And so that was what initiated us to think about using Actemra, which is Roche's anti-IL-6 antibody, to study it in severe COVID-19-associated pneumonia. Now looking over there at the data on the right, and I know that Bill already alluded to some of this, you can see the results from our global Phase III COVACTA study in severe COVID-19-associated pneumonia. Now we presented or we put the data out there in late July, if I'm not mistaken. And what we did show was that, unfortunately, COVACTA did not meet its primary endpoint of improved clinical status of patients or the key secondary endpoint of reduced mortality at day 28. However, as Bill had alluded to, there once -- there were some endpoints that showed clinically meaningful benefits, namely in time to hospital discharge and the duration of ICU stay. But these aren't conclusive because, of course, we didn't -- we failed to meet the primary endpoint. So what's important now is that we really look at the totality of the evidence that's being generated around Actemra, and there are still ongoing studies. You can see there, importantly, that we have our Phase III REMDACTA, which is testing Actemra on top of remdesivir, which we'll read out later this year. It's really important that we look at all of this to truly understand the benefit risk profile of Actemra in COVID-19 patients. And we are very committed to transparency, and we are effectively publishing our data real time, so you can certainly expect to hear more from us as this narrative unfolds. So now moving on to the next therapy we're working on in COVID-19. We were very excited to recently announce that we joined forces with Regeneron in the collective fight against COVID-19 to develop, manufacture and distribute what's known as Regeneron COV2, which is Regeneron's investigational, neutralizing antibody combination that targets the SARS-CoV-2 virus. And so biologically, this is a really compelling approach because what this does is that antibodies target the receptor-binding domain in the virus' spike protein, or the S protein, and it effectively neutralizes it and stops its ability to bind and in fact, host cells. And what we found particularly interesting about Regeneron's approach was this notion of a cocktail. And what that means is that there's 2 potent neutralizing antibodies in the cocktail. And given that we're always worried about the emergence of resistance in viruses, what this does by having 2 antibodies is there would have to be a lot of mutations in that S protein in order for it to be able to effectively escape 2 neutralizing antibodies, which we feel is unlikely. So we really do believe in this approach, which is why you can see on the right, there is already a very ambitious clinical development plan that's been put underway. So you can see there that currently ongoing, there are 2 Phase II/III adaptive studies that are looking at the -- at COVID-19 treatment in both hospitalized as well as outpatient treatments. We have a Phase III study looking at basically postexposure prophylaxis; another Phase I study that's actually a multi-dose study in healthy volunteers, and what this is looking at is PK and safety so that we can start to lay the groundwork for whether or not this might be a preexposure prophylaxis drug. And then actually, while we were sitting here on this call, Regeneron just announced that it will also be added to the U.K.'s recovery trial, which is one of the world's largest clinical development programs, looking at various COVID-19 treatments, which Actemra is also a part of. So we're eagerly awaiting data from all these studies, as you can imagine. And the first data that we are anticipating is in September, and this is going to look at both virology as well as biomarker results, and then we anticipate efficacy and safety to come at a later point in time. And of course, should this therapy be proven safe and effective and we get health authority approval for it, you can rest assure that both Regeneron and Roche will be working expeditiously to get this to patients as quickly as possible with Regeneron taking the lead in the U.S. and Roche taking the lead outside of the U.S. And so that really rounds out what we've been looking at in COVID-19, but I know I speak on behalf of every single one of us at Roche when I say that we are really proud to play our part as industry comes together with NGOs, with hospital systems as well as society at large to really do now what the world really needs. And so with that, I'm going to hand it back over to Karl for our questions session.

Yes. Many, many thanks to all the speakers. Before we go into the Q&A, also allow me to thank Bruno actually from our team, who took the overall lead on this event; [ Lauren Karmin ] in the U.S.; [ Lisa ] in the U.S.; [ Claudia ] here in Basel; [ John ], who helped to bring the presentation together; [ Beatrice ] and [ Melanie ] for the administrative support. And there is also our famous epidemiology chart, which you can also download from the web as a kind of a helping hand for you to frame the market opportunities. With this one, don't be surprised. We have reconvened in the room here, so we are all together because we can hopefully better address your questions. And with this one, we will do the switch now into the room. It's, of course, COVID, let's say, tested, I would like to say. So let's go for the switch.

Sure. Go ahead.

Okay. Very good. It works, actually. Very well. Good.

So the first question, we have lots of interest, I can say. Maybe Henrik, before we go into the Q&A session, maybe you can kindly remind the people on the line on how they can ask questions. There are basically 2 ways, but it would be perfect if you could kindly remind us again.

Yes. Exactly. So there will be now a Q&A session. [Operator Instructions]

Very good. So the first question is we have a Q&A chat. It comes from Michael Leuchten. He was asking about the BTK fenebrutinib. I guess Paulo, this is going to you. There are quite a few in development he was asking, how will they be differentiated? And is Roche on the same kind of trajectory as Sanofi and Merck?

Yes. No, thank you for that question. And I'm sorry, I kind of glossed over all the details in the presentation. There wasn't a lot of time. But I'm happy to go into detail. So I think there's really 4 main areas of differentiation, right, the first of which is around potency, so how potent the BTK inhibitor is. And here, we think that fenebrutinib is a highly potent one, even though it's a noncovalent binder. It stays a long time in the enzyme pocket and therefore has the same level of suppression of that kinase. The selectivity is super important also because of safety, and there, that's the data I showed you on that slide. We actually feel we have the best-in-class selective BTK inhibitor here. When we performed the test against 219 kinases, kinome approach, basically, what we saw was that fenebrutinib, besides BTK, really only inhibited 3 other kinases at the, let's say, at 1 micromolar concentration. And for the comparable concentration for tolebrutinib, which -- and evobrutinib, which are the 2 other molecules we developed in MS, their numbers are actually 19 and 18. So they have over 15 more kinases that they're touching at the therapeutic level, which obviously, from a safety standpoint, is a concern or can be a concern for -- especially for a chronic dosing. The third element has to do with the reversibility of binding. And fenebrutinib is the only noncovalent binder. That's important because it binds the enzyme that can release the enzyme. And again -- so selectivity is important, but being able to then release the enzyme and let it function again is very important as well. We know for fenebrutinib, this is a noncovalent binder, and therefore, 24 hours after dosing, B-cell function starts to come back. And the final one is something that's been made a lot of noise about, which is brain penetration. And just to be clear, we have preclinical data that showed that fenebrutinib is brain-penetrant as well. We don't have human data. We don't really know if that's necessary, but we're looking at plans to generate those data as well. Suffice it to say, though, that in MS, we have tons of medicines approved with higher levels, lower levels of brain penetrants. Peripheral action is super important. We know our drug, it's in the brain as well, and therefore, we are confident that, that's not going to be a main differentiation factor. And regarding time lines, I think it really depends on how agile we are with the execution of your program. We think we are making a really good proposal for patients where they get to have an active control for lapsing MS trials. And for the PPMS trials, they're comparing themselves to OCREVUS so you know they're not on placebo. And for PPMS patients, I think that's super important. So I think, yes, it's still too early to tell, really.

Okay. Maybe you can just take also the next one, which is on Sarepta. There was some news, as you know, in the recent days on the potency assay for product release. So how has it been worked through is the question. What is the issue? And how do you got involved with it?

Right. So this is obviously an important thing, especially for a new technology that's maturing. The ability to manufacture the gene therapy at scale at a commercial level with the same characteristics that you have for the clinical level is super important. We -- Sarepta is planning a switch from the clinical supply to the commercial supply for the pivotal trials. And there's obviously, let's say, questions around how you can do that and what the FDA is asking essentially for is another assay to look at the potency of the new commercial supply. That is under discussion between the FDA and Sarepta. We hope that we can go through that issue soon, but there -- but it's still early. Really, we don't want to put any pressure on regulators or anyone to try and solve this. Obviously, we're focused on a better long-term outcome.

Okay. Thank you. And I'll take the last one here from the line, pricing. Bill, I guess, this is one for you. There was questions on the pricing on Hemlibra, OCREVUS so favorable that we have actually priced it at, let's say, comparable lower rates but there are still big price gaps within the U.S. and EU, given the present preferred nation U.S. -- from U.S. administration. How will Roche or the industry deal with this ongoing gap? And what -- how do you see -- I guess this is the overarching question here is latest initiatives from the White House, which they have been actually published overnight.

Well, it's obviously a really important topic. I think we've had a long-standing position that reform to the way medicines are priced in the U.S. is really important. And the keys to a proper solution is to enhance patient affordability, to affect or to lower societal cost and to protect innovation for the future. And we have to judge any solution against those 3 things. And we, I think, have demonstrated our commitment to this through our longtime actions towards responsible pricing, whether it's setting the prices when we launch or whether it's price increases. We've also been very responsible by making a large R&D investment. And in other words, we're not just banking the revenue, but we're putting a lot of it -- paying a lot of that forward for tomorrow's patients. I think in the last 24 months, I've been really encouraged that the whole industry has really come along in offering tangible solutions, for example, in Part B, concrete solutions to improve competitiveness in Part B to ensure a more dynamic pricing environment; in Part D, ensuring that there's a rebate reform so that we can end this really perverse practice of having sort of the rebates from sick patients' medicines go into the bank to pay for healthy people's insurance. That's not what insurance is about, and that desperately needs reform. So I think the industry has come along and offered those kinds of solutions. And I'm confident that we will get to reasonable pricing solutions working with Republicans and Democrats. In terms of the executive order, this is really not the right way to go. These types of discussions have been in play for several years now with IPI. Latest is this MFN concept. The fundamental problem with MFN is it really just brings the policies from other countries that don't support innovation, just brings those into the U.S. So that -- and then we have basically a global problem instead of a U.S. versus rest of world or other developed countries problem. The White House's own Council of Economic Advisers in the summer came out with a study that said, if this type of approach was implemented that there would be approximately 100 new life-saving medicines that would never make it to patients just in the first decade, and that's not taking into account what happens in, say, the next decade where you've had sustained time with less investment. So I would say, the executive order, if you look at it, it's basically one page. It's light on details, but it surely exceeds the authority of an executive order to make changes that would affect the prices across Part B and Part D across America and result in permanent changes to pricing. That is a change that should be done by law, and we're remaining eager and willing to work with legislators and the administration to make appropriate changes. And I guess I would just say, maybe to close out, if you go back to our discussion and my presentation on our ambition and our 10-year ambition, I hope you'll all agree that what we're doing is right in line with what the world needs, what the U.S. needs. And it's a strategy that will do us well in fair weather and fell. And so I think we have a lot of confidence that we're on the right track. We will continue to work with policymakers. And I think we'll -- yes, we'll fare very well through it all.

Thank you, Bill. I would take 2 questions from the phone as they arrived. So Richard Vosser is the first one, so I'll allow you to talk, please, Richard.

Hopefully, you can hear me.

Yes, perfect. Thank you.

So 2 questions, please. Just on the Merck's TIGIT data that was released in ESMO overnight, just how you're seeing that efficacy, early efficacy stack up versus your TIGIT. And perhaps you could contrast your thoughts of the TGF-beta target versus TIGIT as well. And then second question, just on crovalimab. Just PNH market is a fast-evolving space with many agents targeting the intrinsic and extrinsic pathway, the factor B inhibitor. So how do you see your product fitting and stacking up versus the competition there? And then third question. Bill, you mentioned the strategic shift in the go-to-market model. Is that going to lead to a shift in cost from SG&A to R&D? Or can some savings reach the bottom line from that as well?

Thank you, Richard. Good to see you. Just to complete the picture. The question on the TIGIT, there was also one additional question from Michael Leuchten, just to complete the picture. But I guess, Levi, this is questions mostly for you and then one for Bill.

And one for me.

Great. Yes, yes, yes.

Okay. So yes, thanks for the question on TIGIT. So of course, big picture, we can't comment on competitor molecules. I think as a general rule, of course, the interest in TIGIT as a target is, of course, it's a positive development for patient and underscores, I think, our interest in the potential as a target. Certainly, we're following the data -- following our data in terms of our program and the efficacy signals that we've seen. We also have been encouraged by the fact that the safety profile, when combined with Tecentriq, is quite manageable and bodes well for other kinds of combinations as well. So I guess it underscores, I think, our excitement for the target. Regarding TGF-beta, certainly, we and others have studied this mechanism or this IO resistance mechanism for quite some time. And I think it's -- maybe a high-level comment is that it's fair to say that IO and IO resistance is multifactorial, and we know that there are certain tumor types in context where TGF-beta signal may be a relevant mechanism. But that's not true across the board, and we think there are going to be plenty of opportunities to improve benefit for patients with IO. And certainly, it's great to see interest in so many targets continue.

Thank you.

And with respect to tiragolumab, I think you're right. This is a fast-evolving space. But we do believe that the molecule that we have will not only produce best-in-class efficacy but also will be convenient. Further, we think there is -- one of the biggest unmet needs in this area is just actually patient access and patients being able to afford the drug. And so I think this is another place where you will see our commitment to patient access really come into play.

Thank you.

And yes, Richard, regarding the shift of SG&A to R&D versus bottom line. I think if you consider our ambition for the future and doubling the output of new medicines, I think -- we think we're already at a very high level of profitability. So my guess is, at least in the first 5 years, that most of the savings we would extract in one part of the P&L will go into R&D to support that ambition.

Thank you. I hope that addresses all your questions, Richard. Let's go for the next one in the telephone queue, would be Matthew Weston. Matthew, please. You're unmuted, Matthew.

Apologies. I am coming. I am coming, I think [indiscernible].

Yes.

One of those ones where on, off, on, off and off again. Apologies, everybody. 2 questions, please. Bill, just some follow-up on your comments to President Trump's executive order. Do you have any indication that HHS is about to announce the pilot program? Because the change in language from now versus July seems to be the immediacy of the action. And I guess if something were to happen quickly before the election, what would Roche's reaction be? Because everything you suggested that would happen to the industry would be a meaningful reduction in cost and innovation over time. But obviously, the immediate impact on the P&L would be potentially more severe. So would you wait and see the outcome of the election? Or would you be forced to act? And then secondly, just a specific question about Tecentriq and triple negative breast. Clearly, we've seen the data from IMpassion131. What's interesting to me is that IMpassion130 only has accelerated approval from FDA. So what data are you waiting for to actually convert that to a full approval? And can you confirm that it wasn't the IMpassion131 data?

Bill?

Okay. Yes. Matthew, on your question regarding what would our response be, we really -- sorry, you asked whether we were going to wait and see or whether we'd be forced to act. And I think we'll have to wait and see whether we would wait and see or be forced to act. So we just -- there's just so little information right now that it would be really impossible to speculate.

Levi, on the triple-negative breast cancer.

Yes. So thanks for the question. So as I mentioned in my talk, in general, we remain confident about the activity of Tecentriq in triple-negative breast cancer, in large part because of IMpassion130. So certainly, the 131 results could have been a path to full approval. So with that result being negative, we -- there are a number of other options that we're actively in discussion with regulators here. So that's ongoing as well as the insights from that assessment will also inform, just in general, existing or future studies that we have ongoing or might do. So we'll provide more details as they come together on those discussions.

Yes. Thank you. Hope that addressed your question. So I have one here over -- which was sent to me via e-mail, from Sam Fazeli. I can only say that this is Bloomberg is really a terrible font, and you need a magnifier here, but I'll try my best on all of them. He asked about the risk of inhibition of FAP-4-1BBL in the brain and potential for impact on normal brain function. That is one for you.

Okay. Yes. I mean it's a very interesting scientific question. It's really hard to speculate. There's no evidence one way or the other that inhibition of BTK in microglial will have any direct action on brain function. I mean microglial cells have multiple actions in the central nervous system. I'd say that possibly the one can speculate about is the role that it plays in controlling CNS infections, generally. But that's why we're going to do studies and monitor safety carefully. But as far as brain function normally, I don't know if there's any evidence anywhere that, that would lead us to be concerned about that.

Okay. Yes. Thank you. Wimal, you will be the next one from the lines, please.

Can you hear me?

Yes, we can hear you.

Wimal Kapadia from Bernstein. So just a few, please. So you previously flagged neoadjuvant nonsmall cell lung cancer has an opportunity of up to CHF 500 million. And it now seems that you include the adjuvant, neoadjuvant opportunity greater than CHF 1 billion. I just wanted to just clarify, is that change driven by the inclusion of the adjuvant setting? Or are we now more optimistic about the opportunity? And then just tied to that within -- again, sticking with non-small cell lung cancer, specifically. How do you think about the penetration within this population? Should we be thinking only high-risk patients within the neoadjuvant setting? And how do you think about continued strength in lung cancer could impact Tecentriq is first essential for market uptake in this setting? My second question is risdi. Tied to your earlier comments, do you envisage that combination therapy of Zolgensma plus risdi could become part of the treatment paradigm? Scientifically, it seems to make a lot of sense because the viral vector doesn't get taken by every cell. Do you think the main pushback will be cost to the combination use? So just your views on that combination usage within this setting. And then my final question is just on SRP-9001. You put the indicator product at between $0.5 million and $1 billion opportunity. Just based on the price you paid for the partnership with Sarepta, I would have expected a little bit more in terms of peak sales potential. So has your view on the asset changed since the acquisition? So any comments there would be really helpful.

Good. So I can start with the neoadjuvant, adjuvant lung cancer data. So yes, the greater than $1 billion is the combination between the 2. Penetration within neoadjuvant will, as always, ultimately depend on what the clinical trials show and what the efficacies that we can provide to patients and at what level of tolerability. Being first always helps, but being best is better. So I think this is one area where we'll have to follow the science and see what the data tell us and make the judgment when we have everything in hand.

Yes. And I would just add that, as to Keytruda's strength in lung cancer, we have a very strong position in small cell lung cancer. I think that's a great example that physicians still make their decisions based on the data in each tumor type, and I don't think it's an issue at all. I think if we have great data in neoadjuvant management, we'll do very well.

[ Antigen ], I guess so.

Certainly. Yes.

Combinations.

Well, to your question around the combination of Zolgensma and risdi, I mean I don't know if combination is really the best term to use here because Zolgensma, once you've given it, it's given forever. So if you're talking about then adding something on top of that later on, so not at the same time. And that's the data we already are seeing from JEWELFISH. And actually, we're seeing already with the early access data from a number of patients who are wanting to have Evrysdi too. So gentlemen, for a variety of reasons, some of them for perceived lack of efficacy, some of them because they want to achieve higher efficacy. I think theoretically, it makes sense because, again, one does not know the durability of a gene therapy yet or how many of the cells are actually taking it up, we do know that with Evrysdi, you get systemic wide distribution of risdiplam, and therefore, potentially all cells in our body will benefit from that. And I'm not possibly the best person to speak about the potential commercial barriers. But as a physician, thinking that for a small baby with type I, you're paying $60,000 a year to start the Evrysdi after you've done a gene therapy that's not -- that should not be a major barrier, but maybe Teresa, it's more your shot.

Maybe, Teresa, before you go into that question, there is Marietta Miemietz, which goes a bit in the same direction. So maybe you can just actually cover both questions. There is a question of where the patients are coming from. I mean, the launch, you commented was actually very good. So the question here from Marietta Miemietz was, on the patients who were switched, do they come -- did they come from Zolgensma? Do we really know that because Zolgensma maybe didn't work or did they take it before starting Zolgensma? Was it -- basically, what is the treatment schedule at the moment where you've got the patients from these early starts? And maybe you can basically go for both questions here.

So what I can say is that very early data from the U.S. launch has about 2/3 of patients being prescribed Evrysdi having had prior exposure to Zolgensma or Spinraza, but I don't actually have the breakdown of which is coming from which. Would that make sense over time? I mean, A, I think we need to see the data; and B, I think this is one area where, quite frankly, the clinical benefit that we can provide to these children is pretty significant. And I do believe that if we can demonstrate the appropriate level of benefit at a good safety profile, which will hopefully be what we see, I would expect that, that would be a regimen that would be acceptable.

Yes. What I can add is that from the JEWELFISH data, the early data we see on pharmacokinetics and biomarkers, Evrysdi works equally as well in patients who have switched from other therapies as the ones who are naive to any therapy. So there's no biological reason to think that it wouldn't work. I mean there's every sense that it would work, right? And again, the early data we have from JEWELFISH is that the desire, the main reason for switch are either desire to achieve higher efficacy or concerns about tolerability or safety, et cetera. So -- and those are going to be natural for any new technology.

And maybe just another way to think about it is that because of the weight-based dosing for Evrysdi and the majority of the patients on other medicines are very small children that there may not be much of a barrier there from a cost standpoint.

Yes.

Yes.