Welcome to our 2024 Pharma Day in London. It's again a great pleasure to have you all with us and have the opportunity to meet you in person. Let me quickly take you through today's agenda and let me also make an upfront comment first. You know, last year, around the same time, at the same place, we provided you a thorough review, not only of our pipeline, but also some very important topics, you know, which we uncovered in our internal business review. Topics like, for example, R&D Excellence. At that occasion, we also had the new management team on stage for the very first time, and since then, I think twelve months have passed, and a lot has happened at Roche.
Some smaller news items, I think, became public, indicating that there is a lot happening at our company. Today, I think we have now the opportunity to wrap up all these bits and pieces and to provide you with some bigger picture insights and also what is going on behind the scenes. So with that, let me quickly take you through the agenda and mention a few housekeeping items. We will have two sessions today, so we will start with a two-hour, ten-minute morning session, primarily focusing on strategy, and then we have a two-hour afternoon session, which will be focusing on our evolving pipeline. Both sessions include a 30 minutes Q&A, where you will have the opportunity to ask your questions here in the room but also then via the web.
Let's start with the morning sessions. The first speaker of today will be our CEO, Thomas Schinecker, providing an update on the overall group strategy. The second speaker will be our Pharma CEO, Teresa Graham. Teresa will outline the new pharma strategy based on the five newly defined therapeutic areas, and she will also highlight some of the capabilities we are focusing on to win in the future. Teresa will also take us through our compare to the industry young on-market portfolio, focusing on additional growth opportunities, and she will summarize some of our mid- and long-term opportunities. The third speaker in the morning will be Levi Garraway, our Chief Medical Officer and Head of Global Product Development. Levi will share with you some insights on our R&D Excellence initiative, which was started about a year ago.
He will outline our ambitions and also provide an update on what has been achieved so far. Following these three presentations, we'll have a 30-minute Q&A with the three speakers of the morning session on stage before we go into the lunch break. Lunch will be for fifty minutes, as you can see, from 11:40 A.M. to 12:30 P.M. At lunch, you will have the opportunity to meet all of our speakers and also the IR officers who will be around. After lunch, then we continue with our deep dive into the primarily late-stage pipeline. We will have five sessions, one session each for our newly defined five therapeutic areas. So, the first afternoon presentation will be given by Charlie Fuchs, our Global Head of Oncology and Hematology Product Development, who will take us through the oncology and hematology pipelines.
Charlie will also provide us some details on the Regor deal, which includes the acquisition of a next-generation CDK inhibitor portfolio just announced today, and he will provide also an important update on our next development steps for hemophilia A. The second presentation of the afternoon will be held by Azad Bonni, our Global Head of Neuroscience and Rare Diseases at pRED. Azad will represent Hideki Garren, our new Global Head of Neurology Product Development, which just got announced last week, and was not able, due to the short notice, to make it to the event today. Azad will provide us with updates on some exciting pipeline projects, including our anti-amyloid beta Brainshuttle and gamma- secretase modulator, both projects in Alzheimer's disease.
The third presentation, then will be held by Larry Tsai, our new Global Head of Immunology and Infectious Diseases Product Development. Larry will share with us an update on the TL1A development program and summarize our efforts in kidney disease, where we just had a positive readout for Gazyva in lupus nephritis. And he will also present two novel antibiotics with truly novel MOAs now in development. If successfully developed, these antibiotics would represent two novel classes, the first ones to actually discover since more than 40, 50 years. The next speaker, Chris Brittain, our Global Head of Ophthalmology Product Development. Chris will take us through our exciting ophthalmology pipeline, summarizing the most recent progress made.
He will also cover the AntlerA acquisition, which we have announced today, and will provide the background why we are excited about targeting the Wnt signaling pathway in diseases like DME and AMD. The final presentation will be with Manu Chakravarthy, our new Global Head of Cardiovascular, Renal, and Metabolism Product Development, which we just had him on stage two weeks ago when we hosted our IR call related to EASD. Manu will summarize again our ongoing efforts in obesity, diabetes, and share some additional preclinical combination data with our PYY analog. After the closing remark from Teresa, we will have an additional 30-minute Q&A with all the speakers from the morning and the afternoon session on stage. In addition, we will have our Group CFO, Alan Hippe, joining on stage as well.
The event will close at 2:30 P.M., but you have the opportunity here to stay around for a buffet reception, which will give you additional time here to talk to the management. Let me also please mention one additional housekeeping item. We have again prepared a short 10-question feedback survey. The link to the survey will be shown to the participants in the webinar 50 minutes before the end of the event. Participants in the room will receive an email about one hour after the event, and we would very much appreciate if you could give us your feedback, as we always strive for improvement. And with that, it's my pleasure to hand over to Thomas Schinecker for a group strategy update. Thomas, please.
Thank you very much, Bruno and also welcome from my side. Really looking forward to giving you an update of what has happened over the last twelve months. I think the team has been very busy and has made a lot of progress, and I hope that we can demonstrate that during the day today. Let me start with the performance and what we believe is the outlook over the next years in terms of our performance. Here on this slide, you see the progress that we've made over the last twelve months on a high level, but we'll give you a lot more detail during the presentations. On the Pharma side, we've launched two new NMEs, so we're on track to really delivering two NMEs on an annual basis. We've had eleven regulatory approvals in the time period.
Also, Diagnostics has been very productive, with five new instruments being launched and 39 new assays being launched. One number that's really, I mean, amazing, is that we've had, over the last five years, more than 50% of all FDA approvals, PMA and BLA in the entire industry. And for sure, we don't spend 50% of all the R&D money that's being spent in Diagnostics in the industry. So you can see how productive we've been over many years in Diagnostics. On the external innovation front, we've already announced in the past Telavant and Carmot, but two further acquisitions that we're just announcing today is the CDK portfolio, which is the next generation CDKs, and also the Wnt agonist, which is a very conserved pathway, which plays...
There's a lot of data that shows that it plays a role in ophthalmology. LumiraDx, really a breakthrough technology in point of care, both from a, you know, modality perspective because you can do clinical chemistry, immunochemistry, but also PCR on that one system. And the cost position makes it just very unique for the point-of-care setting, an area where, which is actually the only area where Diagnostics is not number one, and with that, we can go for the number one position. We've also worked very hard on operational efficiency. One topic that Levi will talk about in detail is R&D Excellence and how we've applied the Bar and how we're prioritizing our portfolio. But we also worked very hard in making our R&D engine a lot more efficient, and Levi will talk about that.
One way to do that is actually, as we looked at all the systems and processes across the different R&D organizations, we worked a lot on harmonizing those systems and processes. And we've also aligned our structure, as you can see with the people here today, to the five therapeutic areas that Pharma has defined as the focus areas, and we've done that throughout the organization. This includes also, promoting good talent within, but also bringing talent in from the outside, that will help us, you know, build a good franchise in these areas in the future. We are still working on optimizing our manufacturing network. I know Teresa will talk about that, too. On the Diagnostics side, we've had in Diagnostics, basically two organizations: Diabetes Care and Diagnostics. We have merged these two organizations. That's complete.
Went live middle of this year, and with that, we've really simplified further our organization, and we could leverage a lot of synergies we have within Diagnostics. With that, also improve our cost position. Lastly, we mentioned that before: we shifted FMI into Diagnostics because at the end, it's a Diagnostics business, and it should be led out of Diagnostics. Now to the sales momentum. On the left-hand side, you can see the group sales growth over the last four and a half years, approximately, and you can see that between 2020 and 2022, we had a contribution of about CHF 19 billion in COVID sales. Now, we always knew that COVID sales would come, and they would go. The good thing is this has washed out.
So you can see that if you look at the second quarter, 2024, versus on the left-hand side and the right-hand side, the two numbers are the same. When we now look into Q3, you will have the same situation. The two numbers will be the same. So we will not have any COVID effect in Q3, which is very important. But what you also see is that for the last one and a half years, we've been growing around high single digits. So there's a really, really good momentum in our business, and we believe this will continue for this year but also will carry us into next year. So very, very optimistic about the momentum that we have. Furthermore, we've been very disciplined.
So, you know, we've been reallocating money, looking for areas where we can reduce our spending in order to shift into areas that are much more valuable to our business, and we've been very, very stringent in doing that. So even though we don't, and that's, I think, a company culture, we don't make huge announcements to the outside. I can tell you there's a lot of movement within the organization, because otherwise you would not be able to get to a P&L that is the shape of this one. So very good cost discipline and operating profits growing double digit.
Now, I would assume that the second half year from a shape of a P&L will look very similar to what you see here, and it's our ambition as we go into next year also to have a good, to carry this momentum into next year and for our R&D spending to be broadly flat into next year. Now, let's take a quick look back at how the performance of Roche has been over the last 10 years. And here you can see that Roche has been growing 5% on average in constant exchange rates and 7% in core EPS. Diagnostics has always contributed during this time period, and you can also see how we have substituted the AH&R business through the diversification of our portfolio. We went from eight blockbusters in 2013 to 16 blockbusters in this year, by the end of the year, we may have 17 blockbusters.
You can see that, you know, the new portfolio is really performing for us, and that's why we're also confident as we go into the future. Here on this slide, I would like to focus first on Diagnostics, so build from the bottom up. On the Diagnostics side, we have a very strong growth on our on-market portfolio, but this year we have probably the biggest launch year in the history of our company. We have a number of launches coming up, also in next year, so we have, you know, a very good performing R&D engine in Diagnostics. That's why we are confident, and we've communicated that also over the last couple of years, that Diagnostics will continue to grow ahead of the market, and the guidance that we've given is mid- to high-single digits for Diagnostics.
I think that's a good number to start out with. At the same time, we've communicated that core growth will be ahead of sales growth. Now, on the Pharma side, we know that we have a very good on-market portfolio, and that's in the light blue. We know that this portfolio will give us growth until 2027. What will happen after 2027? There is no patent cliff situation for Roche, and that's very different to a number of other pharma companies who have significant cliffs coming up. What we expect is that, you know, if there are no new launches in the next couple of years, all that would happen is we would get in an equilibrium state. We would not be in a downward trend.
Then the other thing that we can also commit, and that's very important, is that our margins will be at least stable. So that overall, whatever the situation, we'll manage the costs always efficiently. Now, what can happen on top of that? On top of that, first, it's our in-house pipeline, and we have a number of very important shots on goal, and you will hear that from Teresa later, that can continue to drive growth in the other years. Now, this gray line is kind of risk-adjusted, so, but we also know you have binary events. If the event is positive, the curve upwards can be very significant. But we always have to wait for the results of these trials, and then we know how the future will look like.
But it's very clear that something will come on top. And the last element is BD, which can also help us to continue to drive growth. And so we're very confident that we can deliver this kind of growth also going into the future. Now, looking at what you tell us, and this is basically looking at the consensus. On the consensus, you see on the left-hand side that you expect that between 2023 and 2028, that there is a biosimilar gap of about CHF 7 billion. That, I would say, is basically also something that we agree with, that there is a biosimilar erosion of CHF 1 billion- CHF 1.5 billion on an annual basis, which we can cover with the momentum that we have in our portfolio.
On the middle column, again, taking it from the consensus, you see the on-market portfolio and what the on-market portfolio contributes, and it contributes approximately CHF 14 billion in growth. So CHF 14 billion is significantly higher than the CHF 7 billion. And then there is, some, you know, sales are in there, about CHF 3.7 billion, which is from the pipeline. Again, these are risk-adjusted numbers, so I guess if the trials are positive, the potential is even significantly higher. But what's very clear is that we'll continue to grow until 2028, because what's very clear is that at least already, the on-market portfolio will drive the growth, and everything that comes after that is basically the cherry on the top and will drive more growth going forward.
On the right-hand side, you see those molecules that have pretty much no coverage, and some of them, for example, Gazyva and lupus nephritis, is coming already next year. So, you know, so these are models that don't have a lot in their portfolio in the model. But there is a lot that's coming, which can then add also to this improved sales outlook. Now, let me go into a strategy piece. When I started in March last year, we did a survey with leaders where we asked them about the strategy, we asked them about the goals and how should we achieve them. Is there clarity? And this we used as a basis so to drive the change and adapt some things in the organization. Basically, we've now completed the entire house.
So what we started with and rolled out at the beginning of the year is our 10-year ambition. So what goals do we want to achieve? We started with the group strategy, which we've now rolled out. Digital health, which used to be called Insights, on what do we want to do with that, sustainability, People & Culture , but also on the Pharma and Diagnostics side, and very importantly, operational excellence. Now, here are our 10-year ambitions. Let me start with Pharma, which was updated. It is to deliver 20 transformative medicines addressing diseases with the highest societal burden, and I know Teresa will go into that. These must be very differentiated medicines that are really impactful, that will be delivered by the end of this decade. The Diagnostics side, launching 75 novel differentiated assays.
Now, we know that last year we launched more than thirty, but here it's about completely novel assays. As a leader in Diagnostics, we want to develop assays that no other company has in their portfolio, and we're tracking really well on that. We're actually ahead of this plan. On the group side, we wanna realize more the synergies between Diagnostics and Pharma. One, by providing solutions to healthcare systems to more effectively deliver care. But also, in the value chain, we can be much more effective in delivering the synergies between the two divisions. And in data and digital, we wanna transform our business, the way we do our business, from R&D throughout the entire value chain. So these are the goals that everyone is following through on. Now, let me go through the group strategy.
And there are six key trends that really informed our group strategy. One is there's an increasing disease burden over the next ten years, and interestingly, 50% of this disease burden is in only three different disease areas. So cardiovascular and metabolism, oncology, and neurology. Those three will contribute to the 50% of the disease burden in the world. So this is where the biggest need is in the healthcare systems, and that's why this is a major focus for us. Second, the healthcare systems are massively under pressure. If you look at the last twenty years, healthcare budgets have always grown faster than GDP. Now, this will not be a trend that will be able to go on forever, so it's also our responsibility to help the systems address the costs in the system.
One of the ways they do that is decentralizing care. So care no longer only delivered in the hospital, but really at home or in the outpatient setting. So what does that mean in terms of the Diagnostics, but also in the Pharma products that we deliver, that we actually meet that trend and treat patients where they are, and not where we think they are? The other trend that we see is early detection, monitoring, and intervention. And as you go into even more earlier detection, Diagnostics will play a bigger, bigger role, a much bigger role in the future. And also, taking the treatments into much earlier settings will be critical. Access to healthcare is still a topic, and will continue to be a topic, when not even half of the world's population have access to good healthcare.
There are transformative technologies, like AI, that we need to leverage in order to accelerate and become a better organization. Now, just one proof point from what I've just mentioned is on this slide. On the left-hand side, you can see all the disease burden across the world, and you can see the highest disease burden is cardiovascular and metabolic. So now you also understand why we have to be in cardiovascular and metabolic. It's the number one problem in the world. Second is oncology, third is neurology. All of these areas are growing in terms of disease burden, between 14% and 24%. The other areas. So these are the shared areas that are of interest for Diagnostics and Pharma. Now, the other areas where P harma is focusing on is immunology and ophthalmology. Again, areas that are growing significantly.
If you then look at all the other areas, they are declining by 5%. So we're really focusing on those areas that have the biggest unmet need, where healthcare systems will focus on, especially when they have less budget available. They will focus on those areas where they can have the biggest impact on better healthcare. So what does it all mean for us? Well, we have to prioritize those diseases which cause the highest burden in the healthcare system, and where there's the biggest unmet need for patients. Because this is where, in a future environment, where healthcare systems will start to prioritize the money more and more, we'll actually also focus on.
Second, we need to find ways in order to reduce costs in the healthcare system, and really understand the patient journey on how we can intersect the patient much earlier, so that the patient has a better outcome. And with that, we can also reduce cost of care. On the decentralized delivery, really focusing in point of care, the one area that I told you we were not a market leader, to make sure that we are set up for the future, where care is more decentralized. But also deliver devices, so that people can, you know, medicate themselves at home. People that have multiple sclerosis or other diseases, they don't wanna go to the hospital every time, sit in an infusion chair for hours, and then, you know, get reminded of their disease constantly.
They actually want to live a normal life, especially in chronic diseases, and with that, they want to treat themselves at home. Also, we need to move into earlier detection, prevention, but also curing diseases, because this is what the healthcare system will expect from us. And on access to healthcare, clearly a big focus, and also investing in the breakthrough technologies. So overall, with Diagnostics and Pharma, and digital products that link the two, we believe we are very well set up for a future where care will be much more decentralized. Where the combination of diagnostics and medicine will play a big role, where treatments will become more chronic and you have to monitor yourself, treat yourself. This is where Diagnostics in combination with Pharma will play a significant role.
In moments where, you know, it's much more important to detect diseases so early, that you can actually improve the outcome for patients. And once people are being treated, they wanna be monitored, and they don't wanna go to the hospital every time to be monitored, they also have to do that at home. So we need to be prepared much more for a future in that direction. And we have three shared priority areas with cardiovascular and metabolic, oncology, and neurology, which are the key areas that will drive the increase in disease burden over the next ten years. So clear focus for us, that these are the areas where we wanna work together and improve outcomes for patients along the patient journey. Now, beyond the products that we can build, there are other significant synergies that we have across the organization.
Just on the research and development side, developing biomarkers for research is one, but also diagnostics instruments for R&D. So as we launch, then our sequencer, our R&D organization can have the sequences at cost, because we don't recognize sales within intercompany sales. So we can actually sell between our organizations, systems of cost, our PCR systems, our nucleic acid extraction systems, digital PCR. We can sell everything at cost. So with that, reducing the cost of our own R&D significantly. That's a good example in R&D. On the manufacturing side, we've actually shared antibody production methods, and Teresa will share how the team in Pharma has been able to increase the yields 5x .
So with the same amount of manufacturing footprint, you can produce 5x more of that antibody, and we use that in diagnostics to actually not have to build a number of new manufacturing buildings. And with that, we're saving hundreds of millions already because we don't have to build new manufacturing sites for Diagnostics. And on the commercialization side, we are doing this already. We are the market leader in cardiovascular metabolic. We can leverage our know-how, our market leadership position, to position us well in the cardiovascular metabolic space, also Pharma. So all in all, what we want to achieve is improving outcomes and reducing costs for patients, because we know that this is what the healthcare system expects from us, and we wanna do the same for the healthcare system: improve outcomes and reduce cost to patients.
And we can do that by combining Pharma and Diagnostics by identifying high-risk patients early, and then treat these patients with the right medicine, because the earlier you detect, Alzheimer's definitely one of those, the earlier you detect, the better you have in terms of outcomes, and sometimes you can prevent the disease completely. Also, by stopping the progression of diseases, by accurately diagnosing and stratifying patients to halt disease progression, but also we need to go towards cure. We need to understand diseases better and the cause of these diseases, and with that, also using diagnostics and to restore health through curative medicines, and we need to do all of that where patients are, and patients in the future will not be necessarily anymore in the hospital, but they will be also in a home setting.
Now, let me take you to digital health, something that was called Insights before. This is an area where we've rolled out the strategy already last September, because we worked on it for the first couple of months last year, and that's why we now call it the Digital Health, no longer Insights. And what we also said is, we are not going to have a third pillar. Digital health is supposed to help us make better products in Pharma and better products in Diagnostics. And in that, we've agreed at the time that we will have four product segments that we'll focus on.
At the same time, because in a very decentralized way, we had different platforms and technologies all over the organization, we agreed that we will only have one infrastructure platform, we'll only have one data and analytics layer platform, and that we are going to use reusable pieces throughout all of the digital solutions. Meaning, for example, logins. Logins, you don't have to have fifty different logins that you develop, but you can use one, use that as a reusable piece, and then basically roll it out through all of the software programs. Which, by the way, is a big benefit because then people will actually know that they're working with the same company, and then on top of that, you can build the products.
Now, on the operating model, we said that the informatics organization will deliver the infrastructure platform, and diagnostics will provide a lot of the data analytics layer. In terms of operations, selling products, that will then be in Diagnostics or Pharma. Now, we implemented all of that, and what happened? What happened is that we have consolidated a number of products in Diagnostics and Pharma and took some of them out. We actually generated, after implementing that, savings for this year of about CHF 170 million. We provided 50 reusable components, all going into different softwares. We reduced the data analytics platform. We had 3 data platforms, now into one, which will also help data flow much more effectively. And we also discontinued a duplicative infrastructure platform.
You can see this is an area where we've already rolled it out last year, and how consequently, we went through the implementation in order to make sure that our organization is very efficient, very focused, and set for delivery. Because implementation is critical, and I think this is a very good proof point on how we have been very diligent in execution. Let me just briefly talk also about sustainability, because it's an important part. Here, we focus on three areas where we can have the biggest impact. One is access to innovation, second is our people, and the third is environment. Now, let me just focus on this topic of environment, and you can see that on the right-hand side. We are on track to meet our net zero targets.
So far, we've reduced Scope 1 and 2 in greenhouse gas emissions by 67%. By 2025, so that's not far around the corner, we expect to be at 100% sustainable electricity, and we are committed to deliver net zero for Scope 1, 2, and 3 by 2045, and the absolute zero of Scope 1 and 2 by 2050. And with that, we're the only company in the world that has given a commitment for absolute zero, and I think that's a big differentiation to other companies. Now, let me talk about our commitment to global health security, and you will hear about that a little bit, earlier, later.
On the diagnostic side, with SARS-CoV-2, with SARS-CoV-1, with mpox, I think we've shown that our global surveillance program works well, and that we are very fast in then delivering tests to the world. In fact, we're usually the first. For a big company, we are faster than small companies, and I think this shows that we're very committed, and that we can also deliver here. On the Pharma side, over the last years, we've invested and ring-fenced a certain amount of money in terms of investments into developing new antibiotics. This is part of our commitment to sustainability, that we will make a contribution here. And you can see the last antibiotic was discovered in 1960, and so this is 54, no, 64 years ago.
And now we have two in the pipeline that look promising, but Larry will talk about that. Then, let me also talk about People & Culture . Because at the end, anything you do depends highly on the people that you have and the culture that you have in the organization. One topic I already talked about is talent. Strengthening the talent development in-house, but also bringing in key talent from the outside, which we are committed to. It's about creating an environment where everyone can feel inclusive, so diversity and inclusion, and equity inclusion, is a very important part. But also leadership is important part. Drive urgency, effective decision-making, as well as empowerment and accountability. Effective decision-making is very important, that people drive to decisions and drive through implementation.
With that, beginning of the year, we introduced a new performance and reward system, which much more significantly differentiates between high performance and low performance, and sets clearer expectations on what we want, people in our organization to deliver. This, some of these measures, like also around R&D Excellence, is actually also included in our corporate goals, which everyone in the organization has, in order to drive through the changes that we need in the organization going forward. Now, let me give you another proof point, one that's a couple of years back, that also shows how effective we've been in driving changes. Now, I took over the Diagnostics division in 2019. Prior to that, I was head of R&D for the biggest unit in Diagnostics for two years, and then I led the Diagnostics organization for four years.
So for six years, directly involved in managing and shaping the pipeline and also the organization. We made the new strategy in 2019, and then we implemented that strategy. And what happened in Diagnostics? We made the organization much more efficient, much faster. We took out a lot of administrative burden in the organization, cutting in areas that didn't contribute to making a product or serving customer. So we said at the time, everything that's more than two steps away from either the product or the customer, we have to really challenge our investments. We did that at the time, and with that, we could increase the R&D investments at the time for CHF 500 million.
But we took it out of other parts of the organization, and we channeled that money into point of care, things that are developing now and coming to the market, into mass spec, into the new systems into Work Area , into CGM, into next-generation sequencing. So all programs that are now delivering, if we hadn't done that at the time, we would not have been able to make this progress over those number of years. And you can see how effective we were in reducing complexity in the organization. For example, we went from 48 quality management systems to one during that period of time, and you will see we've now done the same in Pharma. We've reduced the organizational complexity. We have reduced the hierarchy levels from nine to five.
So we were very effective in managing those changes, and with that, we could also fund all of these programs and accelerate all of those programs. And I think that's another proof point that we are committed, and when we say we're going to deliver, we will deliver. Now, final point on around operational excellence. And I just wanna say, you know, maybe that's also, maybe one of the benefits coming from a, a Diagnostics organization, where money is not as, much around as in the Pharma world. You know, you learn how to run organizations effectively. That's because you have to, right?
Now, I also believe the same can be happening with Pharma, because it's actually our job, and it's actually our ethical responsibility, that every million dollar or Swiss franc or whatever currency we invest has the biggest return for shareholders, but also for patients. We shouldn't waste money. We should make sure that money is effectively used to produce new products. And with that, we also looked at, okay, we were an organization that was very decentralized, but there are areas where we need to be much more centralized. It doesn't make any sense that you have different organizations that are using the same IT systems but from different companies. Also, the data doesn't flow effectively if you do that.
So really, radical simplification, simplifying the systems and processes landscape, is something that we've been working on for the last year in a very high degree, and we've made a lot of progress here. But we also wanna make sure that decisions are made where there's the best expertise, but you create a framework that people have to make a decision, that we don't carry on projects forever, but there is a framework if these projects don't meet the Bar that we need, that these programs are then attrited out of our pipeline. But that gives us the possibility to again invest into areas that can have an impact, and this is an ongoing cycle that you have to manage.
And, again, the people that are responsible for these programs and the people surrounding them, they may need to make the decision, but you need to create the framework. And so certain decentralization of decisions are important, also in terms of local go-to-market approaches, but there must be some areas where we have a much more, centralized approach, like for example, on systems and processes and governance. And we do the same on the group. We look at where we can share resources, where we can create synergies, and the rest, we keep, in a decentralized way. Good. Now, I'm done for my part, and you'll hear more about pharma strategy that Teresa will talk about in R&D Excellence, where you can then see what's the progress we made in implementing, some of these things over the last year.
Thank you very much, and over to you, Teresa.
Thank you, Thomas. So normally, when I'm here with you in London, I'm here to give you a whistle-stop tour through our portfolio and to talk to you about all of the things that are going on with our in-market products. But today, I have a special opportunity to share with you, for the first time, our first end-to-end pharma strategy, which very neatly lays out how we will work together all the way back from research and early development through commercialization to provide as much impact as possible for patients. Over the next thirty minutes, I'm gonna walk you through a high-level overview of the pharma strategy, our target therapeutic areas and disease areas, the core capabilities that will be necessary in combination with our science to ensure that we are reaching as many patients as possible, and then we will end by spotlighting our significant growth opportunities.
2025 is a big year for us in terms of data, and there's a lot of exciting things that we'll be reading out. So let's jump right in. So I think first and foremost, it's important to know that when we started the exercise around the pharma strategy, we actually started from a place of pretty good strength. We're number one in a number of key therapeutic areas. We're number one in neurology, OCREVUS, Evrysdi, leading in their disease areas. Vabysmo is certainly coming on strong in ophthalmology, and we continue to hold leadership positions in oncology and hematology. Over the last 10 years, we have more than doubled the number of blockbusters in our pipeline. At the same time, we have significantly diversified our portfolio.
This has also allowed us to weather one of the largest patent cliffs in the industry and still grow, something that we committed to you quite some time ago. And that commitment to innovation is clearly evident in the fact that in that same ten-year period, we launched 26 NMEs. We had more than 40 FDA breakthrough designations. And importantly, that history of innovation continues as we now have more than 70 new molecular entities in development. So where do we go from here? Thomas mentioned at the beginning of the year, we set ourselves a very ambitious goal of delivering 20 transformational medicines, addressing diseases with the highest societal burden. This is an ambition that will not just happen. It will require every part of pharma to operate a little bit differently and together in a way that is unique.
We wanna increase the value of our portfolio by 40%, and with the average peak pipeline sales. We want 80% of our pipeline to have best-in-disease potential. We are not satisfied with just delivering medicines. We want to deliver transformational medicines. Most importantly, we need to make sure that those transformational medicines actually reach patients. We've set ourselves a goal that we will increase by 3x the patients treated with our products. How are we gonna do this? Roche is a company that I think you all first and foremost would identify with following the science. It's what we've been known for over generations, and it's something that we never want to lose because it is central to who we are as a company.
But what we also recognize is it's important to have a purposeful balance between following the science and an intentional focus of making sure that we can turn that fantastic science into medicines that actually reach patients, where we can use the depth of our technical expertise and our operational scale to reach as many people as possible. The pharma strategy was designed to help us strike that balance between following the science and having that intentional focus so that we can leverage everything that Roche has to bring to ensure that more medicines reach patients faster. At the core of this is something called the Bar. So now I hate to steal Levi's thunder because Levi describes the Bar better than anybody else you'll ever meet, but I have to talk about it a little bit.
So fundamentally, The Bar is the criteria by which something enters or advances in our portfolio. They are five key criteria that we are now asking ourselves about every asset end-to-end in Roche, all the way back from research through to line extensions. Does this pass the Bar? The Bar does not ask the question: Can this asset be a medicine? The Bar asks the question: Can this asset be a transformational medicine? And if it can be a transformational medicine, it enters the portfolio or it advances. So now, going back to this idea of purposeful balance, between follow the science and intentional focus, the Bar helps us decide what assets come into the portfolio, but ultimately, we need a higher-level look at how we then think about the construction of our portfolio overall, and that's where the pharma strategy comes in.
This is, in essence, a high-level summary of where we're headed. Where we play, we have five priority therapeutic areas: oncology and hematology, immunology, neurology, ophthalmology, and our newest therapeutic area, cardiovascular, renal, and metabolism. In addition to those five therapeutic areas, we know that great science is necessary, but we also need to make sure that we have the capabilities to deliver that science to patients. And so there are six core capabilities that we are also focused on ensuring that we are continuing to invest in, and we are continuing to make sure that we have the ability to be best-in-class in those areas as we move our portfolio forward. And it is the combination of these two things that will ultimately allow us to deliver on that ambition of twenty transformative medicines.
So now let's take a little bit of a deeper dive into our therapeutic areas and our focus diseases. So as we were coming up with our therapeutic areas, we didn't just say: "Okay, well, what are the five things that Bruno's had on his slide all year, and how are we going to retrofit into that?" We actually took a very big step back, and we said, externally and internally, "What are the therapeutic areas that make the most sense for us?" We looked at the burden of disease and societal cost. Thomas talked quite a bit about this. Where are healthcare systems spending the majority of their resources because they have most of their patients who are unable to be controlled today?
These are the areas that have significant unmet need and are needing new standards of care, not only to improve patient outcomes, but to drive down costs in global healthcare systems. But these also have to be areas where there's tractable science. You have to be able to look at where is our understanding of the science, where is our understanding of the biology going, so that we can actually take that transformative science and turn it into medicines that will ultimately help those patients. It's also important that we focused on therapeutic areas where Roche actually had the ability to pull that science through to patients, where in some cases, we already had a pipeline that had best-in-disease potential, but importantly, where we had therapeutic expertise and knowledge that would allow us to make smart and good decisions as we advanced into these therapeutic areas.
What makes us feel good about the choices that we've made is that our therapeutic areas, as Thomas mentioned, comprise 60% of total, total global disease burden, but they also represent 80% of potential growth over the coming decade, so to put this a little bit in more detail, so you can see here with the global burden of disease in DALYs, that we are in the areas that are growing the fastest in terms of unmet patient need, and you can see that we also are in areas that have a significant number of patients, so we know that the science that we're developing has the ability to actually help a lot of people, which is quite important. We also know that we're focused in the areas that have significant opportunity for growth.
So you can see on the Y-axis here, the CAGR from 2024 to 2028, and on the X-axis, market size and bubble size also indicates how large that market is. And you can see that we are in the markets where you have the highest growth and the highest potential to generate revenue. The one question you might ask is ophthalmology, the ophthalmology bubble might seem a little small. That is because largely, it's a little bit about timescale, but ophthalmology becomes much, much more important as populations age, and more and more patients will ultimately need drugs to help them maintain their sight. Because we know when you lose sight, you lose a tremendous amount of what makes you able to actually live on your own and live your life the way that you want to.
But those five therapeutic areas are quite large, and so we wanted to take a next step and say, within those five therapeutic areas, where are the diseases where we believe we have the opportunity to be most transformational? So we took those five therapeutic areas, we put them through another funnel, and we came up with our end-to-end disease areas. There are eleven end-to-end disease areas that we focus on today. What is an end-to-end disease area? These are diseases in which we will have dedicated research teams internally, who are focused on delivering novel science. We will ensure that we have significant early and late-stage development investments, both in our own portfolio and as we look outside, and we will ensure that we have full-scale commercial investments to realize that science as it becomes a medicine.
But don't be fooled. We will never lose what makes us Roche. We will never lose the commitment to following the science. And where we see breakthrough potential in different disease areas, we will absolutely continue to follow it, and the Bar will always be our first question as we enter those new diseases and see new assets. So what are those eleven diseases? So here they are. So some of these are places where we already actually have large end-market assets. Hemophilia, market leader with Hemlibra. Multiple sclerosis, market leader with OCREVUS. Retinal and vascular disorders, fast coming on with Vabysmo. But some are places where we have pipeline assets that we believe will be truly transformational, such as in obesity or in Alzheimer's disease.
Importantly, when we look at these five therapeutic areas and our focused disease areas, we are not just looking at disease. There are also a number of mechanisms or pathways that we know are going to be particularly important in these different, in these different therapeutic areas that would have the opportunity not only to be important in a particular disease, but potentially across diseases. And so there are also a number of priority pathways that we are focused on as well. It's also important to note that categorization is dynamic. We can and will make changes to our categorization as there are changes either in the science or in the opportunity available for patients. So let's take a little bit of a look about how this actually translates into our portfolio today.
So if you actually look at our portfolio today, you can see that the five therapeutic areas are clearly represented, and our end-to-end disease areas are also very well represented. If you look at our on-market portfolio, which, as Thomas mentioned earlier, is going to continue to drive growth in the coming years, you can see that it's very well aligned with the focused disease areas. As we head into products that will launch within the 2025 and 2028 timeframe, again, you can see we're very well aligned with our focused disease areas, fenebrutinib, tronti, vamikibart. These are all things that very nicely fit into our strategy. And then finally, those things launching beyond 2028, zilebesiran and hypertension. This is a great example of what we would call a breakthrough asset.
Hypertension wasn't on the end-to-end list, but we believe that zilebesiran has the opportunity to be truly transformational in the treatment of hypertension. We are actively working with our partner to develop that medicine, and if it comes to patients, we believe that it will provide a tremendous amount of benefit, and we will be supporting it with aggressive commercialization. We have our obesity assets here, and we have our GSM asset for Alzheimer's, which Azad will talk to you about later today. But as Thomas alluded to, we're not just looking at our pipeline today. We're also looking at our pipeline tomorrow, and that includes what are the things that we can bring in from the outside?
So over the course of the last number of months, we've done a number of very exciting deals, and you can see many of them listed on this slide. But the last few that we've done very nicely align with our core therapeutic areas and priority disease areas. AntlerA, the Wnt agonist in ophthalmology. I won't say much about this because Chris is going to talk about it extensively this afternoon, but a great fit for what we're doing in ophthalmology. And you heard this morning about Regor Therapeutics deals, the CDK4/2, CDK4, a perfect fit with our breast cancer franchise. So as we're looking at our partner opportunities, we continue to look for things that fit nicely within our end-to-end disease areas, as well as continuing to explore those opportunities for breakthrough science.
So now let's actually see what this looks like in practice, and let's start with probably one of our most advanced end-to-end disease areas, and that's breast cancer. You can see here that across all phases of development, we have quite, quite a good pipeline of breast cancer medicines. But we also have a very impressive presence already in breast cancer. Our HER2 portfolio, our HER2 franchise is expected to continue to grow over the next several years. We expect that it will retain about 40% of its total peak value, well into the future. We are moving aggressively into hormone receptor-positive breast cancer with the giredestrant trials reading out next year, and in addition, we've just had the Regor deal that is now, that has now been signed.
We are very, very much committed to not only being in breast cancer but in curing breast cancer. One of the assets that's actually coming up on its FDA approval is inavolisib, and inavolisib is actually a wonderful example of one of those priority pathways. PI3 kinase-mutated tumors appear not only in breast, but they also appear in many other tumor types. inavolisib clearly showed phenomenal results for patients who have this mutation. It's been filed. We expect our PDUFA at the end of November. Charlie will talk to you in much more detail about all of this data. But what we see here is something that has the potential between the initial trials in breast cancer to be a $1 billion-$2 billion opportunity but also has the opportunity to move into many other tumor types.
So this is a great example of a priority disease area and a priority pathway. Now, looking at our malignant heme portfolio, again, there are tremendous, a tremendous amount of activity, not only with our bispecifics, but you'll notice down here at the bottom, we have also moved our allogeneic CAR T programs with Poseida into the clinic in phase I in both B-cell malignancies and in multiple myeloma. So lots of activity going on in the hematology portfolio, and that very nicely complements our on-market presence. Polivy continuing to entrench itself in first-line DLBCL. We now have more than 33,000 patients who've been treated. It is beginning to show up as the standard of care. We have just recently submitted the five-year POLARIX data to a conference, so now we'll begin to see the long-term data associated with Polivy.
Columvi and Lunsumio are continuing to gain traction in the market. We have filed, as you know, the positive STARGLO data in second-line DLBCL for Columvi, and we just recently announced positive data in third-line follicular lymphoma in a subcut for Lunsumio, which is also being filed with regulators. So hematology is an area where we have historically been very strong. We continue to make deep investments from a clinical perspective, as well as having a very strong on-market presence. So now let's move over to hemophilia A. So again, this is an example of something that about a decade ago would have been a breakthrough technology. This would have been a breakthrough area for us, but we saw great science, we followed it, and it is now an end-to-end disease category.
So obviously, Hemlibra continues to be the market leader, but you see NXT007 has now moved into phase II, and we're very excited that this could actually be possibly one of the drugs that provides a bleed-free experience for hemophilia patients, and Charlie will talk a little bit more about this this afternoon. I also just did want to highlight for you that Dirlo, which is our Spark program in gene therapy, has been placed on pause while we re-evaluate that program and see what will be necessary for any gene therapy to effectively compete against standards of care like Hemlibra that are already dominant in the market. So that program is currently paused as it is being re-evaluated. Hemlibra remains the global standard of care, 41% market share in the U.S. and the EU5.
It is 80% of patients remain bleed free, and we are continuing to do more and more to enhance the patient experience of people who are on Hemlibra, whether that's new vial options, the updated admin kit, or the auto-injector, which is currently in development. Hemlibra is a great example of a drug that provided transformational benefit to patients, that changed the standard of care in an entire disease, and one where we continue to think about how we raise the Bar on ourselves to ensure that we continue to bring better and better, treatments to patients. Multiple sclerosis is another relatively new end-to-end disease area for us.
Again, you can see that we have quite some investment in the pipeline, whether it's the line extensions for OCREVUS subcut, which has just recently been launched, or OCREVUS high dose, which reads out next year. We have fenebrutinib, which is our oral BTK, which is reading out next year in both RMS and in PPMS, and then we have our Brainshuttle CD20, which is an earlier stage for MS. OCREVUS again continues to be market dominant in the MS sector. The approval of OCREVUS subcut, ZUNOVO, as it's known in the U.S., has recently happened, and it now takes patient treatment down to ten minutes every six months, which is really a tremendous advance for patients.
This has the potential to drive and unlock significant expansion for OCREVUS, allowing us to reach patients who, for whatever reason, were not able to access IV treatment in the U.S., to reach a whole selection of patients who primarily are with community neurologists who don't have access to IV capacity. This is not only a great advance for patients, it also unlocks a significant market opportunity. The other thing I'm really, really proud of for OCREVUS is the amount of time that we have spent doing phase IV trials that actually look at the impact of OCREVUS on family planning. I think most people know that the primary MS primarily hits young women who are in the phase of life where they want to start planning their families.
OCREVUS is the only high-efficacy therapy that has this significant body of evidence that talks about its impact on reproductive health for women, and I think we should be really proud that that data exists. So this is hot news right off of last week's announcement that the Gazyva lupus nephritis study has come back positive. Many of you will remember, this was a trial that I was personally really excited about, being a big believer in B-cell therapy for lupus. Again, you can see that there are a number of trials that Gazyva is currently in. The sum of those trials, if positive, lead to about a $1 billion-$2 billion opportunity for Gazyva.
You will hear a lot more about this trial later this afternoon, but I think, again, the fact that we had positive phase III data in lupus nephritis in a very strict endpoint, complete renal response, represents a really positive opportunity for patients to get control of a very debilitating type of lupus. Moving on to ophthalmology. So I will not spend a lot of time on our portfolio because Chris is gonna take you through this in a lot of detail. But what I will say is, as a company, we have one of the most diverse and exciting pipelines in ophthalmology, covering a number of different diseases and modalities. And so I think there is a lot to look at and be really excited about, as well as some great readouts that will be happening next year.
But Vabysmo is clearly the cornerstone here. The launch of the prefilled syringe has just happened; it is going exceptionally well. I was just at Euretina. Was that last week? Two weeks ago? And what I can tell you is that there was a tremendous amount of excitement about the prefilled syringe. It is getting a lot of positive reception in the U.S. It requires only one hand to use, and the growing body of evidence that we are seeing with Vabysmo, not only with real-world data, but also real-world clinical experience, is incredibly exciting. And so again, I continue to say that Vabysmo should be the standard of care for these patients.
This growth has consistently outpaced analyst expectations, and we expect that it will continue to grow in a really meaningful way, providing a lot of value to patients. And last but not least, our obesity profile or portfolio. So we all know that obesity is a major problem in the world. By 2035, 50% of adults in the world will be obese, and that's not just Western adults. Sadly, this is now not a disease of Western countries; this is a disease of the world. These patients will not only suffer for being overweight; we know that overweight and obese people tend to have more significant comorbidities. We also know that this is gonna be an incredibly large market, with estimates upwards of $100 billion and more by 2030 and beyond.
We do believe that our pipeline has the potential to be best-in-class and extremely competitive in a market that will be highly segmented. You saw the data that was released at EASD, just a couple of weeks ago. There is more data coming by the end of this year and beginning of next year. Manu will cover all of this in a tremendous amount of detail this afternoon.
But I think what is especially exciting to us is the fact that we believe that with the assets that we obtained through the purchase of Carmot, we have a great suite of highly differentiated assets that we believe, either through the efficacy and safety of the individual molecules themselves, or importantly, in combination with drugs that we have in our own pipeline, have the opportunity to be very competitive in a number of different ways. I also want to call out here that we will see data on CT-176, which is our PYY analog as well. So now let's shift to our core capabilities. Again, the science is the first step, but it's not the last step.
We also know that we will need core capabilities that allow us to commercialize that science around the world, and we're focused on six: modalities and technologies, devices, our manufacturing footprint, customer experience and access, data and AI, and our people. Let's start with technologies and modalities. We increasingly know that understanding the biology of a disease is just not enough. You also need to know what is the modality that is most likely to be able to access a target. Roche has a long legacy and a number of leading and different modalities, from monoclonal antibodies to bispecifics. You can see across our pipeline and portfolio, we have a tremendous amount of experience in all of the new modalities that are coming, small molecules all the way from small molecules to our allogeneic CAR Ts.
This is a place that we realize we will need to continue to be strong. We will need to continue to focus, and we are constantly on the hunt for new modalities that help us to better target the biology that we know we need to tackle to provide more benefit to patients and new diseases. Thomas already mentioned the growing trend of decentralized healthcare. A core part of being able to help patients in a decentralized way is actually having a device. We estimate that 60% of our current pipeline, either from a new molecular entity standpoint or a line extension, will require a device, and so we need to remain good at this, and we need to continue to expand how we think about devices.
We already lead in intravitreal delivery, so again, that prefilled syringe for Vabysmo is a great example, but the very unique PDS platform for intravitreal drug implant. This has just relaunched in the U.S. We expect to see it launch in the EU in the coming year. But this is a platform that will not only work with Susvimo, but will also work with our DutaFabs in the next generation. So a lot of really, really impressive innovation in the intravitreal space. We also have just launched two new subcuts with OCREVUS and Tecentriq, and we are continuing to think about what are the kinds of devices that our patients are going to need into the future, how do we manufacture them at scale with the highest quality, and with acceptable COGS.
Speaking of manufacturing, as Thomas mentioned, we have spent a lot of time over the course of the last number of decades looking at how to really streamline our manufacturing processes. We have worked very hard to develop a cutting-edge network that brings the production of our molecules in the highest quality way, as close to our delivery systems as possible. You can see across all of all of a number of different mechanisms, ways that we have really been working to make sure that we are developing a network of the future that allows us to meet our portfolio where it's at and get ahead of the needs of the portfolio of the future. One of the places that becomes particularly important is how we plan to manufacture our incretin profile, our incretin pipeline.
So we've talked quite a bit about our plans for CT-388 and CT-868, so the injectable peptides. We know that we have clinical supply space already reserved at CDMOs. We don't see any near-term capacity constraints that would propose a challenge here. Our commercial production will be a mix of in-house and external manufacturing. We believe that we have plenty of resources within our current capital budget in order to be able to make the necessary investments, as well as working with our CDMO network. We do expect that by the time our drugs come to launch, there will be more capacity in the CDMO network, and I think if you talk to the contract manufacturers, you will hear them say this as well.
We are consistently investing more in-house device development capabilities and strategic partnerships to make sure that both of these molecules come to market with a strong device. And then obviously, CT-996, which is a small molecule, will be manufactured by Roche, as it, it's a fairly straightforward chemical synthesis process. But why can we do this, given the breadth of the portfolio that we already have in-house. That is because for the last three decades, we have focused on making our drug substance manufacturing processes incredibly lean. We have invested heavily in doing a lot of work to make sure that we are getting the highest yield products at the highest quality, at the lowest cost. Right now, we have a fivefold productivity increase from 2000 to 2030 , and we continue to lean into ways to increase that.
In fact, we just launched a new version of Perjeta, which is 4x more efficient to produce than the prior version. So we're consistently looking at our own molecules and thinking about: How can we make them higher yield, and how can we make them at lower cost? I'm going to switch gears a little bit here and now talk about our track record in reaching leadership in new therapeutic areas. So we often get a lot of questions about how we plan to enter IBD and obesity, and what gives us confidence that we can do this. What gives us confidence that we can do this is that we have done it before. We have done it before multiple times and in places where we were getting asked the same questions. OCREVUS, highly entrenched competitor in Biogen when we came in with this molecule.
Hemlibra, competing against factor VIII, extremely well-entrenched. Vabysmo, again, had a very strong incumbent, entrenched competitor when we launched. But by taking the time to understand the market, understand what patients needed, what was important to physicians and healthcare systems, we have been able to create an industry-leading footprint for all of these molecules and position them for very strong growth and commercial success, and it is because of our experience in doing this and replicating it over and over and over again in markets around the world, that we have exquisite confidence that we will be able to do the same thing as we enter into IBD and CV RM, so let's also talk about data and digital, AI in particular. We were talking about ChatGPT earlier today.
AI will revolutionize drug development, and it's not going to revolutionize drug development tomorrow. It's happening today. It's happening now. And Roche and Genentech have really been a leader in this space. Everything from Lab-in-a-Loop , to thinking about how we can utilize AI in our regulatory document writing, to some very interesting things around digital twins in our manufacturing lines, to how we can think about using AI to be more efficient in our commercialization. We have made significant investments in AI, and we will continue. But what makes me particularly confident that we can take full advantage of this going forward is that the number one thing you need to make AI work for you is data. And Roche and Genentech together have more data than just about anybody else.
You heard Thomas talk about all of the work that's happening to streamline and harmonize our systems. This is one of the reasons that becomes so important, because when that data is all together and we can look at it in ways that make sense across the end-to-end portfolio, it allows us to make better decisions and harmonize the power of AI more. We commercialize our products in over a hundred countries. Imagine the power of that second and third launch country being able to know on the day of launch what customer segmentation, what customer messaging, and what kinds of things they need to do the minute they pull up to the parking lot of one of their physicians. Imagine what we can do to help patients have a better patient experience if we can truly understand how they're interacting with our medicines in the world.
This is a place that we are investing in, and we're investing in with a lot of focus and a lot of energy, because we believe not only is it the right thing to do, we believe that it will provide us a distinct competitive advantage that is really unique to Roche and Genentech, and then finally, our people. So as Thomas mentioned, there isn't anything that happens without having the best people. We are committed to maintaining a high-performing organization, but it is important that we make sure that we're bringing in talents and capabilities that have the experience that we might need, where it doesn't currently exist in the organization today, and so at the same time, we're looking to create the kind of culture that maintains that retains the people that we want to retain and attract.
We're also making sure that we're being very open-minded to bringing in talent from the outside so that we can take full advantage of this amazing pipeline that we have. And so I'm going to bring us into our home stretch by covering our growth opportunities. So these are some of our key pipeline assets, both NMEs and line extensions. And you can see in our new molecular entities, we currently have seven NMEs with more than $3 billion peak sales potential. That's giredestrant, it's the anti-TL1A for IBD, it's our obesity assets. These are large potential. These are very large potential new drugs. We also have four NMEs that have between $2 billion and $3 billion peak sales potential.
So inavolisib, when you see the totality of its indications, fenebrutinib, when you see the totality of its indications, Elevidys for DMD. Again, these are projects and programs that are in the clinic close to reading out or already with Elevidys already being sold today, where we believe we have the opportunity to add significant growth to our portfolio. And within our line extensions, we have six-line extensions that could add between CHF 1 billion and CHF 2 billion peak sales per year. So that's clearly the bispecifics that have a lot more room to go in terms of their life cycle. It's OCREVUS with subcut and high dose coming on strong, and things like Gazyva, which still has quite a number of indications left to read out.
So there is a lot of growth that exists in our pipeline today, and a lot of innovation for us to bring forward to patients.... and finally, this is a sneak peek at the news flow slide for 2025. There is a lot happening next year. We're going to keep you very busy next year. We have six significant regulatory filings expected next year, and we have twelve phase III readouts, and we have more phase I and phase II data coming for some of our most exciting earlier pipeline assets. When I think about the opportunity that's before us, we not only have a young, best-in-disease portfolio in the market today that's changing the way the treatment is delivered for patients, we have a very dynamic portfolio. R&D Excellence is helping us to discover ways to actually streamline that portfolio and bring it faster to patients.
We've made some exciting acquisitions and deals, which very nicely supplement where we wanna go with our end-to-end disease areas. We are well-positioned to deliver significant growth and more significant value for patients. I firmly believe that if we maintain the rigor in the science and the discipline in the business, that we will be able to meet that ambition of 20 transformative medicines, and we will be able to bring a lot of value to patients in the coming years. And so with that, I'm gonna turn it over to Levi to talk a little bit more about R&D Excellence.
Hi, everyone. It's great to have a chance to come back to London and talk to everyone, particularly about R&D Excellence, which is an initiative that you heard about last year, but we've been working on a great deal over the past year. So for us, R&D Excellence has really two overarching objectives. The first is to deliver many of the world's most impactful medicines and to do that consistently over time, and in fact, during the present decade, we hope to deliver 20 such medicines. But the second is to sustain top quartile productivity across the industry. And over the past year, we've taken multiple steps to attain both of those objectives across our divisions, and actually, this has involved significant change.
This is change to our pipeline, change to our decision-making and governance, change to our approach to business development, our incentives, and various aspects of R&D engine. So I'll touch on all of those. But we have six solutions that together we believe will help us attain our overarching objectives, and three of them, which are shown across the top of this slide, are really focused on assembling and governing a pipeline that consists solely of programs that have transformative potential. And this should ultimately enable us to deliver many of the world's most impactful medicines. Now, two additional solutions can propel us really towards top-tier productivity, whether that's by making our R&D engine more efficient or by embracing specific objectives that really are tightly coupled to overall financial ambitions.
And then finally, we have one solution that ensures that our incentives of our people are really aligned with efforts that will really elevate R&D performance. So we're gonna start with the adoption of unified portfolio framework, and really, this is about if we're gonna bring more high-impact medicines forward, we first have to be able to recognize programs that have transformative potential wherever they might reside, whether that's in our internal pipeline or in the external world. And just to provide a bit more context on this specific point, you know, in the past, there has sometimes been a sentiment in parts of the sector that perhaps the prevalence of so-called, you know, mega-blockbuster therapeutics might start to diminish, and this perspective was buttressed by analyses such as the graph that's shown on the left.
And, so at first blush, you could say, well, maybe the percentage of launched NMEs that achieve blockbuster status or greater could be going down over time, and you can see there are two five-year segments, and in the earlier five-year interval, about 45% of launched NMEs achieved blockbuster status. That's the blue portions of the graph. But in the subsequent five-year period, that percentage drifted down a bit because you also start to see this growing proportion of NMEs that maybe don't quite get there. And actually, there was a plausible basis for this narrative. You have the expansion of precision medicine, and you have increasingly frenzied competition in the sector. So conceivably, that could push the industry towards greater fragmentation and reduce revenues for NMEs, and perhaps even a changing business model over time.
That has been a narrative that's been out there, but in reality, the evidence suggests otherwise. First of all, the actual numbers of launched NMEs that reach blockbuster status, they're actually not going down over time. There were 32 of those medicines in the first five-year segment, and then there were 38 in the next. But then, of course, we all know that if anything, we're seeing increasingly dramatic examples of transformative medicines in recent years, and that phenomenon is illustrated in the table on the right. In this illustration, we're using financial value as sort of a rough proxy for transformative patient impact. I mean, it's an imperfect correlation, but not completely unreasonable.
But if you simply bin the world's most valuable medicines according to annual revenues, you can readily appreciate that there are 48 or 50 or so medicines that stand apart even in the overall upper tier. And we can all name multiple examples of these types of transformative medicines, and they're evident in all five of the therapeutic areas that Teresa introduced earlier. So, the bottom line is, we must be able to recognize R&D programs with that kind of potential, whether they're in our pipeline or whether they're somewhere else. And then conversely, we have to be honest. If an R&D program doesn't have that kind of potential, we have to be willing to cull it as quickly as possible and divert resources elsewhere as quickly as possible.
So about a year ago, many of our senior R&D leaders worked together to consider: How do we do that? How do we recognize transformative programs? And so one of the exercises was to study some of the world's most valuable medicines. And the concept was maybe we can identify some unifying characteristics, and we did. We observed five criteria, which are shown here, and each of them have to be met. All five of them have to be met if a program or a medicine is going to be transformative, so we call this the Bar. And I will be the first to concede that none of these criteria are particularly surprising or controversial. And of course, many companies, including ours, have utilized frameworks to guide R&D efforts in the past and decision-making in the past.
But the primary difference here, and Teresa articulated it very well, the primary difference is the question that we're asking. We're not simply asking if an asset can make it across the finish line to become a medicine. We're asking if it can become a transformative medicine, and in doing so, we are finding that systematic application of the Bar across our pipeline end to end has evoked different kinds of conversations and provocative questions, as we consider how and where to invest. And so I'll just briefly go over these criteria. So the first one is that the candidate has to answer a clear and addressable unmet need. So in other words, the science has to have advanced to the point where there is a compelling opportunity, a compelling therapeutic opportunity, that exists to bring new clinical benefit.
The second is that we must engage with the medicine, a foundational target, so a foundational target is a protein or some other factor for which there's a causal link between either the disease itself or the debilitating clinical manifestations of that disease, so third, the asset must possess worthy pharmacologic characteristics compared to the other contenders out there, and that obviously includes efficacy and safety parameters, but also combinability with other key medicines, and developability and manufacturability and patient convenience, so a spectrum of considerations there. Fourth, each asset must be capable of meaningful therapeutic differentiation, and in other words, it has to anchor a treatment that is in some way superior to what's already out there, and finally, there has to exist a path to value.
Value, of course, first and foremost, to the health of patients, but equally, meaningful economic benefit to Roche. We've applied the Bar end to end across our R&D pipeline, and we've embedded this approach into our governance and our portfolio review, and we, we've also incorporated these same characteristics when considering business development opportunities. There have been three specific outcomes that we've already experienced as a result of the Bar application, and they're shown at the bottom of the slide. The first is that by catalyzing the right conversations across the board, we see programs with high promise really starting to leap out, and that recognition allows nimble reallocation of resources to either accelerate or maximize their chances for success.
And the second outcome is a logical extension of the first, which is that there are some programs with exceptional promise, and they merit additional interventions to fast-track their path to launch, and so I'll come back to that in a moment. And of course, the third outcome is that the Bar catalyzes removal of programs that do not have a feasible path to a robust impact, and that allows resources to be pivoted elsewhere without delay. Okay, so let me say a little bit more about the assets that we're going to fast track, including some examples. So as I mentioned, the concept is not only can these assets clear the Bar, but they may also have undergone appreciable clinical de-risking, and they have outsized potential to bring value to patients and Roche.
So we will deploy additional resources across our divisions to bring these assets forward more, more quickly. And there are three programs for which we've already initiated fast-tracking efforts, and these are our anti-TL1A antibody for ulcerative colitis and Crohn's disease, trontinemab, our Brainshuttle antibody for beta amyloid plaque removal, and CT-388, which is our injectable incretin for obesity and other indications. So you're going to hear about each of these assets after lunch, but the specific fast-track opportunities, I mean, they differ depending on the asset, but they can include levers to accelerate pivotal trial enrollment or alternatively more rapid expansion into additional studies or indications based on data that's emerging. And of course, we fully expect that other programs will soon progress to the point where fast-tracking options make sense.
Okay, so over the past year, application of the Bar has had a material impact on the composition of our end-to-end R&D pipeline, and so this graph summarizes pipeline additions and removals that have occurred since around the time we last convened with you here in London. So on the one hand, we have 17 NME additions, 8 of which were acquired through business development, and 9 others were added through internal progression. And then there are 26 NMEs that were removed from the pipeline. 9 of those removals were specifically linked to application of the Bar. Most of the others were part of kind of natural internal attrition, but of course, those are indirectly related to Bar criteria. And then, of course, there was a product launch, which is the ultimate outcome. So the...
Leveraging the Bar, the goal is to architect a pipeline that consists solely of programs with transformative potential, and we certainly still have work to do to get all the way there, but hopefully, you see that we've made progress over the past year. So the next R&D Excellence solution is really about reconfiguring our portfolio management and governance, and really, there are two critical elements here. The first is about applying the Bar consistently and regularly across the board, wherever we are in the pipeline. But the second is about achieving a sustained increase in clinical trial success rates over time, especially pivotal clinical trials. So we've made several changes to how our molecule teams and portfolio governance works.
First of all, for each molecule, we have a single team that operates across the clinical development continuum, and this allows kind of a cohesive longitudinal flow, it complements our decentralized structure, and it reduces white space, particularly as transitions occur from early to late, for example. Now, we've also strengthened oversight and technical review during the pivotal enabling and pivotal design stages. And here, it's not just about maximizing the Bar, but it's also maximizing the likelihood of success of our clinical programs that do clear the Bar. And in addition, our R&D subgroup of the Corporate Executive Committee is reviewing regularly sort of the overall end-to-end pipeline profile to ensure the right balance between risk and value potential.
Again, the key concept behind these changes is really to recognize and to resource our pipeline assets that meet the Bar and to maximize the probability of success, in particular, for the pivotal clinical trials. I'm gonna come back to our progress on pivotal trial success rates a bit later. All right, the next R&D Excellence solution really emphasizes the need to recognize opportunities for transformative potential wherever they may be found, externally as well as internally. And at a high level, our progress in this area seems pretty clear. You are by now well aware of the business development deals that we did last year, bringing in our phase III-ready anti-TL1A antibody, of course, the Carmot assets for obesity and metabolism, the partnership with Alnylam, involving the RNAi therapeutic zilebesiran for uncontrolled hypertension.
You're gonna hear more about all of those this afternoon. And in 2024, we've continued to evaluate external opportunities using the Bar framework, and they have resulted in additional deals. And one of the additional deals, which we've already mentioned, is the Regor Therapeutics CDK2 inhibitor. And if you think about this through the lens of the Bar, which is again shown on the slide, in small font for you, there's clearly still considerable unmet need in in ER-positive breast cancer, despite advances from, for example, the CDK inhibitor class. And we know CDK4 is a foundational target there, and yet, the development of resistance to CDK 4/6 regimens is a major element of unmet need, and CDK2 overexpression is thought to be one such resistance mechanism.
So this is a molecule CDK4/2 inhibition that might have worthy pharmacologic characteristics in this setting based on the initial clinical data. Charlie will walk through the data itself and additional rationale, but overall, we are seeing reasonable progress in terms of our external innovation approach, and this is a key component of R&D Excellence. All right, so I've described three solutions that should enable us to deliver many more transformative medicines, and now I'm gonna take a slightly deeper dive into the R&D productivity segment. And one of the solutions here is about setting clear R&D objectives that can elevate productivity.
By way of context, when you look at R&D productivity across the industry, you can see that Roche is industry-leading in annual R&D spend, and the productivity that results is certainly respectable, and at the same time, we see an opportunity to optimize that investment in order to boost annual peak sales even further in the coming years. R&D productivity can be represented notionally as an equation in which the numerator has three components: volume, value, success rate, and these together describe R&D effectiveness. Then the denominator has two components, cost and cycle time, which together describe R&D efficiency. What you see on this slide is that we've identified stringent ambitions for each of these metrics that we strive to achieve by 2030 in order to reach for that top-tier productivity.
And example ranges, they range from increases in phase 0 starts, heightened peak sales potential of pipeline assets, market increase in phase III success rates, and in the denominator, driving costs per NME down substantially, and also making major gains in cycle time. And one thing that is important to... I mean, we fully recognize that the productivity components that we're showing here, they're not independent variables. For example, reductions in cycle time also sometimes come at increased cost. And boosting phase III success rates may require longer cycle times, for example, to boost robust phase II generation. But the point here is to have ambitions that inspire our teams and the broader organization, really, to think creatively about how do we elevate our R&D performance.
So with this framing in mind, let's take a look at some productivity gains that we've already achieved over the past year. And I described the assets that we added to our pipeline through either business development and internal progression, and so those have certainly preserved a robust volume of pipeline NMEs. And then the pipeline additions, together with application of the Bar, have already increased the average peak sales projections of our pipeline assets by over 0.2 billion, as you can see here. Then, over the past year or year and a half, we've had multiple pivotal clinical trial starts, but our estimates for their probability of success, or PTS, are tracking about 10% higher than historical averages for team-assessed PTS.
This is meaningful because aggregate team-assessed PTS, for us anyway, has proved quite useful as a forecasting tool for pipeline performance. So we feel like our implementation of changes of governance and really our overall emphasis on heightened phase III success rates, we think we're setting the stage for that to really play out over time. Now, on the efficiency side, this past year, we have freed up approximately CHF 200 million that can be directed towards higher return on investment activities. And importantly, while doing so, we've also kept overall R&D spend flat thus far in 2024, and Thomas alluded to that point earlier today. And finally, we've seen initial progress on cycle time acceleration.
Now, several of the R&D efficiency improvements we've captured come from a range of ongoing initiatives that are specifically designed to evolve our R&D engine. Some of these initiatives, they were alluded to earlier. They're really focused on simplifying and harmonizing our systems. The decentralized approach to innovation that Thomas outlined earlier today certainly brings many advantages. But in some cases, redundancies have accrued over the years that are probably unnecessary. R&D Excellence provides an opportunity to streamline a whole range of systems, from electronic lab notebooks, to risk-based quality management approaches that may differ across our solutions. We've shown some initial examples of how we've done that streamlining. Of course, as was mentioned briefly, generative AI, of course, presents opportunities to accelerate various types of document generation.
We have an example shown here in which an LLM platform sped up clinical study report generation by several weeks, and this is the kind of approach that we and many others are applying to ongoing work, certainly not only across our regulatory organization, but also beyond. Now, other initiatives that we have ongoing are streamlining various R&D processes. One example here is a major strategic consolidation of our partnerships with contract research organizations, or CROs. We've reduced the number of CROs we work with in our clinical operations groups across early and late development by fourfold. Among other things, this simplification can often eliminate the need for recontracting as programs mature, and that in turn reduces white space. We've already...
In fact, we see initial evidence of cycle time reduction after just one year. And furthermore, this CRO consolidation should reduce costs, again, by as much as CHF 200 million annually in the coming years, and actually, that's over and above the CHF 200 million that I alluded to earlier for redirected investment. So these are just a few examples of R&D Excellence initiatives that should make our end-to-end R&D engine more efficient over time. And I'll conclude just by briefly touching on the last R&D Excellence solution, which is about creating corporate incentives that are fully aligned with these R&D productivity objectives, and Thomas referenced this earlier. The bottom line here is that achievement of several R&D productivity metrics has now been incorporated into our annual sort of performance calculators, performance bonus calculators, et cetera.
And these include specific goals around application of the Bar, pipeline value projection, study cycle time, and various metrics to increase speed, et cetera. So we will continue to work those kinds of opportunities and those kinds of metrics into our incentives over time. So really, the entire company is being incentivized to enable and support initiatives that boost R&D productivity. So in summary, I've described our progress towards six R&D Excellence solutions that should help us together deliver many more transformative medicines, and while doing so, achieve top-tier productivity during the coming decade. And one year in, we can say that four of these solutions have now been implemented and really are being fully embedded into the new business as usual.
And then there are two others where implementation is still ongoing, but both of these, you know, accessing external innovation and also evolving our R&D engine, these are substantial, and they're ongoing sort of enterprise priorities that we will remain attentive to. But overall, we're optimistic about the potential of these solutions to elevate our R&D performance for years to come. So, after lunch, as Bruno already told you, we're gonna shift from sort of end-to-end pipeline architecture to the pipeline itself, and these presentations will be given by the outstanding therapeutic area heads from our Global Product Development organization, and they've already. I won't go through each of them. They've already been introduced. We also, as mentioned, have a new Head of Neurology, Hideki Garren, who's not here today. He just is starting orientation today.
Azad Bonni, who runs neuroscience in our pRED, our research and early development organization, will be presenting that presentation. So with that, I'll give it back to Bruno, and we'll do a Q&A.
Yep. Thanks, Levi . And may I ask the speakers of the morning sessions back on stage? We'll have thirty minutes of Q&A, and you can ask questions in the room, and we also- you have the opportunity to send in your questions via email. May I ask you please to just for the questions for the morning session, just focus maybe on the strategy part and the topics we covered. If you have then more in-depth pipeline questions, I think that's what we can keep for the afternoon sessions when we have the experts on the stage. Peter? Yeah. Yeah. Yeah.
Thank you. Good morning. It's Matthew Weston from UBS. Two questions, if I can, please. One on commercialization, which I know is some way away for elements of the pipeline, and also one about portfolio prioritization. On commercialization, Roche has been very much a specialty care business, but you're now moving forward in some extremely competitive categories, particularly in cardiometabolic and in inflammation. Teresa, I'd love to understand how you're looking to change the commercial organization, and particularly, how you're gonna tackle some of the very significant managed care barriers that some of the existing entrenched competitors will have when you come to market with your assets. Then, secondly, Levi, on your applying the Bar to your portfolio, I assume all of your phase III assets, you just decided that there was no way you could terminate development of those pipeline potential going forward 'cause they were too established.
I'd love to know, did you apply the Bar to your current phase III assets, and if so, did any of them not pass?
I can start with commercialization. I think first and foremost, when you think about when these assets will be reaching market, it is quite likely that the needs of physicians and healthcare systems, which were already changing as part of COVID in terms of how many people you want in your office, how many folks you want sort of traipsing through your clinic, these things are already shifting. I think anyone who looks at the ability. Part of the reason that many primary care companies have so many reps is because it's just shots on goal trying to get through the door. I mean, that kind of old school, share of voice game, I think we increasingly see just doesn't work as well anymore. We have already started to think about, within our existing portfolio, how to change that commercialization model.
It's worked for us exceptionally well. We are prepared to go big if we need to, but we also think that there will just be a different way to commercialize these drugs using technology, using a more focused, commercialization footprint, than the way it happens today. So that's part one. From the managed care perspective, we're certainly not naive to the fact that there are managed care hurdles that exist in the world, and we have a lot of experience working with managed care organizations in the U.S. and around the world, and what makes me confident that we can do it is, quite frankly, we've done it in the past, and we have been able to take those, take differentiated assets and to make sure that they get the coverage that is required so that patients have access.
Yeah, and let me just add to this point, that on the diagnostic side, we are the global leader in the space. So we have a lot of access to KOLs, but we also have access to primary care physicians, and having been a GM 2x in two different markets, one was Sweden, the other one was Germany, having worked with my counterparts at that time on the Pharma side, they were telling me that, "Well, if you have a sales rep in Pharma, they don't really get access to doctors in the primary care segment." We don't have the problem on the diagnostic side. There is zero problem to get access for us on the Diagnostics side. So I think we can also leverage the fact that we have Diagnostics to get good access to these physicians.
Yeah, and to answer your portfolio prioritization question, so yes, we have applied the Bar to our end-to-end pipeline, including all of our clinical assets. And we have, in fact, made decisions in some cases to stop studies that we did not feel met the Bar. One example was in the tiragolumab space. There were two, at least a couple of studies, including a phase III trial, that we terminated because we didn't feel like the aggregate evidence, the emerging evidence, justified that investment. So certainly, there are cases where ethically, it doesn't make sense to stop phase III studies midstream, but we are intentional about redirecting resources no matter where those resources are, if that is what the Bar says to do.
Yeah. And I would just add that we had also certain programs where you could still adapt the program. So people actually went, and they looked at how we could adapt it to increase the PTS in some of these studies. So it's a mix, I would say. You know, some studies were very advanced, where you cannot change anything. It doesn't make any sense to stop it because the cost is all occurred. Some we stopped because we said it doesn't make any sense, and some you could adapt.
Just one quick follow-up, if I can, Teresa. I think what I heard a lot about the commercialization strategy is differentiation when it comes to managed care barriers. So is that something we should hold you to account, and particularly in obesity, as we see you develop your portfolio, that we have to see differentiation for you to feel that you can address those managed care barriers when you come to market?
I think we wouldn't have moved forward with these assets if we didn't feel that they were differentiated. I think they're differentiated from a molecular standpoint. I think they're differentiated from what they could potentially mean in combination with other assets across our portfolio. Differentiation is important. You should hold us accountable for making sure that as we see those differentiations continue to reveal themselves, that we're maximizing them with our clinical development programs. But I would also say that a $100 billion to $150-billion-dollar market, there's a lot of room for multiple players.
Thanks, Peter. Yes, Sachin?
Sachin Jain from Bank of America. Two questions on the Bar, and one that actually just follows up on your last comment. So two examples, Levi, that you used for the Bar were TL1A and obesity, and I think investors, as it sits, are unclear on the differentiation clinically of either asset. So how much of your bar application pertains to what you've just alluded to, which is size of end market, and how are you flexing the Bar as you chase these big disease areas that you outlined at the beginning, Thomas? The second question is just to get a sense of where your PTS sits for some of your larger assets. So you flagged seven assets for greater than 3 billion peak sales.
You said your team's been fairly accurate in predicting that, so I wonder if you could just loosely share, of those seven, which sit above phase III industry average and which sit below? So, you know, for very simplistically, are there high probability greater than three billion assets that you see? Thank you.
Yeah, so maybe so there's two facets of the question. One is, to what extent does size of market factor in? And the second is, kind of a detailed one about PTS. I might defer the detailed question till the afternoon, because maybe the presentation will partly give a sense. But on the size of market, certainly that's a, I mean, the magnitude of unmet need, that is a proxy, it can be a proxy for size of market, although not always. I mean, rare disease that have exceptional opportunity for benefit can clear the Bar on that criteria as well.
What we would say in general is that, and we're seeing this not just with the IBD segment, but also with obesity, when there are medicines or candidate medicines that are emerging. So let's just take the TL1A. That's a situation where, compared to standard of care, the phase II data implies that there could in fact be a differentiation. That could be a therapeutic differentiation. If TL1A, if those results hold up, that could now change standard of care, so that's a differentiation. Now, we're not the only TL1A out there, but certainly, we feel like we are very much in position to be, if not first, tied for first in terms of launch. So I think that actually is wide open, and so that clearly, the Bar is clear for that one.
For other areas like obesity, the sense is that we are in a very exciting space. Not just a large opportunity, but there are multiple parallel ways in which evolution can occur to allow for differentiation, and so Manu will talk more about that. But of course, the weight loss that's seen today is great, but it's not perfect. There are elements that could be optimized. There are combinatorial opportunities that could be optimized, and we think that we have pipeline assets that with those combinations, there could be differentiation. So we think in a space like obesity, there are paths to differentiation that are highly available to us and others, and we think that with the aggregate of our pipeline and the approaches that we're taking, we can capture some of that.
Maybe just to add to your, your question, and I'll try to answer the question partly, because, you know, obviously, we can't tell you every number exactly. That would probably reveal a little bit too much. But what I can say is that, exactly what, what you mentioned, one of the comforting facts, that we found was that our, scientists are actually very good at predicting whether or not a trial is going to be successful. Whenever, scientists say that, the likelihoods, the PTS, is above 50%, I think we had a success rate of, close to 90%, right? It's when it's below 50%, it becomes more risky. And that's why we have this portfolio committee, that we don't only look anymore asset by asset.
We do that too, but we look at the overall health of the portfolio that we have a good mix. And it's okay to take a high-risk project forward, a project where we have a low PTS, for example, is prasinezumab, right? But it's a high, high reward because there's not been anything for, I don't know, how many decades. So it's okay to have some of those in, but only if you have, you know, a high reward on the other hand. What you don't want to have is, you know, high risk and low reward. That's the one quadrant you definitely don't want to be in. So we balance out this risk, and another good example is Gazyva for lupus nephritis. Before the study read out, the PTS was, I think, 60-something%.
So, you know, again, it proved that our people were right because they said, "Well, it's 60-something %," and the study was positive. You know, I can say, you know, TL1A, GLP-1, have very high PTS, right? So these are areas that have very high PTS. So if you have very good, very well de-risked, phase II, that increases your PTS. And in TL1A, for example, you don't only have our phase II, you have the phase II of another company, and there are two companies looking at the same mode of action. So two players right now with long leads versus others. So those are the things that we look at and that people use to assess the PTS, I would say.
Yeah, and of course, each study, it's binary, either it works or it doesn't. But in aggregate, the PTS of the aggregate pipeline, that's, as Thomas was saying, that has value. So if the aggregate PTS is, you know, 40%, then they're actually very good. Our teams are very good. In aggregate, we're going to have a lot of failures, but if in aggregate, it's above 50%, we're going to have a lot of successes.
So our decision making, and this is coming back to over the past, you know, couple of years in particular, has really been focused on let's design a phase II trial that's going to work, and then the team comes back with their PTS, and we've been really intentional about forcing the aggregate up, even though there may be individual instances where we're okay with a high-risk, high-reward bet.
But I think all the deals we made, you know, have very strong proof of mechanism of action and so on. So those things help, right? So the balance in the portfolio is critical, and I think we moved it in a really good direction.
Thanks.
Thanks. Richard Vosser from JP Morgan. Just going to retention of talent, you know, you've mentioned changes. Could you give us more color on those changes, particularly how that has changed in the last year, retention in Genentech or gRED, and what you're doing going forward to address that? And then secondly, just back to this transformational medicine and the size of product on the Bar. How do you guard against the risk that you're looking in exactly the same areas as everybody else, and so that increases the risk of commercial delivery and risk on the project at the back end, not the front end? Thanks.
Two good questions. The first one on voluntary turnover. So if you look at the voluntary turnover, last year, so one year ago, we were at 4.9% voluntary turnover. This year, we're at 4.2%. If you look at industry, we're by far the best company in the industry when it comes to voluntary turnover. Other companies have much higher turnover than we have. So that's the first piece. The second piece is what we decided is that we are going to adapt and reflect our strategy also in our structure. So that's why you see that now in Levi's organization, we have five therapeutic areas. And I think that's important that you have key specialists in each of these areas that are single point of accountability of driving those programs.
We are reflecting that across the different parts of our organization. That means that, you know, when we had consolidated, that, of course, we're breaking up certain pieces, but it also means that sometimes we have to bring in people from the outside to raise the level of what is also a bar on what we expect from people, right? And we do that across the organization to make sure we hire the best people in the industry. And that's the process that we've gone through, and we're still going through, because we wanna have the best people in the industry, because at the end, they are gonna make the difference to make sure that these medicines are going to develop and come to the market. Oftentimes, you have some key players that really make the difference.
And then the other question to you, but maybe-
I'll start, and then maybe Teresa wants to speak specifically on the commercial side. So one high-level comment is that it can't be that part of our criteria is we're not gonna go into an area because it's competitive, because you will not find an interesting area of medicine that is not incredibly competitive. So it has to be that we are going in, and we say we recognize the scientific opportunity, we recognize that there's unmet need, and then we believe that because of either what we have internally or because of our opportunities in business development or both, that we can make a contribution, we can play, contribute to the patient impact that can be had. And so that, that's really what the Bar is about.
So there's nothing in the Bar about competition, because you would not do anything if it was there. So that's our general approach. There have been many things where we've sort of said we've deferred because we've sort of said: Well, actually, yes, one could go bring this thing in, but maybe there's not something special about Roche that will allow us to bring differentiated impact. But certainly for the transactions that we had made, and I think Teresa summed it up very nicely, we feel confident in our ability to not only play, but ultimately contribute meaningfully over time.
You go ahead.
I was gonna say, and, you know, fundamental to the Bar is this idea that you are bringing a transformational medicine. If you're bringing a transformational medicine, you're by default bringing one that's differentiated. And so that differentiation allows you to compete even in the most competitive market. I mean, when you think about some of the markets that we've entered that have been absolutely dominated by particular companies or particular products, if you bring something that has better efficacy, that is safer or more tolerable, that provides a different kind of convenience option for patients or a different kind of delivery option that helps, for example, a healthcare system save money, these are all things that allow us to compete smartly.
And I think this is where a lot of our experience over the last couple of years, we really intend to bring to bear with the pipeline products that are coming in. What are those aspects of differentiation? What really matters to patients? What matters to providers? What matters to healthcare systems? And how do you craft a commercial strategy that actually allows you to do it with maximum impact and minimal investment?
Yeah, just to add one more thing here. I mean, some of the programs that were stopped was, well, actually, we're behind, and there's no meaningful differentiation. So then you just stop, and you shift effort. Now, when you go to the research area, right? So in research, when you look at new foundational targets, their goal is, by the time it goes into a more clinical stage, they have to have proven that this is a foundational target, right? I mean, if you look for foundational target, that's one of the ideas on how can they prove that this medicine is differentiated, addresses the foundational target. And the same we do when we look at external programs in early stage.
You know, are there programs out there where we are not working on, no one else is working on, but this could prove to be a foundational target? So you kind of apply it over the time period, and if it doesn't do what it's supposed to do, you definitely don't go into phase III.
Okay, the next question we take over here. Peter?
Thanks. Peter Verdult, Citi. Two questions. Just given what we've heard today about R&D strategy and the Bar, I'm gonna ask Teresa the same question I asked Manu at EASD. You know, how strategically important is it for Roche, given that you want to go big in obesity, to get an amylin targeting agent into your portfolio as quickly as possible? So, yeah, that's question number one. Do you have anything in internal? And then, secondly, and I'm sorry to come to this topic 'cause I'm sure you're bored by answering the question about capacity, but just to make sure we're all on the same page, you know, Roche, or sorry, Novo or Lilly, when you talk to them, they're actually putting numbers. Their scaling ambitions are 50 million to 100 million patients.
I hear what you said about being able to scale within your budget, the technological advances you're making, but is that the sort of scale of your, Roche's ambition when you get to the end of the decade, to be able to, you know, a similar... to be able to serve a similar population? Thank you.
Can I answer the amylin question?
M aybe we defer the amylin question to the afternoon. Not to pump, but Manu will undoubtedly have plenty to say about that. But maybe the capacity question.
Once I see the wonderful phase III data, then I am positive that Manu is going to deliver to me, I will be able to give you a much better answer as to what my aspiration is with the number of patients that I want to treat. But I will say that our aspiration is to reach as many patients as possible with our medicines, and I think we consistently look at what do we believe the peak potential is for any medicine that we have, and we make sure that we have capacity somewhere in the network to accommodate it.
But clearly, I mean, in the transition time, there is a transition time as well, you know, we have had conversations with CDMO. So we know that there is enough capacity that's coming, and we are reserving that capacity.
Okay, then let's go over there.
Peter Welford, Jefferies. Two questions, sticking to the Bar. Firstly, I didn't necessarily look, and apologies if I missed this, but the Bar doesn't necessarily seem to include within it your own internal capabilities, both in terms of manufacturing, commercial angle. So I mean, I guess is that built into, just to understand that there. And equally, the portfolio effect, I mean, does it consider, and I guess this sort of relates to Pete's question, in the sense, you know, it could make sense to have a lot of some assets that may make a lot of sense with other assets. So how do you sort of account for that?
And I guess related to that, for the obesity, are you confident you can succeed in obesity with only focusing on obesity within cardiovascular medicine? Or do you think you actually need some other Part D diseases within that to actually be able to then go to payers and succeed? And then, just very quickly, have you now applied this to your pipeline? So you know, are changes we see from now, obviously it's an ongoing basis, but are changes from now more gonna be based on success, failure, et cetera, rather than applying, if you like, your big think through it all this?
Yeah. So a number of facets there. So the first question was really about where does manufacturability and developability fit in? And actually, under the criteria of worthy pharmacologic characteristics, so there's the characteristics of the molecule, but then there's also characteristics of, can the molecule actually be generated? You know, what are the COGS , but also from a standpoint, do we trust ourselves that we have the ability and capacity to deliver it? So that's all part of worthy characteristics. It has to be not just a active molecule, but it has to be something that we can deliver to the world feasibly. So that's that is that question.
I'll go to the third question, because it's straightforward, which is, yes, we have applied the Bar end-to-end, certainly for all of our clinical assets, and now it's working its way through research. There are some tweaks about how to apply it in research, because of course, there, it's really about is there a feasible path? I mean, not everything will have already landed at we know for sure this is a foundational target in people, as Thomas was mentioning earlier. But we have definitely applied it across our clinical portfolio, and we will continue multiple times a year to update that application. So, but now, to your question, so certainly, we... There's much now that's in play, and we can say, "Yes, it will work," or it won't.
But there's also an element where sometimes, when we apply the Bar, the relevant question is, the term we often use is the crux. What is the most important next data or next analysis that will tell us yes or no? Because not every criteria is already fully applied at any given point in development. There will be some criteria, well, actually, we don't really know until we get this proof of concept data in phase II, or until we get this signal-finding data in phase I. But we always know what is the gating experiment that will tell us yes or no for a criteria? And that's how we are determining, in real time, whether or not an asset should stay or go or be deprioritized.
And-
And just the topic of path to value. The path to value is always a business case. The business case always includes commercialization, includes manufacturing. You know, you calculate NPV, just as you calculate an NPV also when you look at external acquisitions, right? So, you always do a full cost calculation, and that includes do you have to address new markets, et cetera. And obviously, if you have, like, CDK 4/6, and you have things like giredestrant and inavolisib in your portfolio, then, you know, you have other kind of synergy effects as well.
Then to your question around obesity, yeah, I mean, the other reason why, not only because of the amount of people that are affected by obesity, we believe it was strategically important step for us to acquire the GLP-1 GIPs. It's also strategic because they play a role in multiple disease areas across actually all the five that we were just talking about, right? It's playing a role in immunology, it's playing a role in ophthalmology, potentially in neuroscience. So, you know, we need a backbone that we can combine other medicines with. You know, there is a lot of excitement in potentially combining it with an Alzheimer's medicine. Right? So there is this, you know, we don't wanna be locked out from entering all these other diseases in the future because we don't have a backbone.
I think that would have been a huge strategic mistake, if you ask me. Just to put the point on that as well.
Go to Lisa. Other side.
Thanks, Bruno. Thank you very much for the presentation. A couple of questions, first with the Bar still. How substantial is the change? Like, are the five criteria completely new? How much were they already present? Is it the end-to-end nature, that's really the difference here? So what's the amount of change in the Bar? And then secondly, on... I saw on the slide on AI, specifically in commercial, a mention of some revenue gains this year, CHF 500 million-CHF 700 million, I believe. Could you put some context around that? Is it higher than last year? Where are they coming from, assets, regions? And what are you assuming going forwards, given your revenue ambitions you've highlighted today? Thank you.
I'll start with the Bar. Thanks for the question. As I mentioned, it's not as though these criteria are revelatory, you know, they come down from the sky. They're actually you can look at them, and they intuitively make sense. But I would say that maybe the biggest difference is to be intentional. For every program we sit down, and so let's go through criteria by criteria and have the honest conversation. Is there a there there or not? And because, you know, sometimes there may be reasons why a program has stuck around, and it may or may not be because there's an outstanding business case or that there's an outstanding differentiation case, but this is really now let's call the question. And if there's a plausible rationale for why it could land, great.
But let's be clear about what that is and when we're gonna know about it. And if there's not, let's call it, and I think you can see that we called a number of NMEs in the past nine months. So I would say, although the concept is not a radical from to, the application has had meaningful impact.
Yeah. I mean, having talked to all R&D organizations across the board, I mean, you know, everyone has something, right? They didn't really apply the same kind of methodology, but some of them had something similar, like to the five Rs that AstraZeneca introduced a number of years ago, et cetera. So there was no, I would say, one approach to everything in the entire company, and there were others that, you know, we're following the science, and, you know, that was good enough. So but, you know, the issue is that if you are not effective in decision-making, what actually happens is that you become slower, right? And what actually happens is that you get too much risk in your portfolio. What happens is that you cannot reallocate the money to more promising things.
And that's what we are much more intentional about, and having the same kind of assessment throughout the organization. And what we have reintroduced, which we took out probably four or five years ago, is so-called development boards. And these development boards are some of our best people that we have in the entire company, and they give advice and challenge project teams on their project work. And with that, what you actually do is you also increase the PTS because you have people who have a lot of experience in developing these medicines. They can give advice on how they should design the study, et cetera, et cetera, but they will also challenge the team, okay, and say, "This program doesn't make any sense." Because, scientists, and that's good because they're really believers in their own program, they will never stop their own program, right?
I think this more systematic approach is really effective, I would say right now.
Yeah, one thing to add to that, because you could listen to what Thomas said and say: Well, why were those taken away five years ago? And there are the other way to be slow is to be very heavy-handed in your bureaucracy and your governance, and so by bringing these things back, we've been. I mean, there's a whole series of conversation, but how do we make it nimble? How do we make it so that it's not a burden to the teams to have to go through these things, but it's enabling? So that's been a big part of the architecture in recent months.
And to answer your other question, that primarily is the result of the full year, first full year implementation in the US of what we call Next Best Action . So this is a mechanism by which when field representatives put information in our CRM system, they are presented with what a most reasonable Next Best Action would be with a customer. So that additional revenue is the first full year realization of that programme being in place, primarily in the U.S., and it is being rolled out globally.
Next question is Emily.
Hi, thanks. Emily Field from Barclays. A question, another question on PTS. And we talked at Pharma Day last year about the, at least the phase III success rate being somewhat depressed due to perhaps too quick acceleration into phase III and not running robust enough phase II. So I was curious, how much of the increase in PTS is due to some of those changes, or most, more so if it's a result of the constitution of the overall portfolio in terms of molecules? And then a question on the recent closure of the Genentech Cancer Immunology Research Unit. I believe this was merged into another unit of gRED, but just wondering, from a higher level, if you've changed your thoughts towards the broader IO opportunity in oncology, and if so, how much of this was driven by tiragolumab?
So I can answer the second question. I'll answer the second question. In Genentech, we had basically two oncology groups. One was the cancer immunotherapy group, and the other one was the molecular oncology group. In fact, we know more today that, you know, if you look at the tumor microenvironment and all these different things, actually those two are very much overlapping. And so we felt it's better to actually have it in one group instead of having two separate groups addressing that. I mean, TIGIT, definitely based on CITYSCAPE data, people had a high hope on TIGIT, but there are other programs that we have in-house, like the personalized cancer vaccine and other areas where we do believe that cancer immunology will play a significant role.
But, again, I don't think it makes a lot of sense to have two separate groups working on these topics. You can use the synergies much better in this way.
Yeah, and just specifically on the previous question, the short answer is that there's no single. There is a range of things, but for example, in some cases, the design was to really focus on the patient population, where we know from our clinical data that the benefit is likely to be maximal, as opposed to speculating about other segments that might make the market larger, but we actually don't have the same data. That'd be one example. Another example was, in fact, we have in some instances waited several months for the complete data set to inform that. So even though you might want to go faster. But if you don't have the data to really guide the design, then it's risky to go forward.
So there, that was another example. So there are examples like this, where we think about the elements that predict success and ensure that the teams have all of those pieces and not to rush without the essential pieces.
Important is speed matters. Even though the entire development process is a long process, I mean, you have to be very, very fast in the beginning so that you don't get in a situation where you have to take shortcuts, right? So you have to go really fast, and that's what we are really focusing on. How can we accelerate the whole process from the very beginning? Because it's a competitive world out there.
Okay, I think with that, we are already at the end of the first Q&A session, unfortunately, but you will have the opportunity to, you know, ask the questions during lunch or later on. We will have fifteen minutes lunch break, and then we will meet back here at 12:30 P.M. Please be on time, so we still have a lot to cover today. Yeah. Bon appétit!
I'm Charles Fuchs, and I'm the Global Head of Hematology and Oncology Product Development, and I have the privilege of kicking off the second portion of our day, that is the journey through our portfolio, with my privilege to share with you some key highlights of our hematology oncology portfolio. You know, I part of the reason I chose to come here about three and a half years ago was the very rich legacy that Roche and Genentech has in transforming the therapeutic landscape and improving the lives of patients with cancer and blood disorders. Today, our strategic pillars include advancing best-in-class precision medicines, such as inavolisib and divarasib, leveraging novel modalities and technologies, including, as I'll describe further, our entry into the next generation off-the-shelf allogeneic CAR T therapy, as well as next-generation antibody drug conjugates.
Leveraging our broad portfolio for rational and high-impact combinatorial therapy, including the addition of Columvi to now the best-in-class Pola-R-CHP regimen in the first line setting of diffuse large B-cell lymphoma, as well as our combinations of our growing portfolio in hormone receptor-positive breast cancer, and no less importantly, accelerating all of these assets and combinations into the curative setting of cancer, including our successful ALINA study, which documented the benefit of Alecensa in the curative setting of ALK-positive non-small cell lung cancer, and our ongoing work, adding our best-in-class SERD giredestrant in the curative adjuvant setting of HR-positive breast cancer.
We have a privilege to, in service of this, of these strategic pillars, to advance one of the richest and broadest portfolios in oncology, which uniquely leverage a series of technologies that Teresa outlined earlier today, such as small molecules, a gamut of novel protein engineering, neoantigen vaccines, cyclic peptides, among others, and we're equally privileged to have a broad array of novel molecules in hematology, targeting a series of malignant hematology conditions, hemophilia A, as other important unmet needs in. The slides changed. There used to be in my deck, the next slide was our hematology portfolio, and I wasn't looking down. So, turning actually to our breast cancer portfolio. Namely, Roche, as you know, really wrote the book on targeted therapies for breast cancer, improving the lives of patients with HER2-positive breast cancer.
But we remain committed in this space now in HR-positive, hormone receptor-positive breast cancer, which represents 70% of the market, and doing so through a series of interventions. Our best-in-class SERD, giredestrant, which we believe can be a new backbone for endocrine therapy. Our play now with the acquisition of the CDK portfolio, a next-generation CDK from Regor Therapeutics, as well as novel targeted therapies, most specifically our best-in-class PI3K inhibitor, inavolisib. Endocrine therapy remains the backbone for HR-positive breast cancer, but there continues to be a need for more effective and better-tolerated therapies. For instance, in the adjuvant setting, 50% of patients stop their endocrine therapy or are not consistently using it. Moreover, among those patients, 30% will go on to develop progressive metastatic disease. Giredestrant shows the highest potency of SERDs currently in development, as well as fulvestrant.
Moreover, it's combinable at full doses with all available CDK 4/6 inhibitors, and it avoids any of the serious toxicities that have been described with the other drugs, including no evidence for ocular toxicity and no evidence of any dose-limiting toxicities. In our window of opportunity, coopERA study, we compared, in that neoadjuvant setting, giredestrant to an aromatase inhibitor, showing a statistically significant greater suppression of Ki-67, both when both drugs were compared as monotherapies, and as well, when the two drugs were compared in combination with CDK 4/6 inhibitors. As you also know, our phase II acelERA study in the second- and third-line settings of metastatic HR-positive breast cancer, giredestrant did not achieve a statistically significant improvement in progression-free survival compared to the alternative AI or fulvestrant.
However, we've now come to realize, in those patients with multiply treated endocrine therapies, the majority of those patients have tumors that are no longer dependent on the estrogen receptor, and in fact, driven by other oncologic pathways, pathways that are insensitive to any perturbations of the estrogen receptor pathway. But there was one unique subset in the acelERA study, those patients with ESR1 mutations, those tumors that we believe are dependent on the estrogen receptor. And in ESR1 mutants, we saw a hazard ratio of 0.6. That is a 40% improvement in progression-free survival among those patients randomized to giredestrant.
To understand that phenomenon, we conducted this transcriptome analysis of various subgroups of breast cancer, and as you can see, in the multiply treated ESR1 wild-type patients, in the green, those tumors are no longer dependent on, in the estrogen receptor pathway, and therefore predictably insensitive to any estrogen-directed therapy. However, for the ESR1 mutants, they show a transcriptome dependent on the estrogen receptor, and in fact, in that subset, giredestrant proved to be a superior therapy. Further, when you look at patients with either early breast cancer in the adjuvant setting or first-line metastatic, we see a similar pattern of estrogen dependence consistent with the ESR mutants, and that pattern gives us greater confidence in our ongoing studies of giredestrant in both the adjuvant and first-line indications. Our ultimate plan is to make giredestrant the next standard of care backbone across all indications for HR-positive breast cancer.
Our first-line persevERA study in combination with a CDK4/6 inhibitor will be reading out next year, as well as our giredestrant plus everolimus evERA study will also read out in the second line next year. We've initiated as well a first-line endocrine-resistant trial, the pionERA study, which actually as well allows for a choice of CDK4/6 inhibitors. We are also leading the adjuvant study with lidERA which is comparing giredestrant to an alternative aromatase inhibitor in the adjuvant setting. And finally, we are conducting a study of giredestrant in HR-positive, HER2-positive breast cancer, and we believe this compendium of studies could make giredestrant the standard of care across all estrogen-dependent breast cancers. Beyond giredestrant is our best-in-class PI3K inhibitor, inavolisib.
As you know, we've known about PI3K mutations for decades, mutated in 40% of HR-positive breast cancer and 30% of HER2-positive breast cancer. However, despite our understanding of the pathway, we've been unable to really meaningfully attack it therapeutically because the available molecules were largely ineffective, poorly tolerated, and patients couldn't stay on the therapies, including a high rate of discontinuation with the current commercially available PI3K inhibitor. In contrast, inavolisib is differentiated as a far more potent molecule for the alpha subunit, and as well, has a unique mechanism of action of degradation of a mutant alpha subunit, allowing greater selectivity, tolerability, and efficacy.
The proof has been in the recent readout of the INAVO120 study, in which, in the first-line setting, the addition of inavolisib to palbociclib and fulvestrant conferred a 57% improvement in progression-free survival, with medians of 15 months versus seven months. As well, although overall survival remains immature, we see a hazard ratio of 0.64. inavolisib was extremely well-tolerated. Discontinuations were in the mid-single-digit range, and on the basis of these data, the FDA granted breakthrough designation for inavolisib, and we await the PDUFA date for inavolisib in November, with applications across global health authorities. As well, based on these data, we're advancing a broad portfolio of opportunities for inavolisib. Beyond INAVO120, INAVO123 is looking at the first-line endocrine-sensitive indication.
We also have a head-to-head comparison of inavolisib against the current commercially available PI3K inhibitor in CDK-experienced patients, and finally, we're looking at the molecule in HER2-positive PI3K-mutated patients. Finally, as Teresa mentioned, we're looking at other tumors that are PI3K-mutated, and we're looking at the utility of this in the adjuvant curative setting of PI3K-mutated breast cancer. Further rounding out and creating synergy in our HR-positive portfolio has been our today-announced acquisition of the CDK portfolio from Regor Therapeutics. As you know, CDK 4/6 inhibitors really have transformed the landscape of both metastatic and adjuvant therapies for HR-positive breast cancer. However, there continues to be an unmet need for more efficacious and better-tolerated therapies. Specifically, inhibition of CDK6 has been associated with the unwanted adverse events and toxicities associated with that class of molecules, whereas CDK2 appears to be an important mechanism of resistance.
The lead molecule in this portfolio is RGT-419B, which, as you can see, is a highly potent CDK4 inhibitor but also has therapeutic inhibition of CDK2, that resistance mechanism, which is not present in the three commercially available molecules. Also, rapidly behind this is RGT-587, which is a highly potent, highly selective CDK4 inhibitor, which is brain penetrant and phase I ready. Regor has been conducting a phase I study of 419B, that is the CDK4/2 inhibitor, as a monotherapy in patients who had previously progressed on a CDK4/6 inhibitor. What they find is that 419B can be dosed continuously with acceptable tolerability. It has a favorable PK profile with sustained target coverage of both CDK4 and CDK2, and it, as a monotherapy, is demonstrating durable responses in these patients who have progressed on the available CDK4/6 inhibitors.
On this basis, we believe that this unique CDK4/2 inhibitor has the potential to be a best-in-class, next-generation CDK inhibitor for HR-positive breast cancer. We look forward to sharing the expanded data from the monotherapy study. We as well will be initiating studies combining the agent with aromatase inhibitors, giredestrant, inavolisib, as we accelerate this towards a potential registration process. We, as you heard earlier today, this year, we announced the results of SKYSCRAPER-06. That is our first-line study of tiragolumab plus Tecentriq and chemotherapy in non-squamous non-small cell lung cancer, which did not meet either its primary endpoints of progression-free overall or overall survival. On that basis, we decided to stop the SKYSCRAPER-15 and SKYSCRAPER-05 programs, but we are continuing to see the results, waiting the results of our completed studies.
SKYSCRAPER-01 , as you know, is in PD-L1 high non-small cell lung cancer, SKYSCRAPER -03, SKYSCRAPER -07, and finally, SKYSCRAPER-14 , the latter in first-line advanced hepatocellular carcinoma. Beyond tiragolumab in lung cancer is what we believe are best-in-class G12C, KRAS G12C inhibitor, divarasib. In preclinical studies, divarasib is 5x -25x more potent and 10 x- 15x more selective in vitro compared to the commercially available agents, adagrasib and sotorasib. At the recent World Lung Conference, we updated the phase II monotherapy data in second-line non-small cell lung cancer, and at the targeted dose of 400 mg, as you can see, we had an overall response rate of 59% and a median progression-free survival in excess of 15 months.
This compares favorably to the data for the commercially available molecules, which have response rates in the range of 30%-40% and a median progression-free survival of only 5-6 months. On the basis of this, the FDA has granted breakthrough designation in the second-line setting for divarasib, and we are launching a head-to-head second-line study of divarasib compared to dealer's choice of adagrasib or sotorasib. As well, we're accelerating first-line combinations of divarasib with the anticipated initiation of a first-line registration study next year. Turning now to our hematology pipeline, which covers a broader array of molecules for malignant conditions, as well as several benign conditions, including, most notably, hemophilia A.
Theresa talked about our broad portfolio for B-cell malignancies and described the strong uptake of Polivy in the first-line setting of diffuse large B-cell lymphoma based on the progression-free survival benefit in the POLARIX study. We are looking forward to sharing the updated five-year overall survival for POLARIX at an upcoming meeting. Beyond Polivy are our two CD20, CD3 bispecifics, Lunsumio and Columvi, approved for the third-line relapsed refractory follicular lymphoma and diffuse large B-cell lymphoma, respectively. As you can see on the right, we have an aggressive portfolio of moving both molecules into earlier lines of follicular, diffuse large B-cell, mantle cell, and other indications, and in combinations with currently available agents for these B-cell malignancies.
For instance, we recently reported out the results of the phase III STARGLO study, in which patients who were randomized to the addition of Columvi to the GemOx regimen experienced an approximately 40% improvement in overall survival and a 60% improvement in progression-free survival compared to the R-GemOx control arm. Moreover, the Columvi GemOx regimen was well-tolerated, with cytokine release syndrome being limited to largely grade 1 toxicity. On this basis, the STARGLO data have been submitted to global health authorities, including the FDA and EMA. At the same time, we recently updated the phase I-B/II data for our chemotherapy-free combination of Lunsumio and Polivy, which, as you can see, demonstrated an overall response rate of 59% and a complete response of 46% in the second-line relapse/refractory diffuse large B-cell lymphoma setting.
On that basis, we initiated and conducted the SUNMO study comparing Lunsumio Polivy to Rituxan GemOx, and the results of the SUNMO study are anticipated next year. Finally, turning to the first-line curative setting, certainly the Pola-R-CHP regimen appears to be a best-in-class regimen in the first-line setting, but still, we are committed to further enhancing the rates of cure in diffuse large B-cell lymphoma. At ASH last year, we provided updated data for the addition of Columvi to both the Pola-R-CHP regimen, as well as the original standard R-CHP regimen, and for the combination of Columvi Pola-R-CHP , we see a response rate of 100% with a complete response rate of 92%, and highly durable responses with very acceptable toxicity and relatively low rates of cytokine release syndrome.
Of note, this combination of Columvi Pola-R-CHP compares favorably to the less efficacious combination with R-CHP, and that's important because it really confirms the benefit of Pola-R-CHP , not only on its own, but in combination with a bispecific. On that basis, we launched the SKYGLO study, which compares the standard now Pola-R-CHP to Columvi Pola-R-CHP , and to be clear, this is the only study in which a bispecific is being added to that Pola-R-CHP regimen, which we think has the opportunity to give patients the best chance for cure for diffuse large B-cell lymphoma. Rounding out our portfolio for hematologic malignancies has been our entry into CAR T therapy, cellular therapy, with Poseida Therapeutics. As you know, CAR T has transformed the landscape of hematologic malignancies, but they are highly complex.
They rely on patients to undergo apheresis for the cells to be manufactured, resulting in delays, the need for bridging therapy, and no less importantly, the fact that these therapies typically can only be delivered at high-profile tertiary care centers. As a result, among patients eligible for CAR T, only about 20% will actually receive CAR T therapy. We believe this partnership with Poseida allows us to truly scale CAR T therapy to a much broader population, namely using donor-derived healthy, stem cell memory T cells. We can use a much more robust pool of T cells compared to heavily pre-treated donor-derived T cells that are available off the shelf.
We're also leveraging Poseida's unique gene editing technology, including their piggyBac insertion technology, which allows for the delivery of multiple CARs in a single step with great efficiency and without the need of viral delivery systems, as well as their proprietary Cas-CLOVER gene editing technology, which allows for multiple knock-in and knockouts, thereby preventing both graft versus host and host versus graft, as well as improving efficacy and tolerability. Ultimately, we believe this off-the-shelf, immediately available CAR T approach will allow us to truly democratize cellular therapy. Our lead program is a BCMA-ALLO CAR T, currently in phase I, in relapse refractory multiple myeloma, and that program is now demonstrating a 91% response rate in heavily pre-treated patients with multiple myeloma.
On that basis, we were actually granted an RMAT designation by the FDA, which goes beyond breakthrough designation, in that it allows for accelerated approval based on proxy surrogate endpoints. We also have a CD19/CD20 dual CAR program in non-Hodgkin's lymphoma B-cell malignancies that's currently ongoing. Turning now to benign hematology. There's a slide missing on PiaSky, but ... or it was in my deck, sorry, but it's not in this. Turning finally to our benign hematology portfolio, namely, NXT007. But for starters, as you know, Hemlibra truly transformed the landscape of hemophilia A.
Principally, as compared to what was typically the administration of intravenous factor VIII, that bispecific Hemlibra have given patients the chance to achieve a greater life free of the typical manifestations of bleeding, with zero bleeding rates in the range of 80% - 90%. Ultimately, Hemlibra really has set an extremely high bar for the treatment of hemophilia A. It is on that basis that we designed NXT007, which optimizes Hemlibra in multiple ways. Firstly, changes to the binding domain with far greater affinity for factor X, thereby increasing potency of the clotting cascade, as well as changes to the Fc region domain, thereby improving the half-life. In fact, NXT007 is 30 x more potent than Hemlibra, and an in vitro assay indicates that NXT generates thrombin in the range of patients without any evidence of hemophilia.
We believe that this drug has the potential to allow patients a life completely free of any clinical manifestation of hemophilia A. There's an ongoing phase II study, and we will be sharing the results of that program next year. So in sum, we actually have a number of important readouts, which are not in the slide that I thought was coming next, but includes our readouts for giredestrant, for tiragolumab. I didn't get a chance to share with you our C5 inhibitor, PiaSky, in various indications, including hemolytic uremic syndrome and sickle cell disease, and ultimately, I think, a lot of exciting news to follow in the hematology oncology portfolio.
So I thank you for the opportunity to share all this, and now let me turn to Azad Bonni, our Global Head of Neuroscience and Rare Diseases, who will share with us the exciting developments in our neuroscience portfolio. Azad.
Thank you, Charlie, and good afternoon. So I come to you from pRED, as Charlie mentioned, and today I'm going to give you an update on our portfolio in the space of neurology. And in the spirit of one pharma strategy and end-to-end R&D Excellence, it'll be about both the early and late stages. Now, as you heard earlier from Teresa, when it comes to launch products, we're actually already, we already lead the field in this space, in neurology. And so to match and exceed this success, in R&D, what we're doing is to actually build to take advantage of advances in human genetics, advances in disease biology understanding, and also in therapeutic technologies to establish an industry-leading portfolio.
And today, what I'm gonna do is to give you some highlights on some projects in the following disease areas, as you see on this slide, including MS, neuromuscular disorders, and neurodegenerative diseases, with some of the examples shown below. Now, in terms of our portfolio in clinic, shown on this slide, I wanna make three points. One is that we're actually interested in a number of disease areas, including those that I just mentioned. The second point is that, as you can see on the lower left corner there, the legend, we're actually using diverse and innovative technologies in the clinic in these projects. And the third point, which is not on the slide, and that is that we actually have a large portfolio of preclinical research projects that feed the clinical portfolio.
So let's go to the projects. Now, building on the success, we'll start with MS, and building on the success of OCREVUS in MS, let's focus our attention now on fenebrutinib. Fenebrutinib targets the non-receptor tyrosine kinase, BTK. BTK activates the immune cells in the periphery and within the central nervous system, and in particular, B cells, myeloid cells, and microglial cells, and that's important, makes it an attractive target for MS, because with this, you can see that you can address both the relapsing as well as the progressive aspects of the disease. Now, in clinic, we've already, as shown on the left side panel, we've already completed the phase II FENopta study, and I'll tell you about this shortly.
Also, we have completed recruitment of three phase III trials, including two in relapsing MS, and also in primary progressive MS, where notably, the comparator arm is OCREVUS. Now, fenebrutinib stands out among the BTK inhibitors out there because it's the only non-reversible non-covalent, reversible inhibitor of BTK. In addition, shown in the middle panel, fenebrutinib is quite potent, and also it's brain penetrant, and as shown on the right side, it's quite selective relative to other BTK inhibitors. So with all of these pharmacological properties, fenebrutinib has best-in-class potential among BTK inhibitors for MS, and also, as an oral agent, of course, it has the potential to be best in disease in the oral market for MS. Let me tell you a little bit about the FENopta study.
On the left side, you see the results from the double-blind period. Here what you see is, with the primary endpoint of gadolinium-enhanced T1 lesions by MRI, you see with fenebrutinib, there is a rapid reduction of these lesions by week four, and actually by week eight, you can see, and this is sustained at week twelve, there's deep suppression of these lesions. We see a similar effect on key secondary endpoints as well, that include enlarged or new T2 lesions. In a subset of patients where we examined the concentrations of fenebrutinib in CSF, we see actually that fenebrutinib reaches levels of near maximal inhibition of BTK, and that's important for a couple of reasons. It shows that it's brain penetrant, highly brain penetrant.
The other thing is, these are where, in the CNS, there are immune cells that are thought to be responsible for disability progression, so that bodes well for that aspect of MS. The safety profile of fenebrutinib in FENopta has been consistent with previous studies in non-MS indications, which is a favorable safety profile, and so far, up to 2,700, over 2,700 patients have been dosed with fenebrutinib. Now, the results of the open-label extension of FENopta, shown on the right side, the right panel, are equally. And here, what you can see is that actually by week 48, 96% of the patients are free of relapses, and that's the annual relapse rate of 0.04 that you see. In addition, 99% of patients are free from enhanced T1 lesions.
So now, of course, we're waiting for the results of the phase III trials, which, and with the initial readouts coming in 2025. Now, let me move from MS to neuromuscular disorders and start with SMA, or spinal muscular atrophy, where, as you know, Evrysdi has really transformed the care of patients with SMA. Evrysdi, of course, addresses the proximate cause of the disease. And here, now what we're trying to do is to see if we can build on that by combining it with an agent that should lead to an increase in muscle size and function. And this is where GYM329 comes in. GYM329 is a monoclonal antibody, deploying the technology of the sweeping and recycling technology that makes it much more potent for soluble factors in circulation, in this case, targeting latent myostatin.
This pathway that's regulated by myostatin puts the brakes on skeletal muscle growth and strength. The idea then is to combine it with Evrysdi to see if we can get further benefits. There is already evidence for GYM329 preclinically in mice, shown on the right side, and currently, we're in a phase II/III trial, the MANATEE trial. In the first part, we're looking for the optimal dose, and then in the second part, this would be where we would study the effects, the efficacy, in addition to safety. A couple of words about Elevidys in Duchenne muscular dystrophy. As you know, Duchenne is a devastating neuromuscular disorder, results from mutations of gene-encoding dystrophin, and Elevidys represents a gene therapy approach, a single intravenous dose, delivering micro dystrophin for expression in muscle cells.
From the EMBARK trial, you can see on the left side that although there were improvements on the North Star Ambulatory Assessment score, the NSAA, this did not reach statistical significance and was not met. However, on key secondary endpoints that are clinically meaningful, and a whole number of these were met, including time to rise, 10 m walking test, the stride velocity 95th percentile, and time to ascend four steps. Combined, all of this together provides a positive benefit-risk favorable profile for Elevidys, and this has actually received overwhelmingly positive feedback from key opinion leaders. As you know, perhaps through our partner, Sarepta, it has been approved in the U.S. and now through Roche in six other countries. Now we're actually...
We believe that this is going to be relevant for patients beyond the ages of four to seven, and so therefore, we have trials shown on the left on the right side, extending the age as well as going into non-ambulatory patient population. Now let me move to the early development portfolio and focus on neurodegenerative diseases. I'll start with Parkinson's disease, where, as you know, there are symptomatic treatments, but as of yet, no treatment to slow the course of the disease. This is where prasinezumab comes in. You heard about this from Thomas earlier. Prasinezumab is a monoclonal antibody that targets aggregated alpha-synuclein extracellularly, and the idea is to mitigate the spread of aggregated alpha-synuclein and further degeneration of dopaminergic neurons.
In the PASADENA phase II trial, although the primary endpoint was not met, we saw really interesting signals suggesting that prasinezumab slows on an established motor scale, that it's, prasinezumab slows motor progression, and this was corroborated with evidence on innovative digital readouts that gave us the confidence to move to a phase II-B trial, the PADOVA trial, which I will tell you a little bit about shortly. In the meantime, we've done further analyses, including, as shown on the right side, open label extension on the same scale, MDS-UPDRS Part III, where we see that for up to four years, that actually patients remain stable. For a specialist, looking at this, this looks quite striking. Now, here, we're where it's an open label extension, and we're comparing it to a natural history cohort that's the gray bar that comes from PPMI.
So the other sort of analysis we've done is actually in pre-specified populations in PASADENA, shown on the left side, where we look at, in this case, four populations, and in each. This is a forest plot, and what we see that in each case, look at the very bottom one. In each case, we see that actually prasinezumab has a greater effect on patients that are expected to progress faster. So this is just giving us more evidence that actually prasinezumab may indeed have an effect on motor progression. But the proof of the pudding will come in PADOVA, and that is the trial that's shown on the right side, it's fully recruited. The readout is expected later this year, and the results will be shared in 2025.
Here, we're actually focusing for the primary endpoint on motor progression, using a time to event type analysis. Now, let me move to Alzheimer's disease, and which, of course, as you know, is one of the most important public health challenges of our time. There's been a lot of work in this. We're interested in many, a number of targets, like the rest of the field. But of course, one target that has been studied for quite a long time is amyloid A-beta, where you, as you know, in the last couple of years, has emerged as a clinically validated target. Yet there's a lot of room, even with amyloid A-beta, for improvement, both on efficacy and safety. And here's where we come in with gantenerumab.
This is a novel antibody targeting amyloid, that deploys a technology that's been developed at Roche for the past fifteen years, that's called the Brainshuttle technology. This is gonna be relevant not just for A-beta, not just for Alzheimer's, but actually for many indications in neurology. And so to help you understand how, and myself as well, understand how this works, I'd like to show you a video now.
The brain's gatekeeper, the blood-brain barrier, represents a significant challenge to medicines that need to be delivered to the brain, limiting access to potential treatments, such as for Alzheimer's disease. To overcome this obstacle, Roche has developed the Brainshuttle, an innovative technology that uses transferrin receptors on endothelial cells to smoothly cross the blood-brain barrier while carrying its therapeutic cargo. Once inside, the Brainshuttle antibody disperses throughout the brain to reach its site of action. In this case, amyloid plaques, the hallmark of Alzheimer's disease. Bound to the plaques, the antibody engages with receptors on microglia and triggers the clearing of amyloid from the brain.
Unlike conventional antibodies, whose uptake and distribution is limited to areas where the barrier between brain and vasculature is not as tight, the Brainshuttle enables a high concentration of the Alzheimer's plaque-clearing antibodies to all affected brain regions, accessing even deeper regions through the dense capillary network. This more homogeneous brain uptake can potentially lead to many more benefits, such as reduced local vascular inflammation with antibody treatment for Alzheimer's disease. The Brainshuttle represents a breakthrough that offers many new possibilities for the efficient transportation of large molecules across the blood-brain barrier, ushering in more effective treatments for a variety of brain diseases. At Roche, we embrace this exciting potential, a ray of hope for anyone battling a brain disorder.
Great. So now that you've seen the video, I'm gonna skip the left panel because now we understand the mechanism. I'm gonna go right to the middle panel and tell you about the results of gantenerumab in the phase II-A trial in Alzheimer's disease. And here, what we see is with these four doses, a dose-dependent reduction of amyloid load as measured on PET scans. And we have also here, analyses with the last dose, the three point 6 mg per kilo, shown in the purple, at 12 weeks, where you can see a rapid and robust depletion of amyloid. And in fact, in this cohort, about half of these patients are already amyloid negative, and many of these are deeply amyloid negative. And so this is really exciting for a couple of reasons.
One, it takes conventional antibodies several months to reach this level, and here we're seeing it in a matter of weeks. Why that is important is that there's been evidence in the literature that the faster and the more deeply that you deplete amyloid, the more likely it will lead to a beneficial effect. So this is one major reason. We're seeing rapid and robust depletion of amyloid in with gantenerumab. The other reason we're actually quite excited about gantenerumab and shown on the right side, and that we speculate is because of the route of entry of the monoclonal antibody, is that we're actually seeing less of ARIA, which is this major adverse event with anti-amyloid antibodies, which stands for amyloid-related imaging abnormalities.
And so this is really exciting because now we have a combination of potential better efficacy, better safety. gantenerumab has really the potential to be best in class anti-amyloid. So I do wanna say also that there will be an update on this in one month's time at CTAD. Now, let me move to the last molecule, slide, and I will take you through this. So let's go through the. Let's look at the left side first, the left panel. So whereas with gantenerumab, we're focusing on targeting the plaque, which is shown in that red glob there, we're clearing plaques. With this new molecule, the gamma- secretase modulator is focused on the production of the, on the other side of the amyloid cascade, so on the production of amyloid beta peptide.
Gamma- secretase is a protease that cuts amyloid precursor protein, and together with beta-secretase, leads to the production of A-beta peptides. Now, what's really interesting about gamma-secretase, it's it acts processively. So it's sort of like, think of a chef cutting a piece of meat, chopping a piece of meat. So it cuts it at multiple sites, so you get different species of A-beta peptides. There's the A-beta 40 and 42 that are amyloidogenic. They're considered harmful. There are also other species, including 37 and 38, that are not amyloidogenic and are actually thought to be beneficial. Now, previous attempts at targeting gamma-secretase acted like a sledgehammer. They would inhibit gamma-secretase. They were not very selective, and so they actually did not lead to beneficial outcomes.
Here, what we have is a new molecule that acts very incisively, binds to gamma-secretase, and modulates it so that you get less of A-beta 40, and 42 , less of the harmful peptides, and more of the thirty-seven and thirty-eight. In the middle panel, you see that actually in healthy volunteers, we see in CSF a reduction of A-beta 42, and 40 , and a concomitant increase on the right side of that middle panel, an increase of 37 and 38. Currently, we're now in a phase II study, where it's focused on safety, tolerability, pharmacological properties, PK and PD, and this is in a population of people who are accumulating amyloid. They're either actually cognitively normal or have minimal cognitive impairment. We're very excited about this molecule as well. Let me end with the patient journey.
This will be my very last slide, and actually, this is a concept that Thomas referred to. Here it's gonna be really important for us for neurology in general with chronic diseases, and here I'll just illustrate it for Alzheimer's disease. We already have approved a CSF test for diagnosis of Alzheimer's disease. I would say even more excitingly, in development at Diagnostics, there are tests that are plasma for plasma biomarkers, including pTau181 and APOE E4, that have a high negative predictive value, which means they can be used to rule out the diagnosis of Alzheimer's. In addition, we have pTau21 7 that are being developed with very high positive predictive value, so it can be used to rule in the diagnosis of Alzheimer's.
So in the future, of course, this could be used across the journey, but especially you could see it happening early in the process for people who are at risk, for example, for developing Alzheimer's disease. And the idea over time is once we have therapies that are now in development, that you can match this, so that a person comes in, they're at risk for Alzheimer's disease, these tests are done, and a treatment is given to prevent the progression into symptoms. And then once you treat them, we wanna have additional tests to monitor that, either with digital readouts as well as additional fluid biomarkers. So this is actually a future that is within reach, and I think it's a future that will really transform the way we care for patients with Alzheimer's disease, as well as other neurological diseases.
And with that, I will turn it over to Larry to tell us about immunology.
All right. Thank you so much, Azad. I don't have any slick videos to show you, so just warning ahead of time, but nevertheless, I'm very happy to be here today to talk to you a little bit about our immunology strategy and pipeline. Roche has a long legacy of innovation in immunology, and in the two-plus decades since Rituxan was first approved for the treatment of RA and Xolair was approved as the first biologic for the treatment of allergic asthma, our understanding of immunology has really grown by leaps and bounds, and that's created a lot of new opportunities for drug development, but it's also created some new challenges as expectations for efficacy have continued to rise and competition, competition has intensified.
We feel that we have an immunology strategy, though, that will position us well to continue to lead innovation in immunology over the coming decades, and that strategy consists primarily of four components. First, optimizing pathways, including improving unknown pathways and identifying novel pathways with transformational potential. And we have examples of this, including Gazyva and Lunsumio, which are next-generation anti-CD20 molecules with enhanced B-cell depletion, and selnoflast, an NLRP3 inhibitor, with the potential to be the first new oral asthma therapy in about twenty-five years. Secondly, combinations which target multiple pathways to raise the efficacy ceiling. And here we have early-stage programs in inflammatory bowel disease and in COPD, which combine orthogonal, validated, and novel pathways that are relevant to these diseases. Thirdly, endotypes, which can identify patient subsets to improve efficacy and guide therapy.
Examples here include ustekinumab, which, while directed at an all-comers COPD patient population, does have the potential to address the historically most difficult-to-treat low eosinophil patients, and anti-TL1A in IBD, which is also directed at an all-comers IBD patient population, but is exploring biomarkers which may predict better responses to treatment in subsets of patients. Finally, last but not least, our ultimate goal is cure or long-term remission for immunologic diseases. And here we have a CD19, CD3 T-cell engaging bispecific monoclonal antibody, which may act similarly to cell-based therapies directed at CD19 that have shown the potential to achieve functional cure for a large range of autoimmune diseases. This is something that we're particularly excited about when we think about the future of immunology treatments.
When we look across our full immunology pipeline, we see a whole range of additional programs with transformational potential that support the immunology strategy and our ambitions, and I'm going to spend the rest of our time talking about just a few of these in more detail. I already mentioned Xolair, 20 years young and still delivering new innovation for patients. Xolair, as you probably know, is an anti-IgE antibody that is approved for the treatment of allergic asthma, chronic spontaneous urticaria, nasal polyps, and now is the first and only FDA-approved medicine to reduce allergic reactions to multiple foods. Food allergies continue to increase in prevalence, with about 17 million adults and children affected in the United States alone. About 50% of these patients will actually have severe reactions that result in about 30,000 emergency room visits per year.
As a parent of a child with severe food allergies, I can personally attest to the long-lasting psychosocial, emotional, and developmental impacts that these severe food allergies can have on patients and their families. The approval in food allergy was based upon the results of the phase III OUtMATCH study, which demonstrated dramatic improvements in ability to tolerate an oral food challenge to known allergens, including peanut, milk, egg, and cashew. I think these data point to part of the unique value story for Xolair. It doesn't matter how many things you're allergic to, it doesn't really matter what they are, it's one treatment. Early uptake has been quite strong, with about 15,000 patients treated in the first four months since launch.
Shifting gears a bit, decades of effort have also positioned Roche well for a strong future in immunologic kidney diseases, including lupus nephritis, membranous nephropathy, idiopathic nephrotic syndrome, and IgA nephropathy. In each of these diseases, Roche has a phase III program that's expected to read out in the next few years. I'm going to spend a little bit more time talking about lupus nephritis. Lupus nephritis, if you don't know, is a severe and dreaded manifestation of systemic lupus. About 50% of lupus patients will develop lupus nephritis within five years of their diagnosis, and about a quarter to a third of those patients will go on to develop end-stage kidney disease. Lupus nephritis is also associated with increased mortality, about 6x that of the general population. We recently announced the positive top-line results from the REGENCY study of Gazyva in lupus nephritis.
As I mentioned earlier, Gazyva is a next-generation anti-CD20 antibody with enhanced B-cell depletion, and less dependence on complement for cytotoxicity, which means that Gazyva is particularly well suited to treat patients with a disease like lupus nephritis, where complement levels may be reduced. The phase III REGENCY study results showed that a higher proportion of patients treated with Gazyva compared to placebo on top of standard of care therapy, achieved a complete renal response at 76 weeks. Complete renal response is an important endpoint because it's correlated with sustained preservation of kidney function, as well as delay or prevention of progression to end-stage kidney disease. Key secondary endpoints were also supportive of the primary endpoint, and no new safety signals were identified. We will be filing this data with global health authorities and presenting it at an upcoming medical scientific conference.
Turning to gastroimmunology, tumor necrosis factor-like cytokine 1A or TL1A is emerging as an exciting new pathway relevant to inflammatory bowel disease. IBD affects about eight million patients worldwide, and about 80% of them will not achieve lasting remission with currently available therapies. TL1A also has potential relevance across a whole broad range of immunologic diseases because it sits upstream from some key pathways, which modulate TH1, TH2, TH17, and fibrotic responses that are relevant across multiple disease indications in gastroenterology, rheumatology, pulmonary fibrosis, dermatology, et cetera. Our phase III pivotal program in inflammatory bowel disease is underway at this point, with first patient enrolled, achieved in our ulcerative colitis studies as of earlier this month, and first patient in expected in our Crohn's disease studies in the first quarter of 2025.
We're continuing to explore additional indications to achieve the full potential of this molecule as a pan-immunology molecule, and we're expecting to be able to update you with some details in the first half of 2025. As I mentioned, the phase III program in ulcerative colitis is underway with the AMETRINE-1 and AMETRINE-2 studies, and the first patients have been enrolled in those studies. These studies, of course, were designed based upon the robust safety and efficacy data from phase II-B TUSCANY-2 study in ulcerative colitis, which showed sustained clinical remission and endoscopic improvement from the induction phase through the chronic maintenance phase with treatment, and we'll be presenting an updated analysis of these results from the phase II study at the United European Gastroenterology Conference later on this year.
AMETRINE-1 is a treat-through study, meaning the patients move seamlessly from induction to maintenance and into the open-label extension portion of the study without requiring re-randomization. AMETRINE- 2 is an induction-only study, meaning patients move from the induction phase into the open-label extension directly, again, without requiring re-randomization. And this study design is particularly appealing to patients and to clinicians because it minimizes the time that patients are on blinded placebo. Both studies are directed at a broad, all-comers IBD patient population, including patients who have not responded to more than three previous advanced therapies, so some of the most refractory and difficult-to-treat patients. But they're also exploring a biomarker test, which may predict better response to treatment. COPD. Astegolimab is our first-in-class anti-ST2 monoclonal antibody in COPD. COPD is, of course, the third leading cause of death worldwide, affecting approximately 450 million patients globally.
ST2 is the receptor for IL-33, which is an alarmin cytokine released in the lung in response to noxious stimuli, including cigarette smoke and viral infections. In the phase II-A COPD-ST2OP study, astegolimab treatment was associated with a 22% numerical reduction in acute exacerbations, accompanied by significant improvements in symptoms and forced expiratory volumes. I should note here that the treatment effects seen in COPD -ST2OP was actually similar to the treatment effects seen in other phase II studies of compounds which directly target IL-33, rather than targeting the ST2 receptor. COPD has historically been a very difficult disease to treat, and one of the key reasons for this is the heterogeneity of the disease.
A treatment that might be effective for a patient who has chronic bronchitis might be completely ineffective for a patient who has severe emphysema, despite both patients having COPD with similar levels of airflow obstruction. One approach to this heterogeneity has been to segment patients based upon their eosinophil levels, like we do for asthma, and not surprisingly, repurposed asthma medications have seen some success with this approach. Unfortunately, it only addresses about 20% of the patient population of COPD who have high eosinophil levels. Another approach has been to segment patients based upon smoking status, but in contrast, astegolimab has the potential to address a broader range of COPD patients, regardless of their eosinophil levels and regardless of their smoking status, because its mechanism of action addresses both eosinophilic and neutrophilic inflammation.
Our pivotal program, ALIENTO and ARNASA, the two studies, is well underway with results expected in 2025. Another novel pathway that we're very excited about is NLRP3. NLRP3 is a multi-protein complex that triggers pyroptotic cell death and has been implicated in multiple disorders across different therapeutic areas. Selnoflast is an orally active, potent, selective, and reversible NLRP3 inhibitor that's currently in a phase I-B study of moderate to severe asthma. NLRP3 inhibition was shown to reduce airway inflammation and hyperresponsiveness in preclinical models of steroid-resistant asthma, and that's why we believe that selnoflast has the potential to be the first new oral asthma therapy in twenty-five years. Selnoflast is also being studied in other phase I studies of Parkinson's disease and coronary artery disease, diseases in which inflammation is felt to play a key role in disease progression.
So I'm going to turn for a few moments then to infectious diseases. Infectious diseases is not part of immunology, and it's not one of our five therapeutic areas of focus. Nevertheless, it is a part of our societal commitment to global health security. Looking back over the last few years, one of the things that we're most proud of as a company is the role that we played in combating the global COVID-19 pandemic, and that spans across Pharma and Dia. And we believe that we should continue to aim to deliver curative therapies for infectious diseases that represent some of the highest unmet needs in the world, and in doing so, can continue to contribute to preparedness for the next global pandemic.
In that context, we recently announced the results of the CENTERSTONE study, which showed that a single treatment with Xofluza can reduce transmission of influenza from an infected person to their household contacts when only the infected person is treated. This is the first time this has ever been shown for a respiratory antiviral, and it has important implications for personal and public health because influenza continues to represent a serious threat to public health and a significant burden on economies and healthcare systems, with 1 billion cases annually and 650,000 respiratory deaths. In addition, antimicrobial resistance is increasingly recognized as a silent pandemic that is expected to claim more lives over the next 30 years than cancer if current trends continue.
Despite this, there are significant challenges, both scientific and commercial, to the kind of sustained development efforts that are required to win this battle against the bugs. In particular, what we need is novel classes of antibiotics with new mechanisms of action, and as Thomas alluded to this morning, none has been marketed since 1968. It's been a long time. Roche currently has two novel mechanism of action antibacterials in development. So zosurabalpin is a narrow-spectrum, macrocyclic peptide, which blocks Gram-negative transport of lipopolysaccharide. And this molecule actually has high in vitro potency against Acinetobacter baumannii, including carbapenem-resistant strains, which are the highest-threat pathogen, according to both the WHO and CDC. We also have RG6436, which is a broad-spectrum LepB inhibitor with high in vitro potency against carbapenem-resistant Enterobacteriaceae and Pseudomonas aeruginosa.
LepB is a type one signal peptidase that cleaves and activates bacterial preproteins, and both of these molecules are in phase I development, but we're looking for opportunities, opportunities to accelerate these programs in order to bring them more quickly to the patients who need them the most. And with that, I will close my section, and I will invite Christopher Brittain, the Global Head of Product Development, Ophthalmology, to the stage.
Great. Thank you so much, Larry, and good afternoon, everybody. So it's a great pleasure today to be able to talk to you about the ophthalmology pipeline for the next ten minutes or so. For those of you who were here last year, I talked a lot about momentum, and today I'm going to talk a lot about momentum and execution. Last year, when I mentioned momentum, we had 1.5 million vials of Vabysmo in the market. Today, we have over 5 million vials of Vabysmo in the market. So real momentum is really been going strong on the ophthalmology side since we last spoke. As Thomas talked about earlier today, stopping, preventing, and curing is a kind of one of the backbones of our strategies at Roche, and the ophthalmology pipeline is really continuing with that in mind.
Here you can see we have several approaches. Today, our therapies, such as Susvimo and Vabysmo, are really aimed to improve vision in patients who've already suffered from some form of disease. Oftentimes, you know, 40%-60%, 40%-50% of patients, despite the best available treatment, still don't return to driving vision in their treated eye. Those are in the middle there. We therefore really want to aim to treat patients earlier in their disease spectrum, and that's prevention. Examples here are going to be looking at treatments for intermediate AMD, diabetic retinopathy. On the later stage of disease, we have the opportunity to restore vision for patients who've already lost it and whom the currently available therapies do not work.
We have a couple of examples, one of which I'll talk about later, which is OpRegen, but optogenetics is another disease there, where we're looking at restoring vision for those who currently would be blind or considered blind in many instances. To execute on this strategy, we have three broad pillars, starting with extended durability and future technologies. The best example of the extended durability is Susvimo and the port delivery platform. We really believe this is an important platform for us, and although I'll talk a little bit more detail about it later, currently, Susvimo can provide treatments every six months. We really see future technologies, future molecules going into that platform, being able to go every nine months, every year, and beyond.
While I'll talk a little bit about cell therapy later with OpRegen, obviously, I've just mentioned the fact that we have other novel technologies in the form of gene therapy. And here we're looking at novel, kind of, second-generation capsids to treat blinding conditions with what we call optogenetic technology. So replacing, converting viable retinal cells into photoreceptors. The second column here is around novel mechanisms of action and new indications. Part of our strategy at Roche in ophthalmology is to look at the mechanisms of disease. So examples here, we have the leading technologies in the vascular stability with our VEGF Ang-2 pathway knowledge. We're looking at inflammation with our IL-6 and vamikibart.
Many of you will be aware that we acquired an asset through the SEMA3A partnership a number of years ago, which is addressing retinal ischemia. I'll talk a little bit later about our Wnt pathway, which addresses both ischemia and potentially vascular stability. So all these, as you can see, really address inflammation, atrophy, ischemia, and vascular stability. Finally, you've heard a lot about this morning digital capabilities. Ophthalmology is no different, if not possibly one of the leaders within the organization. What we found is we're really capable of integrating omics clinical imaging data, and this is providing not only insights in terms of disease understanding, but it's enabling us to develop disease algorithms.
A good example of one of these algorithms is actually with a single fundus image, we can predict the rate of disease, we can predict 50% of the next year's rate of progression of disease in patients with geographic atrophy. Then the last piece there is we've in the U.S. we've had a controlled U.S. commercial launch of our myVision Track monitoring tool, which has the potential to be an accessible and effective and low-cost way of tracking disease. We talked a little bit about Susvimo and Vabysmo. The momentum with Vabysmo, I've already mentioned the 5 million vials, but we've also been approved now in over 100 countries. That's going incredibly well, and you've heard about the prefills already.
On the Susvimo side, the relaunch is going nicely, and we're getting good, good feedback from physicians, and we've already had reimbursement from a number of U.S. reimbursement organizations. And then in phase III, which I'm going to highlight in a minute, is going to be around kind of ENSPRYNG and thyroid eye disease and where we are and how we've executed that since we last spoke last year, and also the vamikibart for patients with uveitic macular edema. So as a reminder, vamikibart is an IL, is an intravitreally injected IL-6 targeting therapy with a modified Fc region to reduce systemic exposure. Based on the phase I data, where we had about 30% of patients were able to have a gain of approximately 15 letters or three lines of visual acuity over a 3-month period.
Since we spoke last year when we were announcing our launch of this into phase III, we've already completed enrollment in one of our phase III studies called MEERKAT, and by the end of this year, we expect to complete enrollment of the second phase III study called SANDCAT. So for me, this is a really a real validation of the unmet need by which I mean the desire by physicians to have a therapy which targets inflammation, which is not a steroid. Steroids have horrible side effects in the eye: cataract, intraocular pressure issues, permanent glaucoma, for which surgeries can be required. So really exciting progress and execution on the vamikibart side. ENSPRYNG is our therapy, systemic, subcutaneously delivered thyroid eye disease treatment, which is currently in phase III also. Going very nicely.
Two studies, SatraGO-1 and SatraGO-2 . As a reminder, IL-6 is a key mediator of inflammation and really drives fibrosis in patients with thyroid eye disease. The opportunity here with ENSPRYNG particularly is that the currently available therapy, which is only available in a small number of countries, has side effects which include hypoglycemia, fetal toxicity, menorrhagia, and issues with menstruation in up to a quarter of women. So hopefully, when you see the thyroid eye disease affects about 5x as many women as it does men, there's an enormous amount of unmet need in this disease area. So we're really excited to be able to move these studies forward, and they've been recruiting very nicely.
Coming back to vision restoration, which we talked about earlier, the OpRegen program is our allogeneic cell RPE cell therapy, so retinal pigment epithelium, and it's injected under the retina. The phase II study continues very nicely, and we've been able to share now two-year data from our phase I program, which is very reassuring in that not only do the patients continue to have preservation of their visual acuity, but probably more importantly, their anatomy is also maintained out to the two-year point, as you can see on the graph on the right side. That's showing the mean increase in area of retinal pigment epithelium.
The left-hand side of that, of the right graph shows when you inject these cells in the right place, i.e., under the retina where there is atrophy, the cells really go there and stay there, and that area of atrophy does not increase in size over that two-year time point. A really exciting program and lots more to come in the future. Returning to the port delivery system platform, zifibancimig is our second therapy, now officially in clinic. Zifibancimig is our bispecific VEGF Ang-2 molecule. It's entered parts two and part three, as you can see on the graph of our BURGUNDY trial.
Part two is comparing a low dose versus a high dose, and part three is a larger sub-study comparing a low dose, a high dose, and Susvimo. The goal here is to see how long we can extend the durability of treatment for with this bispecific molecule. Importantly, port delivery is a platform, as I said previously, and the opportunity here is we actually have three DutaFabs in total, which can go into this platform, and two other preclinical model molecules, which can also expected to enter the platform. We're really excited about this, and it's gonna be not just neovascular AMD and DME, but multiple, multiple diseases. You heard a lot about our AntlerA acquisition this morning from Teresa, so I'm delighted to be sharing just a few seconds of information about this.
But as a little bit of a background, the Wnt pathway has been known for many years, and it plays a really important developmental role in developing the retinal vasculature within the human and within animals. It supports retinal vasculature development and also maintenance of the blood retinal barrier. So therefore, it has a role in potentially in both ischemia and in retinal vascular stability. And the exciting thing about the AntFarm, which is what we describe this picture of multiple bispecific molecules, which this acquisition of AntlerA provide us with, is that we can have multiple. It is basically it's the evidence has really grown over the last couple of years.
Number one, we have genetic evidence, so there's a variety of human diseases, one called familial exudative vitreoretinopathy, where deficiencies in the pathway result in disease and blinding diseases in childhood from the age of five years. Secondly, is preclinical models, whereby we've shown that knockouts of various elements of the pathway result in ischemia and retinal leakage and vision loss in animal models. And thirdly, we've seen a clinical proof of concept with a competitor molecule. So all in all, a really exciting time, and we're looking forward to bringing this into the clinic. So with that, I'm just gonna close by saying, I hope you've seen today that we're really building on the momentum of Susvimo and Vabysmo.
We've built the momentum and executed on our phase III studies with thyroid eye disease and uveitic macular edema, and we've really executed now on building, continuing to build our pipeline out with addressing multiple mechanisms of action, from addressing ischemia, fibrosis, inflammation, and atrophy, and vascular stability, so with that, I'm very happy to pass on to our last speaker, Manu Chakravarthy, Head of our Cardiovascular, Renal, and Metabolism Product Development. Thanks, Manu.
Thanks, Chris. I know that I stand between you and the Aperol or the drink, so we'll try to make this, you know, efficient and quick. So let me just start with this slide, because it sort of encapsulates really the genesis of why CVRM at Roche. Both cardiovascular, renal, and metabolic diseases are considered interdependent. And in fact, the American Heart Association recently actually called this the CKM syndrome, cardiovascular kidney metabolic syndrome. And it underscores the fact that all these things likely have a common driver, and that happens to be obesity or adiposity. And in fact, individuals that have a BMI greater than 40, 30, will carry more than 40% elevated risk of overall mortality. So it's clearly not a bystander.
It's really a driver of many of these interdependent diseases. Of course, I mean, from a patient perspective, it's really amazing, and it's really thankfully there are some really transformative treatments available today. But in the field of CVRM in general, there are significant unmet needs that remain, and I'll try to encapsulate some of those. Quite honestly, that's what gets me up in the morning is just all these needs. And to me personally, I felt this was what I was drawn to Roche for, is no better place to do this than in a company that you've heard already is interdependent on both the therapeutics and the diagnostic side of things.
So in terms of the strategic pillars that we're trying to build in for CVRM at Roche, it really includes the backbone of the incretins that was acquired through Carmot, CT-388, CT-996. But also to take that and build upon the other needs that clearly exist in the field, which we all know that, of course, yes, we need to address obesity, but obesity comes with other related morbidities like hypertension, heart failure, chronic kidney disease, and even, as you heard, you know, from Azad, neurodegeneration, Alzheimer's, Parkinson's, and even diabetic retinopathy. So these are all interrelated, and one could argue that that's where the differentiation opportunities at Roche really lie. Obesity is going to be heterogeneous. It's going to be a segmented market, and so we have to be mindful of where the combinations are.
And so another strength that we're trying to bring forward or together at Roche is to be able to leverage the internal pipeline with GYM329 that you heard again from Azad. There's also CT-173, which is our PYY. I'll tell you a little bit more about today. And then you also heard from Larry about selnoflast NLRP3 could be a potentially a great combination to address the vast spectra of ASCVD or atherosclerotic cardiovascular disease. And then probably one could argue the true sort of the strength at Roche is really to marry the therapeutic and the diagnostic approaches. And there's no better therapeutic area that lends itself to diagnostic than CDM. You already have the continuous glucose monitor that's already used as standard of care in diabetes.
The SmartGuide , Accu-Chek from Roche, is at the leading edge of that. There's already detection tools available that we need for heart failure, MIs, and even lipids. So when you bring it all together, it provides us the type of pipeline that will allow us to address this incredible challenge. So this is the cardiometabolic pipeline as it stands today. I'm going to give you brief snippets of each one of them. I'll spend a little bit more time on CT-173, the PYY analog, since that's a little bit new, but many of you were at the EASD and other events that we've had, and so you've already seen little snippets of this, so I'll go through them relatively quickly.
We'll highlight exactly where each of these assets are in their development. One of the questions that I always get is: Is Roche too late in obesity? I think some of the questions were already asked this morning. My answer to that would be wholeheartedly, no. There's a lot to do in this space. And I think, as I said before, it's not only a large market, but actually, when you think about the unmet needs of people living with obesity, it's numerous. Okay, so when you really think about the full spectrum from, you know, yes, you need to reduce body weight, but there's so much more than that, right? So you have to think about: Can you improve tolerability? Can you get to a deeper and more sustained weight loss?
Can you get to a better quality of weight loss? Can you maintain that weight loss? These are fundamental questions that the field is yet to answer, and Roche is well positioned with its pipeline. So when we actually constructed the pipeline, the whole intent was actually to try to figure out where the monotherapies and the dual therapies and the combination therapies can all play. The advantage that we also have is the modality. So there's injectables and orals, and so another question that comes up all the time is, you know, how and why do you need both? We certainly know that patients are in different stages of their journey. Some people like needles. Some people don't.
So having that optionality becomes really vital, and very few portfolios, at least that we're aware of, really carry all those options. So before we go into each of those assets, one of the things to sort of just remind ourselves is, how were they actually designed? So we, of course, knew about the incretins in our Carmot, so it wasn't like we were just entering this field completely blind. But one of the critical questions that actually still remains unknown is, how do they actually work? As seemingly simple as that question is, it's actually still not fully delineated. So one of the insights that Carmot was able to provide was to actually focus the design of these molecules in such a way that we could maximize the efficacy while improving upon the tolerability.
One way you could do that is by what is called biased signaling. Most molecules that are there right now in the marketplace, or even the natural hormones like GLP-1 and GIP, they signal through both cAMP or cyclic AMP and β-arrestin. We knew from the literature that if we could favor the signaling through cAMP and eliminate β-arrestin, which is thought to be the off signal, then the hypothesis was that we would prolong the efficacy and the tolerability. Our preclinical data to date, you know, suggests that, in fact, that is the case. Of course, as we go through and mature our clinical pipeline, we will continue to support that clinically as well.
You know, there are other data, not from [audio distortion] , but including from Bob Lefkowitz, who actually got the Nobel Prize for G protein-coupled signaling, and others actually showed that, in fact, by biasing, you will have greater efficacy and improved tolerability. CT-388, very quickly, again, many of you were at the EASD, so I'm not going to belabor on each one of them but just give you the highlights. We reported on the 24-week data. A strong weight loss, very, very robust. The overall profile is actually in line with the incretin-based therapies for this stage of development. Now we're in, you know, achieved the first patient in for our phase II study. It is a multi-arm, dose-ranging study to really understand the tolerability and the starting dose.
So that's that study is underway already, and we are about to embark on the second phase II in people with obesity and diabetes. 996, again, this was also presented at EASD. So again, as a reminder, this is an oral, synthetic, highly potent small molecule. The phase I data continues to again, you know, tell us that, you know, we have a very potent selective molecule, roughly around 7% weight loss in four weeks. And again, you know, when you compare it to other molecules in this stage of development, the AE profile or the tolerability profile is very much in line, very consistent with that.
Very reassuringly for us, we saw the plasma half-life in the 17 hr-22 hr range, which comfortably puts it in the once-daily regimen, which we believe is a must-win or a must-have for a true, competitive, molecule in the obesity and diabetes space. The main things there are, we're about to start the arm 3, which is, obese Type 2 patients in over a four-week duration. And then, we are planning already, based on the reported data, phase II initiation in 2025. CT-868, very exciting program, because it's the you know, the first-in-class and potentially best-in-class for Type 1 diabetes. While a lot of people focus on Type 2, they get a lot of attention there, but patients with Type 1 often get forgotten.
This is an opportunity to really transform that care. There's a phase II in Type 1 patients underway. We'll have the data in 2025, but the proof of concept that 868 is a very potent glycemic control agent comes from our Type 2 study, which we did over 26 weeks, and you can see a nice dose-dependent decrease in the A1c of almost 2.3%. To the best of our knowledge, that's about as steep as A1c reductions can be. Over 70% of people were no longer diabetic at the end of their six-month period. 173, this is our long-acting PYY analog. And the data, you know, so far, of course, is preclinical, but very exciting.
So when you look at the data on the left, what you see on the green curve is a combination of CT-388 plus CT-173, which shows you this very deep and fairly sustained reduction in body weight, way above and beyond either agent alone. So potentially synergistic response. On the right is equally exciting data, which actually shows that once you achieve the plateau, which you'll, you know, many incretins do get onto the plateau, and then on the plateau, when you treat these animals that are overweight, actually obese in this case, you actually drive even further weight loss. So this is very exciting for us because this is actually telling us, potentially, that there's an opportunity to maybe reset the body weight set point.
That has been always the sort of big question in the field is: Can you actually reset the set point? Perhaps with agents like this, you know, there is an opportunity to do that. Switching gears quickly to zilebesiran. Why do we really care about this, right? I mean, one could say, well, hypertension, I mean, don't we have enough drugs already? It's true, but what was striking, at least, you know, to us, when we looked at this epidemiologically, is that more than half of the adults in the U.S. with uncontrolled hypertension are actually unaware that they're even uncontrolled. That leads to up to threefold increase in overall mortality. That's a significant problem, right? That's pretty much unmet.
When we think about zilebesiran, it's paradigm shifting because this is the agent that actually inhibits angiotensinogen, which is the most upstream of the modulators of the RAS pathway, a highly validated pathway in the field of hypertension. And this medicine, in partnership with Alnylam, that we're working towards, has the potential to be really game-changing because you can give this as a single shot just twice a year and then really get to this very sustained blood pressure lowering. And the proof of that comes from our KARDIA-2 study, where we showed both in the primary endpoint and the secondary endpoint. The primary endpoint is ambulatory blood pressure, and the secondary endpoint is office blood pressure. What's remarkable about this study is that.
All these patients were treated with true standard of care, including ARBs and ACE inhibitors, which is, of course, used quite a bit, and so even in top, on top of an ACE inhibitor or an ARB, you still see statistically significant, clinically meaningful changes in blood pressure lowering, so this tells us that there's a really significant opportunity here to improve the care, and so we are embarking on a pretty extensive development program, so there's the three KARDIA: KARDIA -1, 2, and 3. We're actually just in the midst of KARDIA-3 . Cohort A of KARDIA-3 is fully enrolled. Cohort B is enrolling currently, and that's a high-risk CVD population with CKD as well.
And so the goal is that, you know, we would read out on KARDIA-3 , and that would help us then design our or embark on our CVOT study, which we will have ready as part of our launch package. So just to conclude then, you know, given the fact that these are probably the biggest, you know, diseases, as you heard from Thomas this morning, Roche is well-positioned to address these interdependent diseases with a core foundation of not only the incretins, but a lot of the other molecules that we have in our therapeutic space. So let me invite Teresa to the stage to bring us back home, and we'll be open to questions after that.
Thank you, Manu. Okay. All right. So I hope what we've shared with you here today gives you a strong sense of progress from where we started at the beginning of last year. And to just sort of sum everything up, we're in a place where that young, best-in-disease portfolio will continue to provide growth over the next several years. We have a number of exciting readouts coming from our late-stage pipeline, 12 phase III readouts next year, including a number of phase I and phase II readouts for some of our earlier-stage pipeline assets. A tremendous amount of work going on in the R&D organization to ensure that we're able to accelerate the timeline in which we're bringing transformational medicines to patients and increase our success rates.
And then, of course, the strategy to help make sure that from an end-to-end perspective, we are applying rigor in science and discipline in business to ultimately meet our ambition of delivering 20 transformational medicines to patients by the end of the decade. So we've covered a lot today. I suspect you have a lot of questions, so I'm gonna bring all of our presenters back up to the stage, including Alan Hippe, our CFO, and Bruno, and we will get started on our Q&A. And then you actually go get to have an Aperol.
Very good. Let's immediately jump into the second Q&A session, and Sachin, you go first .
Sachin Jain from Bank of America. I'll take a couple of questions, please, on some phase III reads due next year. First, on fenebrutinib, wonder if you could just reappraise your level of confidence in RRMS, given we've now had two failed molecules. Two specific questions: One, given what you've learned from other molecules, are you thinking about changing the primary endpoint from relapse rate to progression? And then secondly, the phase II data, how do you think about that 0.4 being reflective of phase III, given it was an open-label extension and a very early-stage population? And then I had a follow-on on SERD.
Sure. So we're actually quite confident about fenebrutinib, despite the sort of results you mentioned. Fenebrutinib, as I mentioned, is really actually quite differentiated, and it really comes down to the Pharmacology. So because of the Pharmacology that I mentioned, it's non-covalent, reversible, quite potent, and so it has a good sort of benefit-safety profile, and it really comes down to the dose then. So actually, we're using a high and efficacious dose of 200 mg, 2x daily, and so I think that the dose is gonna be really important, and I think the FENopta results actually sort of bear that out. So it's not just in the double-blind period, but as you alluded to, also in the sort of the open-label. Yes, it is open-label.
Nevertheless, they're quite striking results, both in terms of clinical relapse as well as the MRI results. So we're confident. Obviously, we need to await the results of the phase III, so I think that's, you know, that, that's very clear.
I'm sorry. If I could take one on the SERD, please. So part of the description of your confidence of success is endocrine sensitivity in front line and adjuvant related to ESR1 mutant. So it's hard to see from the chart. Does endocrine sensitivity vary much between front line and adjuvant? I'm just trying to get a sense of which population you're more confident in, and if front line fails or succeeds next year, how that impacts on adjuvant probability.
Yeah. Well, I think what I wanted to address was the findings from acelERA , which I know were really suggestive. You know, the overall intent to treat analysis was we didn't see the giredestrant meeting its expectations on PFS but then recognizing that probably up to 60% of those patients had endocrine-insensitive disease. That transcriptome analysis that I showed you looked specifically at the ESR wild type and mutant, wild type being estrogen independent mutant, continuing to be dependent. If you look, if you line up both early breast cancer, those eligible for adjuvant therapy, as well as frontline metastatic, their profiles match the later line ESR1 mutants in terms of their dependency on estrogen receptors. So certainly based on that transcriptome analysis, that would further our confidence both in the adjuvant and first-line metastatic settings.
Yeah, I agree. I would just add, fully agree with what Charlie said. So essentially, we know that in the frontline treatment-naïve and in the adjuvant, ER-positive breast cancer, they are endocrine sensitive, so that's pretty clear. But in addition, we didn't show it this year, but we showed it in the past, we had a neoadjuvant window of opportunity study where we actually compared giredestrant to an aromatase inhibitor, and those kinds of studies have often been predictive of what will happen in the adjuvant setting. So that's an example where it's perhaps a proxy for the outcome that we have to do the experiment, but what we hope to see in the adjuvant setting.
In addition, obviously, a difference between the adjuvant setting and the frontline metastatic setting is that we're testing in combination with the CDK inhibitor. But there's also equipoise for the idea that if we increase the impact on the estrogen receptor in that setting, there could be a benefit, and actually, there's some clinical trial design elements that may skew us in favor of that. So obviously, we have to wait and see the results, but there's reason to believe in both the adjuvant and the frontline metastatic setting.
In fact, that neoadjuvant study that I mentioned earlier and that Levi is referring to, we showed superiority for giredestrant over an AI, both in the monotherapy comparison and in the comparison with the two drugs were combined with a CDK inhibitor.
Richard?
Thanks, Bruno. Richard Vosser from JP Morgan. Just following up on the SERD, I think in that window of opportunity study there were a number of cases of bradycardia and an MI as well. So do you feel that you've got a safe enough product for the adjuvant and in particular, but also first line? So that's the first one on SERD. And then secondly, on the PADOVA trial, you highlighted the benefit from PADOVA from fast progressors. So I suppose the question is, you know, what proportion of patients do you think you've enrolled to enrich that in PADOVA in terms of fast progressors? 'Cause on the face of it, the population looks pretty stable from what you've shown. So thanks very much.
So across the entire portfolio of giredestrant studies, we're not seeing meaningful issues in bradycardia or other dose-limiting toxicities, and that patients are staying on. And they're, you know, in terms of the IDMC reports from that portfolio, we're not hearing any safety concerns.
So I can take the PADOVA question. So yes, actually, in the PADOVA, we have. These are patients who are. Yes, they're stage one, two. They're actually already on L-DOPA treatment and MAO or MAO-B. So they already are. There is a good sort of representation of patients who will be faster progressors. So we're actually. The other thing we're doing, as I mentioned, is focusing on the motor progression and looking at time to event.
Thanks. Thanks, it's Peter Verdult from Citi. Just two questions for Azad. Just coming back to Sachin's question on fenebrutinib. You know, tole and evo look great on lesion reduction for the first year, but then there's a waning of effect when you looked at all the other data. And I know you've shown some really impressive data up to 48 weeks, but have you got, have you seen, is there anything you have in-house, beyond that, that gives you the confidence that you're not going to see something similar as it relates to that waning effect? That's question number one.
Okay, well, I think I will sort of highlight another aspect of the Pharmacology. It really does come back to the Pharmacology. So without commenting on sort of the other drugs, we're using a dose that's highly we believe efficacious, and that we can afford to do that because of the Pharmacology. An aspect that I didn't mention also is that although it's reversible and non-covalent, it actually has a slow dissociation rate from BTK. So we think that actually that could... I mean, it's speculative, but that could help explain sort of the longer duration of the effect. So again, of course, it is open label, but it's going out to 48 weeks, and sort of the results are quite striking.
So we do have to await the results, but I, the results of the other BTK inhibitors do not diminish our confidence in the potential result. Again, we have to wait for those results. But I think it's a different construct in terms of, you know, the other BTK inhibitors, how they went from sort of earlier studies to phase III. As you know, in one of them, for example, the dose was reduced, whereas here, we have stayed with the 200 mg, 2x twice daily.
Very fair. And then the second question is, and I'm maybe chancing my arm here, just your level of enthusiasm for bepranemab, the anti-tau, because I, I believe that there's a symposium at CTAD, but bepranemab, the anti-tau?
Yeah, so what I can say about that is that this is a collaboration with UCB, and so there will be, as you said, an update. If you have further questions, I think we would direct them to UCB.
But just your general enthusiasm in terms of antibody targeting tau as a strategy.
As a more general question? So I think that this is tau, of course, beyond A-beta, is one of the sort of second hallmark of the disease described since Alzheimer. You know, there are many ways of going about tau, including going after it intracellularly. There has been evidence for extracellular tau. There have been a number of antibody approaches. People think that this mid-domain region of tau that's targeted by this antibody is sort of would be the most optimal way.
Emmanuel, next.
Thanks. Emmanuel Papadakis, Deutsche Bank. Maybe one asset-specific question out of readout next year, astegolimab. You put a three billion plus target on that. Perhaps you could give us some idea on whether that's a reflection of your perspective on market potential or molecular differentiation, where we obviously have just had one molecule approved in that space. We have several more reading out next year. So just perspectives on both of those would be interesting. And then a question, a follow-up from this morning, the R&D session. A couple of things that jumped out from your platform capabilities, modalities slide. You had next to no ADCs. Obviously, the industry's been moving in the other direction. So is that a deliberate decision to disinvest in that modality? Or you just think other opportunities fulfill the same function?
And then, conversely, you seem to have more accumulation of more small molecules. Again, industry moving in somewhat the other direction. Is that a function of the opportunities that you have in hand, or are you expecting some change in IRA that would make that rational? Thank you.
I can start to answer the astegolimab question from a sort of a clinical and scientific perspective, and then I can hand off maybe to Teresa to talk about the commercial opportunity. But when we look at, you know, this first generation of biologics for COPD, these are, again, largely repurposed asthma medications, and they are directed at patients who have high eosinophil levels. The highest levels of eosinophil levels, again, which is really a subset, a minority, maybe 20% of the overall COPD patient population. So we think that really kind of, you know, that's the low-hanging fruit, and really, the, the, the most important patients to treat are those who do not actually have high eosinophil levels. Those are kind of the historically most difficult patients to treat, 80% or so of the patient population.
astegolimab, again, because of its mechanism of action, is targeted not only at patients who have high eosinophil levels, but those who have low eosinophil levels as well. So we think it is a much broader patient population that actually is targeted by astegolimab. I don't know if Teresa wants to.
That is why we actually believe it has a higher market potential because it's just targeting a much larger group of patients.
I can take your question about antibody-drug conjugates. Others can chime in. You know, I, I think that in many respects, this organization launched the field of antibody-drug conjugates with Kadcyla and Polivy. You know, I think it's been a bit of a rollercoaster, the molecules really falling out of favor a decade ago, and then with renewed interest. But I would say even in the results we're seeing this year, I think what we're learning is that it's a challenging space. Preclinical models of this class of drugs are not particularly predictive of clinical results, and that in certain circumstances, it's empiric. That is, the science is not clear that there's a specific target linker and payload that can add up to a clearly winning molecule. That doesn't mean we've retreated from ADCs, absolutely not.
As you saw, we made a deal with MediLink, but I think we're, you know, really watching carefully as we develop in that space, recognizing that I think the approaches have been more empiric than scientifically driven in terms of understanding, design, and preclinical work, but that, you know, we continue to be interested, and beyond, obviously, the ADC that we have with MediLink, we're continuing to develop antibody-drug conjugates with novel payloads internally, so it's a space we're interested in, but we realize it's not as easy as one might think, given the difficulties predicting a clinical outcome.
Yeah, just one final point on that. In general, from a R&D Excellence lens, the first question we would ask is: Is this a foundational target? And then the question would be: What is the optimal modality to kind of engage the target? And I bring it. It sounds kind of obvious, but we don't do it the other way around. It's not like, "Oh, what's the foundational modality?" And then go searching for targets. So I think that's gonna be a guiding principle for us. And the good news is, there are. I mean, ADCs is one, but there are many now modalities that are at our disposal, and of course, the industry.
I think it makes sense to start with the target and the disease, and then pick the right modality, and ultimately that may require iteration on how to actually leverage that modality.
And then I think your other question was on what I believe you suggest was a greater expansion to small molecules. You know, whether it be in hematology, oncology, or really across our therapeutic areas, I'm not sure I would characterize our portfolio as a greater interest in small molecules. I think what we have is a broad array across modalities and technologies, really to the point that Levi just made, about given the target, what is the best way to confer a therapeutic effect and the best outcome for patients. You know, in terms of the effect on IRA, I defer to Teresa.
Yeah, I just wanted to add, there is also a class between the small molecules and the antibodies, which is basically peptides, right? And so, Chugai has really mastered that technology, and it's quite interesting because one of the issues with the small molecules is, although you can get into the cell, you may not create the binding affinity. So you have to target something that has a pocket in order to create that kind of binding affinity. Now, the cyclic peptides, they can actually, through conformation and change, get through the membrane and create the pockets, and I think that will enable us to target targets in the cell that today are very hard to target, and I think here we have a leadership position in terms of that modality.
And then from an IRA perspective, I think it's just important to make sure that as you're developing small molecules, you're doing it wisely in terms of thinking about how your development program is unfolding, how you're thinking about indications, given the constraints that we know that the IRA conveys. Let's also remember that there are a lot of people who live outside of IRA-affected populations, and small molecules are actually very, very useful for getting drugs to places where things like cold chain or IV capabilities just aren't possible. So, I mean, I think we do need to really follow the biology here and pick the modality that's gonna work for the biology, and then you figure the rest out.
On astegolimab, just to be clear, I understand you think there's more potential beyond the eosinophilic high patients, but I was asking more in terms of differentiation with the other IL-33 and ST2 molecules that are reading out next year. Is there anything you'd particularly highlight there?
Yeah, sure. Happy to talk more about that. Obviously, you know, astegolimab is the only molecule that's targeting the ST2 receptor, as opposed to targeting the IL-33 ligand. And in terms of what difference that will make in terms of clinical outcomes, that remains to be seen. But I think if we look at the, you know, other two nearest term competitors, again, both IL-33 ligand inhibitors, one is actually significantly behind in terms of their launch timelines, and the other one is targeting actually a more narrow patient population. In that case, they're segmenting based upon smoking status, whereas again, astegolimab is actually targeted at a broad patient population, regardless of eosinophil levels and regardless of smoking status.
Yeah, I mean, essentially, astegolimab allows you to go after the entire population, and that is a very significant group of patients. There's probably also a group of COPD patients who are just undertreated and not seeking treatment right now because the treatments aren't very good. So I think you'll both see. We have an opportunity to go after a much bigger slice of the pie, and I think you might also expect the pie to get bigger.
Simon, please. Over there.
Thank you. Simon Baker from Redburn Atlantic. Two questions. One, firstly, on oncology modalities. Another one missing from the slide is radiopharma. Just be interesting to get your perspectives on that. And then one for Azad, on multiple sclerosis. There's been a lot of work this year on the potential involvement of Epstein-Barr virus infection in MS. Be interesting to get your thoughts on that, and whether you see that as an opportunity or a threat to the MS franchise. Thank you.
Specifically on radiopharma, as I mentioned at the beginning, we have engaged in a partnership with PeptiDream on novel targeting radioconjugates, and that certainly is a continued active area of investigation. I think it, you know, there's the field of radioconjugates, in general, is an evolving field. That's certainly an area we're interested in, and that's an investment we are advancing as we continue to follow the field.
With regards to your second question about EBV, I think that's a really interesting development scientifically. We do not see it as a threat. The B-cell targeting approaches, for example, with OCREVUS, targeting B cells and B-cell depletion, most people think that actually a lot of the way that the B cells work is more from an antigen presentation rather than autoantibodies, although that can be also involved. With EBV, that is something, the idea is that there would be autoantibodies to specific proteins. So I think it's a very interesting idea. There's a lot of interest in following up on this. One of the challenges will be, of course, a lot of people get EBV virus, but only a few people get MS from that.
So, figuring that out is also gonna be important, and that's really all of that means that it's going to be an opportunity for us to build on.
Can you please pass it on to Luisa?
Thank you. Luisa Hector from Berenberg. A couple of clarifications. On the twenty transformative medicines by the end of 2029, I think that you said that started in 2020. How many have you launched so far? And Thomas, you also mentioned R&D flat next year. I just wanted to check that's as a percentage of sales. And then, lovely to see you all there, and thank you for your presentations. I'm wondering if all of you are pole vaulting over your bars very well with your internal assets, and you all see exciting external assets. Is it Alan that gets to say, "No, we can't afford it?" Or how is that final decision come to be made? Thank you.
So let me answer the first question around R&D flat. That's an absolute flat. So in percents, it will come down, so in percent of sales, it comes down. So similar, as you can see, it's this year. So we just wanna make sure that we make sure that our engine works extremely efficiently. That's the first thing. The second thing is, when we assess the targets, I can tell you, we have very often very late-night calls. Many people, you know, in this group are then on these calls, depending on the topic, plus then the scientists and so on. And then you get kind of an evaluation, how strong is the data, you know, and you get the financial component in, you know, what does it mean in terms of, you know, what's the purchase price?
Does it make sense from an NP, NPV perspective, and so on? I would say we look at, I don't know, how many companies every year, but probably in the hundreds, if not thousands. We say no to 99.99999%, right? Because we have to be firmly convinced that the science is strong, the data is strong. Oftentimes, we actually take the antibodies or these molecules in, we test them in-house because we don't only rely on other people's data, right? So we really do a very thorough due diligence, and then if it also makes sense financially, then we say, "Okay, this is a good one. It makes a lot of sense," and then we go forward.
We are very, very disciplined, and I think it's a very strong team approach from key experts across the organization. May it be, you know, from people here, but also from finance, et cetera. If I look into it-
Seven.
Sorry?
Seven.
I mean, the way we define transformational medicines, it's important, you know, to keep the bar high. You know, if you look at how many we've launched per year, we've been launching two a year. But if we say what we consider transformational, then we would say we've launched seven transformational, which still needs thirteen till the end of the decade to launch. So the bar is high.
Yeah.
Maybe we can to Peter? Ken.
Just two quick ones, please. First, just as a continuation from Louise's question, actually, just to be clear on the R&D budget. So 2025 is flat in absolute terms. Looking beyond 2025, 'cause it sounds like Manu's basically got an open checkbook. The you know, the not disrespectfully. Everyone else is-
One medicine
...is kind of, you know, managing it, but equally, the pipeline's getting bigger, trials, biomarkers are getting bigger. Can we just try to understand, is R&D long-term? Should we consider that a source of leverage or not, I guess, is one for you, Alan. And then secondly, just curious why the decision was made, IBD and COPD as the focus disease areas. And I say that just because there's a lot of other areas in immunology, which, you know, a lot of people see allergy growth, HS, atopic dermatitis, you're not looking at. And equally, asthma, we've heard several times today, and actually, you're in asthma already, and yet you're not mentioning that. So curious what the decision was for IBD and COPD.
Do you want to-
Do we want to do the first question first, and-
Should I take...? No, look, I think we have said 2024, 2025. I think we keep R&D. I think that's really what we, what we bring to the table at this stage. I think everything else, I think we, we have to look at and see how things develop. But I would argue that's already pretty strong commitment because it requires that we really reprioritize, yeah, within the R&D budgets quite a bit. You know, we have done quite some M&A, M&A transactions, and I think that certainly means we have to bring these things into the budget, if you like, and have to make room for it.
How we did that, I think, Levi went through it, said: "Okay, what did we do with the compounds and whatever?" So I'm very confident that we can achieve this, but I think really, this applies to 2024, 2025.
Yeah, let me just give two examples that we've shown you today. I showed you on how we became much more focused on our digital portfolio in the four segments. These are segments that enhance our products, both in Pharma and Diagnostics, so we're not venturing into something completely different, and with that, also harmonizing the platform and so on, we've saved CHF 170 million. Now, the other example that Levi brought up is on how we reduce the amount of CROs. We work with them more end-to-end, so that we reduce the white space. We talk about savings of CHF 200 million.
And so I can give you a couple more examples, not all of them are public, where I can see that we have an opportunity to take money out of the system without actually not making smart decisions in terms of investments. So it's a way to reprioritize the money and be very diligent with how we spend the money. And you know I call those internally no-regret moves, where we don't regret actually making those moves, and it will actually I think help the organization. Because if you do a lot of things and you don't focus enough, you actually slow down, and by really focusing, you can accelerate, right?
There are things which we can do in a much more efficient way, and we take that one by one and, you know, make sure that we implement that. That's over this time period, and with that, we reprioritize the money to, you know, programs that we were just talking about, phase I-A, and so on and so forth.
Just on the disease question, so the eleven diseases that Teresa described this morning, these are diseases where we feel like as a company today, it makes sense to have end-to-end investment across the value chain, starting all the way from research, early development, late development, commercial, et cetera, but it doesn't mean that if there is an opportunity that a target or a pathway opens up in another disease, that we're not gonna invest there. I think COPD or asthma is a good example. I mean, if we astegolimab, you know, hopefully it works, but there are other targets and pathways that are in our pipeline and that are of interest to us, that could be relevant to COPD.
So, you know, regardless of what happens with Asti, I mean, we're very confident, but regardless, you know, there are other opportunities, and we feel like because of that, it merits sort of an end-to-end investment. But we're not. In no way is this sort of an implication that, oh, we wouldn't do something in asthma because it wasn't on that list, or. This is really about a framework for a prioritization of investments, because you can't invest equally end-to-end across the value chain in every single disease, even with a large investment like ours.
Okay, I think we have time for one more final question. I think, Jo, I promised you one question, so.
Thank you. I've got one big picture question, a couple of clarifications, and a challenge for you. So my first question is just a simple one. You've talked about having the backbone of therapy, particularly in things like obesity. When might we see an amylin on your development program? My main question, though, is to invite Alan and Thomas to be a bit more ambitious in terms of the growth rates going forward. I think every other drug company that has the ability to say that it doesn't have major patent expiries before 2030 is telling us what its growth rate should be between now and 2030. You've done 5% recently in a timeframe when you've had some big patent expiries that you've had to absorb, and you're telling us about this great pipeline.
Can you put your money where your mouth is and give us some idea of what you think a target growth rate top line should be between now and 2030 for you, considering your base business, what you can do perhaps to be better than that CHF 6 billion of headwind? You know, maybe you're reformulating things into subcut, et cetera, and making them grow longer. Just give us some idea of that growth rate going forwards. And just while you're thinking about the answer, my clarification question is prasinezumab. I believe you said that the data was at the end of this year, but we would hear the results next year. Do we get the top line this year and the full data next year, or is it just so close to the end of the year when you actually get it, that we may not hear prasinezumab until early 2025? And my challenge to you is, when you next come back, can you bring more women?
Let me answer two questions first. Regarding more women, just to say that if you look at the Corporate Executive Committee , which is the most senior team in Roche, we have more women than men on the team. So you can look at the website. You can see that we have more women than men. So, you know, if you take a selection of five or six people or seven people, then, you know, it's not representing the entire company. I just want to say that. Also, when we look at metrics on DE&I versus other companies, other p harma companies, we're pretty much on top of that list. Just wanted to put that a bit into perspective.
Now, I know that there are companies that give out certain targets, some starting with an eight in the beginning, and then they have sudden trial that fails, and then everyone questions that, right? And we've had, I would say, a number of discussions with also investors and analysts, where we said, "Okay, you want us to put out a target?" Now, most of them say it's actually not very credible because you know that all the events are binary, and so you don't know exactly how things are going to develop. When you look at the graph that I showed at the beginning in terms of the consensus, we showed you that, we believe that some of this is right.
We believe that the CHF 7 billion seems to be ballpark the right figure in terms of, you know, by similar erosion over those five years period. When we talk about the CHF 17-point-something billion, we believe that, you know, that makes sense, except that there are other assets that are not in there yet. So you're at already a net increase of CHF 10 billion, and Diagnostics will add at least a billion every year to that. So you get a little bit to the ballpark where the middle ground is, but we don't give, and we've never done that, give out a multi-year guidance, right? Again, we've discussed this multiple times internally, we have discussed it externally. We don't...
What we give as an indication is the spectrum of what we believe that can happen, and you can see that we don't have a clear situation. And, you know, all the assets, basically, that we're launching will build on the growth momentum that we have. And that we can commit to, and then we'll see each trial that comes out. I mean, we have very clear visibility for the next three years, but after that, it's really dependent on the three outs.
Can I chime in here?
Yeah.
So I would argue, I think we compared to standards we have set in the past, I think we've set quite a bit already. I think, first of all, let me start with 2024. We have upped the guidance, I think, for 2024 at half year, on the EPS side. I think we have said that we think kind of that momentum, you can also expect in 2025. And Thomas has even today said in his presentation that, the margin that we achieve in 2024, the EBIT margin, that we would like to defend that, perhaps even improve it in 2025. I think we have said this. He said that pharma will grow until 2027, 2028.
I think that was also something which was mentioned, and I think once again, you made the point about Diagnostics, where we now, with the three new technologies, three new platforms that we bring to the market, that we have high expectations here, mid- to high-single-digit growth, yeah, for the foreseeable future. So I think there is much more granularity, in these perspectives, if you like, compared to the past, and I can say that with conviction.
Okay.
I can help answer the amylin question real quickly.
Yeah, go ahead.
So you know, in the graph that I showed you, I mean, the unmet needs of obesity, we certainly think that there's more room for other modalities. So it's not a question of if we should have one or X, Y, or Z. It's more about when is the right time to bring the right combinations, and for what reasons are we doing that? So we believe that the current backbone is actually quite important. We need to prosecute on that first. The advantage of having a GLP-1 as a backbone is it's a very well-validated mechanism, as you know. If we bring something else, all that validation has to go through yet again.
But having said that, we are very open to looking at all things, you know, whether it's gut hormones, whether it's modulators of energy expenditure, whether it's things that can, you know, be exercise mimetics, et cetera. So it's not the pipeline that I showed you is just a snapshot in time for today. But we certainly, you know, expect that over the course of our building of this franchise, we will bring what is necessary or develop it internally, if necessary.
Prasinezumab, I think the question, we always guide it for the fourth quarter. That's when we roll out the data, and in case it would be materially different, we would have a top-line release data then to present it next year. For 2025, that was for sort of once we have the full picture and present it at a scientific meeting.
Okay. I think with that, we are at the end of the second Q&A session and the broadcasted part of the event. You still have thirty minutes with the management team at the aperitif. Let me also take the opportunity here to thank all the many people who contributed to really make this event happen. I think it was a very busy September, so we only started when everyone was coming back from holidays. And from the IR team, I have to call out a couple of people: Jan- Philipp Schwarzhans, Jon Bayard, who managed the morning sessions, and then for the afternoon sessions, we have Loren Kalm, Anita Tang, Richard Sali, Julia Breuer, Sabine Borngräber, and Julia Breuer, who were managing all the afternoon sessions.
And then from the back office as well, Melanie Wolf, Beatrice Hau, and Effat Oezsert, who did all the event organization. There's, of course, many other people in the organization who continuously contributed in the last four weeks, which I could not all name now because it would be a long, long list, but also a big thank you to all the other silent contributors. And with that, I think, we close the event. Thank you.