Welcome to our Pharma Day 2025 here in London. It's good to see a full house. I was told we have, I think, a record attendance here on site, and we also have quite a high number, I think, of web participants. Let me quickly take you through today's agenda and make a few upfront remarks before we kick off the event. Regarding the agenda, we will have again two sessions. We have a two-hour morning session focused on strategy and a two-hour ten-minute afternoon session focused on the evolving pipelines of our five therapeutic areas. Both sessions include a 30-minute Q&A at the end where you will have the opportunity to ask all your questions here in the room and also via the web. Let's start with the morning session. Our first speaker, as you can see here, will be Teresa Graham, our Pharma CEO.
She will provide an update on the pharma strategy based on our five therapeutic areas, and she will also take us through our well-established on-market portfolio. In addition, and for the first time, Teresa will focus also on our emerging obesity strategy, where we have made significant progress in building a leading portfolio with two major deals announced this year: the Zealand Pharma deal and just last week the 89bio deal. The second speaker for the morning will be Levi Garraway, our CMO and Head of Global Product Development. Levi will build on last year's presentation, providing an update on our R&D excellence initiative, which was started now two years ago and which has had a tremendous impact on how we manage our pipeline portfolio and how we allocate our resources to achieve long-lasting success and to really make sure that we achieve the best outcomes for most patients.
Let me also mention here, and I think you have a little card on your desks as well, that we will have a fire alarm going off at exactly 11:00 A.M., and this will be for 30 seconds. There is no need from your side to rush out of the room. Just to be very clear and to avoid any rumors, I have not been behind this fire alarm to make sure our speakers stay in time. I just want to avoid any mistakes here. Following these two initial presentations and the 30-second fire alarm, we then will have the 30-minute Q&A session. On stage, we then will be joined by our speakers, but we also will be joined by Karsten Jung, our Global Head of Pharma Strategy, and by Morten Lammert, our Global Therapeutic Area Head for the CVRM franchise, who joined us from Novo Nordisk.
Afterwards, we will go to lunch. Lunch will be 50 minutes from 11:30 A.M. to 12:20 P.M. At lunch, you will have the opportunity to meet all of our speakers, and also our IR officers will be around. We also will be joined by our sponsor, our CFO, Alan Hippe. After lunch, we will continue with the deep dive sessions on our late-stage pipelines. We have five sessions, one each for our therapeutic area. The first session, as you can see here, will be held by Charles Fuchs, our Global Head of Oncology and Hematology Product Development, who will take us through the oncology and hematology pipelines and who will comment on our news of the day.
As most of you have probably seen, we had a top-line release out this morning on the positive phase III evERA results for Giredestrant in second line, plus a hormone receptor positive breast cancer in a post-CDK4/6 setting. The second speaker will be our Global Head of Neurology Product Development, Hideki Garren. Hideki will provide us with updates on some exciting pipeline projects, which have recently entered late-stage development. This is Trontinemab in early and late Alzheimer's disease and Prasinezumab in Parkinson's disease. He will also touch on exciting emerging early-stage assets like the gamma-secretase modulator in Alzheimer's disease and the NLRP3 molecule in Parkinson's disease. The third speaker then will be Larry Tsai, our Global Head of Immunology Product Development, who will share with us an update on different B-cell depleting approaches developed for autoimmune diseases like lupus. These are CD20, CD19, CD3 bispecifics being tested or allogeneic CAR-Ts.
He will also provide an update on our TL1A development program, where we are exploring additional indications beyond IBD and where we have taken a bispecific P40 TL1A into clinical development. The fourth speaker then is Chris Brittain, our Global Head of Ophthalmology Product Development. Chris has also some exciting early news to share. We just got data in-house for several studies, and the data are currently still analyzed. There is data for Vabysmo phase II/III in DME and UME. There is also the phase III data for Satralizumab in TED. These data are planned to be presented in the next few weeks at two conferences, ASOPRS and AAO. We have also scheduled now an IR call for October 21, where we will cover these data in more detail.
And finally, to close with, we will have the presentation of Manu Chakravarthy, our Global Head of Cardiovascular, Renal, and Metabolism Product Development. Manu will take us through the significant progress we have made over the last 12 months in building a leading obesity CVRM portfolio, creating a lot of development and combination optionality. As you have seen, the latest add-on to this has been the deal announcement from last Thursday, acquiring 89bio with the FGF21 analog in late-stage development for MASH stages II, III, IV . After the closing remark from Teresa, we will have a 30-minute Q&A with all speakers from the morning and afternoon sessions on stage, including Alan. The event will then close at 2:30 P.M., but you are invited to stay around for a buffet reception. Let me also mention one more housekeeping item.
As in previous years, we have again prepared a short 10-minute feedback survey. The link to the survey will be shown to the participants in the webinar 15 minutes before the end of the event. Participants in the room will receive an email roughly one hour after the event. We would very much appreciate it if you could give us your feedback, as we always strive to further improve. Let me quickly go to my next slide. I just wanted to have this slide in here to remind you that Roche has consistently delivered strong top and bottom line growth over the last decade. This slide summarizes our sales development from 2015 - 2024 at constant exchange rates. What you see here is that we have delivered a 10-year CAGR for group sales, which has been a + 5%.
If you look at the core EPS level, even a CAGR of + 8%. Of course, reported numbers look slightly different since the Swiss franc has, throughout this 10 years, continuously strengthened versus all other major currencies in the world. Let me also highlight here that during this period, we had to manage several challenges, especially the CHF 21 billion patent cliff in 2018. By successfully managing this cliff through in-house innovation, we are now left with a rather fresh portfolio relative to many of our peers in the industry, with currently 17 blockbusters on the market. This brings me to my final slide. As you can see here in light blue, this is the segment of our current on-market pharma portfolio, which now is expected to deliver growth until 2028. This has been pushed out one year. Last year, we had communicated growth until 2027.
After 2028, actually, we expect this current on-market portfolio to be stable until the end of the decade. This means our current growth products are expected to always compensate for any generic erosion occurring in this period. There is no patent cliff forecasted. Teresa will provide you some more details and an update on this on-market portfolio. You also see here two layers on top. In light gray, you see the expected contribution from the current in-house pipeline. In dark gray, additional contribution from future business development. The in-house pipeline we'll discuss later today. Let me also quickly add here that we have made new epidemiology slides for our pipeline projects available on the IR homepage, so you can download them. To close, let me also quickly comment on the DIA division.
As you know, we are quite optimistic on the long-term outlook as we have a couple of launches ongoing and upcoming, including our unique mass spectrometry solution for the hospital setting, the launch of our CGM solution, and our revolutionary, truly revolutionary SPX next-generation sequencing solution. All of these are clearly blockbuster opportunities, just to use pharma slang here to characterize the opportunity. Finally, one remark I have to place on group profitability. We have been continuously communicating we strive to keep the group margin at least, defend the margin and keep the margin at least stable. With that, I hand over to Teresa. Teresa, please.
I have to admit I'm a little hurt that this fire alarm was about us not staying on time. We will have to talk about that, Bruno, later on. Thanks, everyone. Thank you, Bruno. Thanks to everyone who's joining us here in London live and also to everyone on the phone. Welcome to Pharma Day 2025. When we were together here last year, I shared with you for the first time our pharma strategy. At that time, I also made a commitment to you about what you could expect to see from us at Roche going forward. My commitment to you was that you would see rigor in the science and discipline in the business. I think what we have to share with you today is going to draw a double underline under that commitment.
We'll show you how the pharma strategy is doing exactly what we expected it to do, to provide focus and clarity across the entire enterprise. R&D excellence continues to identify efficiencies and to allow us to accelerate our pipeline. As Bruno mentioned, through the course of the day, we're going to share with you how we are consistently applying the BAR evaluative framework across every aspect of our R&D organization, allowing us to make rigorous scientific decisions. We will share our laser focus on the commercial success of our on-market portfolio and how we're thinking about lifecycle opportunities in each of these areas. We will show you how we are applying significant financial discipline across the entire enterprise, and most importantly, how we are maintaining the culture that has always defined Roche and Genentech, allowing us to attract the best talent and develop the best science.
We have quite a morning ahead of us, as always. There's a lot to talk about. Let's go ahead and jump in. I'm going to start with outlining a little bit of the progress that we've made since we were last here. I'm sure all of you have printed out this slide and have it hanging above your desk in terms of what the 10-year ambitions are for Roche. We have committed to delivering 20 transformative medicines, addressing the areas of highest societal burden. We committed to increasing the value of our portfolio by 40% by ensuring that our portfolio continued to provide the best level of innovation, with 80% of our pipeline having best in disease potential. Most importantly, because it is fundamentally what we are here to do, we committed to treating 3x more patients with that transformational pipeline. How are we doing?
In 2025, we're halfway there to our transformative medicines. We've launched 10, and we have more than 10 additional NMEs with transformational potential that could launch by the end of 2029, one of which we just received some very positive data on today with Giredestrant, which Charlie will talk to you more about later this afternoon. This does not include any potential BD deals that might be coming post 89bio. In terms of the value of our portfolio, we have actually overachieved what we had hoped to do. Definitely not going to complain about that. We've added 55% in terms of value to the portfolio, with the average peak sales per pipeline project. In terms of innovation, we're on track. Today, 67% of our late-stage projects have best in disease potential, and that's an increase of 9% from when we first started talking to you about these things in 2023.
When you look at access, you might say it feels like you're a little bit behind the curve here because we're at plus 40% versus our goal. You have to remember that when you look at our pipeline, the majority of our large launch products that will treat significantly more patients launch more towards the latter half of the decade. That is what gives me great confidence that we will still be able to achieve, that we will still be achieving this goal. It's just a little bit more time shifted towards the back half of the time frame. You can already see that we're making tremendous progress. What else has happened since we were last together? You saw at half year that we posted 10% growth with our in-market portfolio, 13% cop growth at half year, and 1.7% cop margin growth. Discipline in the business.
R&D excellence, 26% total portfolio value, 55% of NMEs are now post the BAR, and we're fast tracking those assets that we believe have the most potential to help the most patients. Levi will talk a lot more about this in his section. How are we pulling through the pharma strategy? All five of our TAs now have TA strategies that have been in line to the overall pharma strategy, and we are in execution mode. Our 11 end-to-end disease areas are taking shape, and we will go through each, we'll go through quite a number of them in the later part of the portfolio. Finally, we'll also be able to share with you a first look at our obesity strategy. Over the last 12 months, a tremendous amount has been accomplished, and we've done it with rigor, and we've done it with discipline.
Now let's talk about that on-market portfolio with 17 blockbusters that we have in market today. Let's start, as always, with solid tumors. Our well-established HER2 breast cancer franchise is expected to peak in 2026. No change here with that strong tail. As Bruno mentioned, no cliff. We also now expect, with our positive data in Giredestrant, to be able to expand into the HR-positive breast cancer segment, again, the largest part of breast cancer overall. Our lung cancer franchise is also stable, but with some exciting potential with Divarasib, which Charlie will go into later today. For hematology, we continue to have one of the most established portfolios in NHL, with the potential to further improve that standard of care as Polivy continues to entrench and the bispecifics continue to launch and as new indications are added.
We also continue to maintain our leadership with HEMLIBRA and Hemophilia A, with a lovely life cycle extension with NXT 007 entering late-stage development. Speaking of leadership, OCREVUS remains the undisputed leader in MS. The sub-Q launch is ongoing, and we are eagerly awaiting the Fenebrutinib data end of this year, beginning of next. Evrysdi continues to lead in SMA, and we're excited about the opportunity to potentially launch into two very large additional diseases with Alzheimer's and Parkinson's, something Hideki will share much more with you about in his section. In terms of immunology, Xolair food allergy continues to do very well. Strong uptake in food allergy, and again, no biosimilars expected here until 2026. GAZYVA, DUFA is expected in October.
I think many of you have heard me say over the years I'm a big fan of GAZYVA in immunology, and I'm excited to actually have this first indication onto the market. Of course, Vabysmo is their foundational asset in establishing that leading position in ophthalmology, and it is absolutely redefining the standard of care in retinal diseases. As you will hear from Chris later today, we have one of the most diverse pipelines in ophthalmology in terms of targets, MOAs, devices. We are clearly positioned for long-term leadership here in ophthalmology. I always find this phrase a little funny, but even though it's not yet in the donut, our obesity profile, get it, donut. Yeah, okay, there we go. Maybe that joke plays better in America.
We have an emerging obesity portfolio, and we have one of the broadest obesity portfolios out there, and we are well positioned for leadership in obesity, something we will talk about much more later today. Let's talk a little bit more about the numbers. We are delivering this best-in-disease portfolio with an amazing amount of financial discipline. If you look at our OpEx development over the last three years, we have steadily controlled costs while increasing sales double digit. That means that our margin development has been impressive. We focus on this every day. How are we spending our money? Are we spending it in the best places? Are we getting the best return? Are we redeploying those funds in the best possible way? Let's talk a little bit about our portfolio focus and the implementation of the BAR.
Roche has been and always will continue to be a company that is fundamentally grounded in following the science. One of the most important things that the pharma strategy has allowed us to do, working in close concert with R&D excellence, is to ensure that we are following the science with intention, that we are looking in those disease areas where we can help the most patients, where the science is most fruitful, and where we believe we can have the biggest impact. What allows us to make sure that we're making those decisions in a rigorous fashion, end to end, across our R&D portfolio, is the application of the BAR. You can see the five BAR criteria here. Again, Levi will talk to them in a lot more detail in his section. The BAR fundamentally defines what makes it into our portfolio and what advances in our portfolio.
It allows us to ensure that the R&D leaders across our entire organization have a consistent way to make those decisions. What does the outcome of those decisions look like? Today, 55% of our portfolio is now officially post-BAR. You can see that these assets are really compelling and have significant sales potential. This is truly a rejuvenated portfolio from where we were 12 months ago and certainly from where we were 24 months ago. There are a lot of things on this list that you'll be familiar with, a couple that you may not: [Avastin] and relapsing remitting multiple myeloma. Charlie will talk about this a little bit later today, but this has now been moved into phase III. Of course, you all saw this morning that CT-388 in obesity has also been advanced into phase III, and Manu will talk about this a little bit later today.
Then, post-closing, pegozafermin for MASH will come into the portfolio as well. A very nice range of assets across our core therapeutic areas, all with the potential to help a significant number of people and all with significant value. Some of this has happened through business development, and the BAR evaluative framework is also a critical part of how we assess opportunities in BD. You can see across this slide a number of deals that we've done, all of which closely align to our end-to-end disease areas. 89bio coming in, very exciting addition to our CVRM therapeutic area. Zealand Pharma as well, very exciting deal to bring in a best-in-class amylin. You can see we cover the gamut here, and we're very pleased with the assets. We were very pleased with these assets and their opportunity to be best in class.
Let's take a little bit of a deeper look in each of our therapeutic areas and how we are defining where we want to play and how we intend to win. As you know, the pharma strategy was introduced last year, and at that time, we defined clearly our five therapeutic areas. You can see them here. What's really important to remember about these five therapeutic areas is that they constitute 60% of the total global burden of disease. They also represent 80% of where we believe growth is coming from in the pharmaceutical sector in the coming years. We are targeted in the right place to help the most people. Currently, we have identified 11 disease areas in those five therapeutic areas that we are investing in end to end, all the way back from discovery to commercialization.
This allows us to gain the kind of experience that leads to better judgment and scale and commercialization, which will be critical as we think about moving into the future. Let's start our deep dives, as always, with oncology. The focus with oncology today is to strengthen our franchise through a very focused approach. We are focused on our end-to-end disease areas: breast cancer and lung cancer and solid tumor and malignant heme and hemophilia in hematology. Where we are intending to play or where we are intending to win is to find ways to accelerate innovation in the most effective way, depending on which therapeutic area or which disease area that we're in. Breast cancer is probably our most well-developed end-to-end disease area in the portfolio.
It's anchored certainly by our HER2 franchise, which, as I mentioned earlier today, is expected to remain the standard of care in the majority of early breast cancer settings. I think we've seen a lot of KOL feedback to this end. The recent studies sort of indicate there is not going to be a one-size-fits-all solution for patients in breast cancer. Physicians are going to make very tailored and individualized decisions based on the need of these individual patients, and our HER2 portfolio is both well understood, it's well characterized, people are familiar with it, and they're very comfortable with its efficacy and its safety profile. Phesgo will play a big part in how the HER2 program actually plays forward. We're currently at a 46% global conversion rate, and we are set on converting as many patients as possible.
Of course, that expansion into hormone receptor positive breast cancer is something that we've been eager to do. The positive results from this morning's AVERA trial, as announced, will enable that further expansion. You can see we have a very strong on-market presence, and we have a robust breast cancer portfolio that Charlie will talk to you a little bit about later this afternoon. Moving on to malignant heme, this is another place where we are very much currently a leader. Polivy, first improvement in DLBCL in 20 years, raising the bar on our own therapy, Rituximab therapy. That's exactly what we love to do. We love to raise the bar on ourselves. Polivy is establishing itself as the new standard of care. You can see these are the U.S. market shares. They continue to grow.
We have no doubt that over time, this is Polivy will be the treatment that the majority of patients with DLBCL receive. Our two bispecifics, Columvi and Lunsumio, are rapidly differentiating themselves in the real world. Much like we expected, their individual profiles allow them to treat and reach different kinds of patients and are uniquely beneficial to health systems in different ways. This will only become more evident as we move into earlier lines of treatment. Finally, as you hear more about this afternoon, we are expanding into multiple myeloma with [Avastin] and our allogeneic CAR T programs. Multiple myeloma, very significant patient population, a significant amount of continued unmet need, and we think we have several assets here that could really make a difference. No discussion of hematology is complete without talking about Hemlibra and Hemophilia A, the undisputed standard of care around the world.
More than 30,000 patients on treatment currently. We all know that it has around 80% of patients who are not experiencing bleeds without factor VIII inhibitors. This is supported by a tremendous amount of real-world evidence and experience. We're very excited to be moving the next generation of this molecule forward with NXT 007. We have just moved that into phase III, including a trial that will go head to head against Hemlibra. We also recognize that in any chronic disease, convenience for patients is extremely important. We plan to bring an autoinjector forward, not only for Hemlibra, but also for NXT 007, to ensure that we can help patients have as convenient a therapy as possible. Moving on now to neurology, where again we are already the leader. Our goal is to extend that leadership position.
Where we want to actually extend it is into preventative neurology, actually helping patients prevent progression into severe neurological symptoms. We also are very keen to work closely with our DIA colleagues to ensure that we are creating an end-to-end integrated journey for these patients. This is one of the disease areas, as you'll hear from Hideki later today, that we're probably the most far along in that partnership between pharma and DIA. We have two end-to-end disease areas, unsurprisingly, MS and Alzheimer's, but we're very encouraged by the data that we have seen out of Prasinezumab for Parkinson's and are eager to see what that phase III data holds. The MS franchise, clearly the cornerstone of that is OCREVUS. Firmly established as the global standard of care, more than 420,000 patients treated globally, and its reach just continues to grow.
We are, of course, in the middle of the subcut launch. We now have more than 12,000 patients on treatment. 50% of those are new to brand. We are rapidly moving into development with our new device, an on-body injector with a high concentration of OCREVUS that will hopefully allow at-home treatment twice a year, every six months. I think we should never forget when we talk about lifecycle for OCREVUS , we are always also talking about extending that convenience. Treat your MS today with subcut, 10 minutes, twice a year. That's a very compelling message for patients. Launch of the on-body autoinjector would be projected in 2028, and it is our intent to convert as many of our IV patients as possible to subcut and then subsequently to the on-body injector. Fenebrutinib has the potential, as a very selective oral BTK, to be very disruptive in the MS segment.
We're very much looking forward to that data. Switching over to immunology. Immunology is a really unique area of science. Our goal here is not only to maximize the individual indications that we have with drugs like TL1A, but to actually leverage those mechanisms across different TAs. Leadership for us in immunology not only means being successful in specific disease areas, but how those mechanisms may actually also allow us to grow into different therapeutic areas. Our end-to-end disease areas here are IBD and COPD. I want to call out here the pan-immunopathways, TL1A, CD20, CD19, OSMR. These are pathways that we are very early looking at, not only in immunology, but how they apply in different parts of the portfolio. Immunology today, of course, Xolair is the star in this portfolio right now. You can see the growth in food allergy just continues, as I mentioned before.
No biosimilars expected until 2026. GAZYVA and LN showed superiority over the standard of care. Lupus nephritis is a devastating disease, extremely serious. We believe we can help many, many patients with GAZYVA and lupus nephritis. That PIDUFA is set for October. Moving on to ophthalmology, where Vabysmo is clearly paving the way to a leadership position. We have a broadly diversified pipeline that has significant transformational potential. We intend to be a big player in retinal vein disease for many, many years to come, but would also like to expand into other therapeutic areas, including geographic atrophy and dry eye. Winning in ophthalmology is a lot about how we win commercially today with Vabysmo. Let's look a little bit at what's happening in Vabysmo in ophthalmology today. Clearly, there are challenges in the U.S. commercial market. The dynamics that we reported at half year are largely unchanged.
Vabysmo continues to gain market share in the branded segment in naive patients. That is precisely what we need it to do. There has also been new clinical data that was just recently presented that continues to reinforce strong efficacy and demonstrates the ability to get out from a duration perspective to intervals up to five months. Chris will talk to you a lot more about the additional data that we have now in ophthalmology. You can see again, we have a large portfolio and one that is very diversified relative to competition. We are really excited about the ability to be a player in ophthalmology very long term and to maintain that leadership position. Finally, moving on to CVRM. Our ambition here is to be a strong entrant before 2030 with competitive products.
We intend to differentiate by using the unique capabilities of Roche, and we are going to talk a lot about that in the next couple of minutes. Our goal is to become a top three player. I want you to know that I am serious about this goal. I believe we have the pipeline. I believe we have the commercial capabilities. Most importantly, I believe we have the will. The end-to-end disease area here, of course, is obesity, but there are numerous places that we are looking at breakthrough innovation, including MASH. Why do I believe that we can do this? Because I do. A, we've done it before. MS, hemophilia, SMA, retinal vein disease, we know how to enter new markets. We know how to understand our customers. We know how to understand our patients.
We know how to understand ways to drive to market that actually allow us to do that efficiently and effectively. While the disease areas that we are headed into are larger and we know that they will require us to do things differently and at a different scale, I am just as convinced in our ability to make it happen. How are we going to succeed? When we were in London last year, we talked about the core capabilities that were resonant within the pharma strategy, and there were six of them. All six of these are going to be necessary for us to succeed, not only in obesity, but frankly in all of our disease areas going forward. We have made significant progress in all of these areas in just the last 12 months. I'm going to start with R&D and manufacturing.
As you well know, Pharma and DIA have the full value chain in the U.S. It has always been our belief as a company that you should manufacture your products close to the people who need to use them. We recently expressed our commitment to invest CHF 50 billion into the U.S. until the end of the decade. That includes, importantly, one manufacturing site in Holly Springs, North Carolina, where we have already broken ground, and a site in Boston, which is focused on R&D and AI and ML in CVRM. All of our key medicines are already produced today in the U.S., with the tech transfer for the one remaining product well underway. As you all know, we have a high level of flexibility in our very large and diverse manufacturing chain.
Because we have invested so significantly in the productivity of our manufacturing organization over the last number of years, it means when you look at our existing capacity in the U.S., we are at less than 50% capacity, which means we have a lot of opportunity to continue to grow in the U.S. with the facilities that we have and the ones that we continue to invest in. I call out that we are a company that actually never left the U.S. We stayed when we acquired Genentech. That footprint is very much there. All of the IP for medicines invented in the U.S. is held in the U.S.
One of the things that has been key to many of the investments that we've made in our Pharma Technical organization, and part of the reasons that we've been able to see such efficiencies over time, is our investment in data analytics and AI in Pharma Technical. We have spent a lot of time thinking end to end across Pharma Technical about ways that technology can actually help us speed delivery to patients, avoid costs, and continue to make our processes more robust. We have invested significantly in these areas, and we can see those benefits today. Our tech times have dropped. Our output yield is up by more than 10%. We can generate required reports faster than we have ever been able to do before, which frees up time to do many more value-added things.
We've been able to reduce our CapEx because we can actually do more with the facilities that we have. This is a really practical application of data and AI in a way that has real fundamental impact on our business every day. Related to manufacturing is our investment in devices. You heard me talk last year about the fact that 60% of our current portfolio is going to require a device. We need to be able to manufacture various kinds of devices for different uses at scale. In order to do that, we are moving to a drug delivery device platform, which will allow us to be able to do this much, much more quickly. We've already identified the first four: the autoinjector needle safety device, the ophthalmologic prefilled syringe, and then our intravitreal device. There will be several more that will be added.
These are going to be critical to ensuring that when we have a product that requires a device, we can get it very quickly into trials. Part of what will allow us to do that is the investment in a device pilot facility in Basel for medical devices and drug delivery components. This is going to give us a platform where we can actually look at how we do this at scale before we actually have to move into big manufacturing facilities. That's the old building, by the way, in case you were thinking it didn't look very impressive. That's going to be replaced with the new building. That's just the site. We are also leveraging AI in different parts of our business.
Right now, in the commercial and medical organizations, we are singularly focused on making sure that we have one of the most robust customer engagement models in the industry powered by AI, allowing us to look across the globe at how our customers are reacting, what they're doing, what that means, and how we can inform decisions going forward. This will remove a lot of manual work out of the system, which is great. What it does is it makes the people on the ground vastly more effective and efficient. That means we can continue to deliver more medicine to more patients more economically. These AI solutions will also help us continue to increase our share of voice, which, as you enter into more and more highly competitive markets, is critically important.
Of course, all of this is just so many words on a piece of paper unless you actually have the most talented people in the industry working in your organization dedicated to making change. Culture has always been a significant part of what makes Roche and Genentech Roche and Genentech. We are singularly committed to making sure that we continue to be an attractive employer, that we drive to be the most high-performing organization that we can be, and that our ways of working continually elevate us in the industry. Our people strategy is critically important to making that happen. We are constantly looking to make sure that we are identifying the needs of the organization. Where do we need critical experiences and competencies that we don't have today? How are we bringing them into the organization?
You'll see a wonderful example of that in a little bit when Morten joins us on stage. I know many of you have been waiting for this, which is a look at our obesity strategy and how we intend to become a top three player in obesity. We firmly believe that our capabilities strongly position us to deliver in obesity and that there are five capabilities that are going to be critical in order to make that happen. We have a best in disease portfolio, we are able to leverage the synergies across our TAs, we have an appropriate manufacturing and supply chain, we have a highly efficient and effective global commercial footprint, and we are maximizing our partnership with DIA to create a meaningful end-to-end patient journey. Manu is going to talk to you about the end-to-end patient journey, so I won't make you listen to that twice.
We've talked a little bit about the global commercial footprint, and we've also talked about manufacturing and supply. In my talk here, I'm going to focus primarily on how we believe the obesity market looks today, how we think it is going to evolve and fragment, and why we believe we have a right to win in this space. Let's start with the obvious. Obesity is different from the other areas that we're in at Roche. The patient is the key decision driver. There is actually a multi-track system for how patients get their prescriptions. You're not talking with just one type of physician. You have to talk with multiple types of physicians. In many parts of the world, obesity isn't even established as a chronic condition, which means there is no reimbursement.
Yet, it is of unprecedented size and scale, something that we have not seen in the industry before. There is a deep amount of heterogeneity and fragmentation that results from all of these components. Let's start by actually looking a little bit about the patient journey. In the U.S. today, 55% of patients are actually the ones showing up at the doctor's office and asking to be put on an anti-obesity medication. They do that for a variety of different reasons. It may be about their health and making sure that they can address things that are physically troubling. It could be emotional and about their psychological well-being. Or it could be that they have a lifestyle goal that they wish to achieve. The reality is every patient shows up for a different reason with a different ask of their physician, and they show up to different kinds of physicians.
88% of the time in the U.S., they show up to their primary care physician. The rest of the time, they're showing up to an endocrinologist or some other kind of specialist. Why is this actually so important? It's so important because depending on the kind of physician you are, you're going to ask a different set of questions about why that patient is there, and you're going to care differently about the treatment that you select based on how you're evaluating that patient and any potential comorbidity that they may have. If you go to an endocrinologist, chances are the first thing they're going to care about is diabetes, then cardiovascular, then potentially renal. Probably true for GPs as well. Cardiologists are mostly going to care about the heart, and then they'll also think about type 2 diabetes and renal involvement.
What that means is that every patient is on a different journey, and every physician is going to have a different set of questions. Even when they align on the fact that an anti-obesity medicine is appropriate and they make the selection as to which one they're going to go on, there is actually no guarantee that that prescription gets filled. Again, focusing on the U.S., just because this is where the most data is available, obesity is already identified as a chronic disease. Reimbursement is available, but 33% of the time, a patient who has been deemed appropriate and received a prescription will actually not get a drug reimbursed. They will have to pay out of pocket, which means there is a significant out-of-pocket component to this market, not only globally, where I think is where we relatively always talk about it, but also in the U.S.
When you're talking about a cash market, that is also a different thing that you have to think about commercially. We also mentioned the size and the scale of obesity, which I think everybody understands. I think this chart does a great job of identifying how many people in the world today are actually eligible for a treatment. 51% of the global population will either be overweight or obese by 2025. That is truly an epidemic. That is a massive amount of people who are at higher risk for significant comorbidities and mortality. Yet today, with the treatments that we have, we see a relatively small amount of people with obesity are actually being treated, about 10% or 15%. The mean BMI of those patients being treated is 39.
You have a relatively small percentage of your most heavyweight patients being treated, leaving a tremendous amount of potential opportunity for patients who could benefit, but for whatever reason, are not receiving therapy today. This leads to a market which is exceptionally fragmented. There are many different ways in which that fragmentation could actually present itself in the commercial setting. Many different drivers of why a patient or a physician would potentially choose any given therapy. I want to start by talking about comorbidity management, because from a human health perspective, this is a very significant one. We know that patients with higher BMIs have many more comorbidities. Over 70% of patients with just one, 70% of patients living with obesity today have already one comorbidity. That number dramatically increases as BMI increases. What does that mean?
It means that obesity is a major risk factor for over 220 different diseases. All of these diseases have significant impact on human health. It should be noted that we are one of the only companies that has treatments in a lot of these diseases. Not only do we have the ability to help patients with overweight or obesity, but we also have the opportunity to look across our therapeutic areas and see how we could potentially combine different therapies together to actually address some of the most significant health needs that patients have. That is something that is materially different about our portfolio relative to the rest of the industry. That patient-centric approach is going to be really critical moving forward. These are just three different types of potential patients who could show up at a doctor's office.
There's the patient who is overweight and eligible for an anti-obesity medication, but is probably not morbidly obese, but still eligible. There are people who have an early sort of diagnosis of obesity, class one with some comorbidity. Then there are class two to three that have high-risk obesity. What these patients are looking for and what their physicians need to treat them with is very different. If you just to orient you to this slide, if something is bright green, that means it is of highest interest to that patient. Unsurprisingly, if you think of depth of weight loss, that's actually most important to people who are at highest risk, for the people who are the heaviest who need the most weight loss. They're not as interested in how quickly they lose it because they're on this journey for a longer period of time.
For those people who are potentially looking to lose less weight and have fewer comorbidities, you can see that speed to weight loss is much more important. Tolerability is much more important. Convenience is much more important because they have a very different set of treatment goals than the people on the other side of the spectrum. What's exciting for me is that our portfolio allows us to address all of these patients. It is undeniable that incontinence has unlocked a new era in the treatment of obesity. If you look in the past decade, this was a relatively smallish market at about CHF 6 billion. We hit an inflection point with the GLPs coming into the market in force. We're now looking at a significantly larger market and significantly more options for patients or more options for patients.
The reality is that in the real world, there is still a lot of unmet need. Treatment persistence, as you guys know, is a big problem. The share of patients who are able to get to that higher dose, highest dose, and be able to experience all the weight loss they want to see, not able to be done so much. Actual weight loss is often below target because of those two things. Whatever comes next is going to have to address that remaining unmet need. We've identified six things that we think are going to be really critical to whatever comes next to addressing that unmet need. Tolerability. We all know that nausea and vomiting are major drivers of discontinuation, particularly as you think about those patients who have the lower desire for weight loss spectrum. The ceiling effect on weight loss.
Most patients plateau after 12- 18 months. They never get to their target weight. Weight maintenance, even if you lose the weight, once you stop treatment, the weight comes right back. Because many patients don't find existing treatments tolerable, it's harder for them to stay on longer term. We've talked extensively about the comorbidities and the need to treat those, as well as to treat the underlying weight problem. Lean muscle mass loss. Again, you guys know this, 40% of weight loss comes from muscle loss. That's less optimal, clearly. We want to find ways to preserve that lean muscle. Less talked about, there's about 20% of patients who actually have no or suboptimal response to these treatments. The existing treatments actually aren't working for them. That's where our portfolio comes in.
Our differentiation potential relies on having that breadth of options to address all of the different patient needs. From Petrelintide to CT-388 and monotherapy to all of the different kinds of combination therapies, we can cover the breadth of this unmet need completely. That's not even talking about the opportunities to actually look forward into ways to combine to address comorbidities. To sum it up, our capabilities strongly position us to deliver here. From multiple pipeline assets with best-in-class and best-in-disease potential to the ability to leverage the synergies across the portfolio, our global robust manufacturing network, our presence in more than 150 countries around the world with our global commercial footprint, and of course, our very unique ability to leverage our Pharma DIA connection, we believe that those capabilities in total, executed correctly, will allow us to become a top three player in obesity.
We are committed to making that happen. Now, to close out on future growth opportunities, these are the new eight NMEs that are new to phase III in 2025. I think we've talked about all of these. Again, just to call out the addition of Pegozafermin in MASH, our newest addition after closing, and [Avastin] in relapsing remitting, as well as CT-388 moving into phase III. You've all seen the consensus slide before, but just to reorient you to it, after half year, we went and took a look at what the consensus was saying. In 2024, this is sort of where people believe we are in terms of sales, or where we were in terms of sales. In 2029, if you look at consensus, it looks like we have a gap of about CHF 6 billion related to loss of exclusivity. This is primarily Xolair, ACTEMRA, Perjeta, and Kadcyla.
If you then look at where consensus says we have growth opportunity in that same time period, consensus says we can grow by CHF 12.9 billion. This is a lot of opportunity in our pipeline. By the way, there is a significant number of things in our pipeline, including many of the things that I've talked to you about today that aren't even included in consensus in a meaningful way today. Our cardiovascular metabolism assets in general are not yet included in models. There are a number of things in the oncology, neurology, immunology, and ophthalmology franchises as well that are currently not represented. We believe the true value of our pipeline is actually quite underestimated. Why do I say that? By 2030, we have the opportunity to launch up to 18 new NMEs. That includes 15 NMEs with blockbuster potential.
We are well set up within our five therapeutic areas to continue to diversify and add leadership in the areas that we know will matter most to patients. Importantly, we have the skills and capabilities and resources in order to ensure that we will make those launches successful and that we will reach the number of patients across the world who deserve to be reached. Before I turn it over, Levi, I just want to reiterate what I started with. As an organization, we are committed to bringing transformational medicines to patients. We are committed to doing that in a way that is uniquely Roche.
I am committed to continuing to deliver rigor in the science and discipline in the business to ensure that when we're standing here next year and we're able to share the advancements that we've made, we're continuing to make progress at an even faster clip than we have today. I hope you'll agree a lot has happened in 12 months. We're very pleased with where we are. We're also very excited about the opportunities ahead. With that, I will turn it over to my colleague, Levi Garraway, to talk to you more about R&D excellence. Thank you.
Good morning, everyone. It's always a privilege to have the opportunity to describe our pipeline progress to the investor community. As Teresa mentioned, I'll provide an update on R&D excellence, which we first rolled out here at Pharma Day a couple of years ago. After lunch, our five Therapeutic Area Heads will provide deeper dives into specific programs. By way of reminder, our overarching objectives for R&D excellence are twofold. First, we want to deliver many more transformative medicines to the world. Second, we want to become one of the most productive R&D engines in the industry, as measured and evidenced by top quartile performance. Here are the solutions that we've been implementing over the past two years to achieve these objectives. Three solutions, which are shown at the top of this slide, are focused on expanding the transformative potential of our pipeline.
I'll delve fairly deeply into each of these. Two other solutions are about improving the efficiency of our R&D engine. One is focused on incentivizing the organization to perform in this way. In addition, streamlining our system landscape and our data foundation is also necessary to make sure everything works well. That effort has essentially become a seventh R&D excellence solution. I'll touch on that briefly at the end. A key premise for R&D excellence is that if you want to deliver transformative medicines, you need a pipeline that consists exclusively of assets that are capable of becoming such medicines. Of course, that's easier said than done because most therapeutic candidates fail. On the other hand, pharma R&D pipelines do obey the power law. That means that although most fail completely, some become medicines that are so impactful that they truly transform the lives of patients.
We must intentionally identify candidates with that type of potential wherever they might be found along the R&D continuum. That's where the BAR comes in. The BAR is an evaluative framework that we developed a couple of years ago to describe the essential characteristics of transformative medicines. We've now applied the BAR end to end across our R&D pipeline. That has allowed us to identify and prioritize assets that do have transformative potential, but also to attrit and deprioritize those that do not. The BAR consists of five criteria, which I'll come back to actually several of them over the course of this presentation. None of them are particularly surprising in and of themselves, but each of them must be met if a medicine is going to have transformative impact. First of all, the drug must answer a clear unmet need.
That need would have, of course, become addressable through advances in disease biology and understanding. Second, it must engage a foundational target. That means a protein or pathway that drives disease pathophysiology or the salient clinical manifestations. The third is that the asset must possess worthy pharmacologic characteristics compared to other contenders that are out there. Fourth, it must be able to achieve meaningful therapeutic differentiation. Finally, the medicine must unlock a path to value. First and foremost, that's value for the patients being treated, but also value for the company that delivers the medicine to the world. Adoption of the BAR end to end has now become business as usual across Roche Pharma R&D. One way to visualize the impact of the BAR is through our pipeline evolution at the NME level. Two years ago, our pipeline consisted of 81 publicly disclosed NMEs.
You can see that on the left. Today, we have 20% fewer NMEs, 65 instead of 81. We've been quite active in sculpting our pipeline during that interval. On the one hand, the initial application of the BAR in 2024 brought a fair bit of pipeline attrition, and we expected that. However, we've also achieved many pipeline additions, either through our internal pipeline or from business development deals. Those pipeline additions are starting to mature nicely, especially in our late-stage pipeline. As you just heard from Teresa, we're on track to progress quite a large number of NMEs into our phase III portfolio in 2025. We've actually done eight thus far, and there might be still other opportunities before the calendar year ends.
Having applied the BAR, although we have fewer overall NMEs today than we did two years ago, the quality of our NMEs seems to be increasing as we had hoped. Two examples specifically illustrate this point. First, the percentage of projects that we believe could have best in disease potential has increased to 67% of pipeline projects, up from 58% just 18 months earlier. Also, the projected average peak sales for pipeline asset has increased by more than 60% to CHF 1.3 billion. In keeping with average peak sales estimates, overall portfolio value estimates have also increased significantly. One of the most important questions that we can ask is whether application of the BAR evaluative framework is improving our success rates. Of course, it'll be several years before we know for sure. One possible leading indicator is the impact on team-assessed probability of technical success for our phase III trials.
Here, we're looking at a plot of pipeline projects for which the decision to initiate pivotal trials happened prior to application of the BAR evaluative framework. Team-assessed PTS is shown directionally on the Y axis. Adjusted net present value is shown also directionally on the X axis. For obvious reasons, we're not disclosing the actual names and values, but the graph shows that several of these projects had either a team-assessed PTS or an adjusted NPV that was lower than we would like to see. In some cases, actually, both of those things were true. Those are the dots in the lower left-hand quadrant. Now let's overlay the projects that underwent pivotal trial go decisions after introduction of the BAR evaluative framework. These are the dark blue dots.
You can see that a much larger proportion of these phase III projects has a team-assessed PTS within our target range, so above the center horizontal line compared to what we were seeing before application of the BAR evaluative framework. Most of these projects have a much more robust adjusted NPV than what we were seeing before. Actually, even for the couple of cases where the PTS still seems maybe kind of borderline, there are sometimes additional upcoming data cuts that could push the final assessment upward. It's still early days, but we can already draw two conclusions from the results that I've just described. First, adoption of the BAR evaluative framework has been successful. Second, it appears to be having the desired effect both on pipeline quality and the potential for future phase III trial success.
Another important R&D excellence solution was to reconfigure our portfolio management and governance so that it would be centered entirely around executing the BAR evaluative framework effectively. Implementing this solution has required multiple changes, one of which was to establish cross-cutting
Review boards are panels of functional experts who provide critical assessments at key points along the molecule journey. We have development boards that focus on asset strategies and clinical development plans. We also have business boards, which assess key commercial drivers and risks. All of these review boards are jointly chaired by leaders from early-stage and late-stage R&D. That ensures the end-to-end cohesiveness that we're looking for. These boards have been highly successful. Teams are benefiting from rigorous reviews, but they're also preserving the speed necessary to ensure that programs are competitively positioned. Another change, which is summarized along the bottom left, involves the creation of what we call one-asset teams. Once a molecule demonstrates proof of concept, so in phase Ib, for example, we form a single team that will guide that asset through the remainder of its development and eventually its life cycle.
The team has membership from both early and late development, and the membership evolves over time with the needs of the asset. We've also created an enterprise-level pharma portfolio team that includes several members of the Corporate Executive Committee, including several people who are here today. This group meets regularly to make holistic assessments of our end-to-end portfolio health, from research all the way through late-stage development. This can include composite assessments of the BAR evaluative framework. It can talk about volume at various stages, risks, strategic fit, et cetera. These frameworks inform broader strategic considerations to shape the nearer term or the longer-term shaping of the pipeline. The changes to portfolio management and to governance are all well and good. How do we know that these are evaluating the quality of our decision-making? Again, the ultimate proof will be in the delivery of transformative medicines.
However, we can give you at least a flavor of the thought process around some recent pivotal GO decisions. One thing I want to emphasize first off is a desired outcome of reconfigured end-to-end governance is to ensure that we generate early clinical data sets that are sufficiently robust to inform optimal phase III decisions. In the past, sometimes competitive pressures to move quickly made it challenging to fully de-risk certain programs early in development. That meant that our phase III pipeline was carrying extra risk. We unfortunately saw that play out with more disappointments than we would like at times. Going forward, one goal here is to generate enough data early on to learn not only whether to do a phase III trial, but also how to design one that is maximally likely to be positive. Zilebesiran on this slide is a good example.
Our partner, Alnylam Pharmaceuticals, completed three phase II trials of Zilebesiran in hypertension. Manu is going to discuss the trials this afternoon, but it's actually unusual to have that much phase II trial data available. We were actually quite glad to have it. When the first trial, KARDIA-1, read out, we gained confidence that Zilebesiran engaged its foundational target, angiotensinogen, very effectively. That's obviously a BAR evaluative framework criteria. The second trial, KARDIA-2 , taught us that Zilebesiran could lower blood pressure meaningfully when combined with three different types of blood pressure medicines. Its effect was particularly pronounced in combination with a diuretic. KARDIA-1 and KARDIA-2 taught us that Zilebesiran had worthy pharmacologic characteristics, another BAR evaluative framework criteria.
There were still important unanswered questions, including the right dose, whether Zilebesiran would work safely in combination with multiple medicines, and the exact population of patients to study in a cardiovascular outcomes trial. We ran KARDIA-3 to help resolve those questions. In KARDIA-3 , the Zilebesiran effect on blood pressure was greatest, once again, in the subset of patients who are on a diuretic. Very importantly, we also learned that Zilebesiran works best in people whose hypertension is clearly uncontrolled at the time of enrollment. This actually makes sense because if your blood pressure is already adequately controlled, you don't really benefit from adding another medicine. If people whose blood pressure is already adequately controlled make their way into a clinical trial, the risk of a type 2 error increases. That means you falsely conclude that a blood pressure medicine is less effective than it actually is.
The big picture is because of the full KARDIA phase II data set, we can feel confident in the ability of Zilebesiran to achieve meaningful therapeutic differentiation when studied with the right treatment combination and in the right patient population. In other words, the robust early clinical data here has taught us how to design a phase III trial that has a good chance of working. Now, Prasinezumab is another example of the importance of having a robust phase II data set to guide both decision-making and design of a confirmatory phase III trial. For context, there are no disease-modifying treatments for Parkinson's disease and really only a few options for symptomatic relief. The unmet need is very high. The first phase II trial we conducted, which is the Pasadena trial, was suggestive of possible benefit.
It was hard to be sure that those results by themselves weren't simply due to chance. We did another much larger phase II trial, the PADOVA trial, to further explore the signal that was seen in Pasadena, but also to assess how Prasinezumab might perform in combination with medicines such as L-DOPA , which are commonly used for symptom relief in Parkinson's. Hideki is going to describe these data this afternoon. The results were certainly supportive of the hypothesis that Prasinezumab could bring a meaningful therapeutic benefit, and the effect was even more pronounced in combination with L-DOPA. When you take the entire phase II data set together, Prasinezumab shows a consistent efficacy signal. It looks safe. We learned that combining Prasinezumab with standard-of-care L-DOPA has a reasonable chance to show clinical benefit in a well-powered phase III trial.
Of course, early clinical data sets don't always need to be that large to be highly convincing, and Trontinemab provides evidence for that. Pathologic beta amyloid, we all know, clearly, it's a foundational target. Yet the existing treatment options have still barely made a dent in the unmet need surrounding Alzheimer's disease. Hideki again will describe the data for Trontinemab later. Already, even in phase I-B, it became evident that Trontinemab possessed worthy pharmacologic characteristics that offer the potential for meaningful therapeutic differentiation because we're seeing rapid and deep clearance of amyloid plaques. More than 90% of patients have become PET negative after several months. The safety profile is encouraging. Less than 5% incidence of RAE after 28 weeks.
Based on the phase I-B, II-A trial results, we already felt confident to ungate phase III trials both in early Alzheimer's disease, but also in the preclinical Alzheimer's disease setting, where we'll see if we can prevent or delay progression in patients who have beta amyloid plaque deposition but do not yet show symptoms of cognitive decline. Hopefully, these three examples make it clear that configuring our decision-making around the BAR and ensuring robust clinical data are enabling a data-driven approach to design confirmatory phase II trials that have a good likelihood of being successful. The next R&D excellence solution I'll touch on briefly involves accessing the best external innovation.
When the concept of the BAR emerged two years ago, a vision that we had was that we would invest in candidate medicines that cleared the BAR wherever they might be found, whether from our internal pipeline or the external biopharma landscape. For this to be feasible in practice, we needed to make several adjustments in terms of how we support pharma partnering across our organizations and vice versa. Although we're certainly not done, it's fair to say that the business development results thus far speak for themselves. The clearest example, of course, is in our cardiovascular, renal, and metabolism therapeutic area. As you've already heard, this progress was, of course, anchored by partnerships with Alnylam Pharmaceuticals and with Zealand Pharma and through acquisitions of Carmot Therapeutics and now 89bio pending successful closure.
Equally, our other therapeutic areas have also been enhanced, as evidenced, for example, by the Zion and the Regor and Poseida Therapeutics deals in oncology. Poseida Therapeutics, by the way, also opens a potential door for allogeneic cell therapy in multiple sclerosis. We have acquisition of Telavant, which brought afimkibart into our immunology therapeutic area. There was the Antler A deal, which boosted our ophthalmology pipeline. Overall, we're leveraging internal and external innovation to architect a pipeline that is enriched with candidates that can become transformative medicines. In my remaining time, I'll highlight our progress on the second overarching R&D excellence objective, which is to achieve top-tier productivity. Here, one of our solutions involves embracing ambitious productivity objectives. Just to remind you, there are five key components of R&D productivity. You have volume, value, and success rates on the one hand, which define the effectiveness of an R&D engine.
You have cost and cycle time, which describe the efficiency of the engine. The bottom line here is that we remain on track towards our 2030 ambitions for each of these components. For example, we've added 29 assets to our pipeline since we launched R&D excellence, including 12 thus far in 2025. I already described the increase in average peak sales per pipeline asset. On the efficiency side, we've reallocated approximately CHF 1.2 billion towards programs that meet the BAR and also to other productivity initiatives. We've done that while keeping our overall R&D investment flat since the end of 2023. We're on track to achieve a significant acceleration in our end-to-end cycle times. Of course, we can't yet quantify phase III trial success rates, but I've shown you that the team-assessed probabilities of technical success have already increased substantially.
Based on progress across these five components, our R&D productivity seems to be moving in the right direction. The ultimate proof for increased R&D productivity will require a meaningful reduction in R&D spend per NME launch. It will take years to show that conclusively. However, we do see some preliminary evidence that this might be starting to happen. In the graph on the left of this slide, we're looking at R&D spend per NME launch for Roche together with 11 peer companies. We're looking at this across two adjacent, partially overlapping five-year windows. Overall, across the peer group, the average spend per NME launch has increased from the 2018- 2022 window to the 2020 - 2024 window. Roche, shown in the middle of the graph, is pushing against that trend. If anything, our total R&D spend per NME has decreased slightly from one window to the next.
Remember, R&D excellence didn't kick in until the last year of the second window. This suggests that even a single year of productivity improvement has already had an impact. The graph on the right of this slide illustrates that our internal reallocation has produced a markedly increased proportional investment in high-value R&D programs. I should point out that many of the so-called lower-value programs are actually line extensions. We certainly need to be committed to line extensions to realize the full value of NMEs. Overall, we are starting to see qualitative and quantitative productivity gains from R&D excellence. Last year, we created an internal fast-tracking mechanism for a few programs with exceptionally high potential. This, by the way, is not to be confused with the FDA fast-track designation. This approach has been quite effective for us.
You can see that the reductions in projected time to filing range from six to nine months to as much as 21 months compared to original expectations. There are a wide range of interventions across these programs that have contributed to the acceleration. I won't read through them all here, but they're listed on the slide. What's really nice about this is that the learnings from this program are becoming best practice across our pipeline, regardless of whether the program receives a special designation. There are several additional ways in which we are evolving our underlying R&D engine to make it more efficient and more cost-effective. For example, resource optimization. A moment ago, I mentioned the extensive reallocation toward higher-yield investments over the past couple of years, which amounts to more than CHF 1 billion since the beginning of last year.
We've invested over CHF 600 million of that savings to fund programs that we brought in through business development. An additional CHF 70 million was deployed to ensure pull-through of the fast-track programs that I just described. Furthermore, CHF 370 million has been deployed towards future capabilities, some of which I'll describe further in a moment. All of this sums up how we have aggressively funded programs that clear the bar, all while keeping our overall R&D spend flat during the same interval. A year ago, we described to you how we were radically simplifying our outsourcing model to help make our clinical trial infrastructure more efficient. Twelve months later, that effort is starting to bear fruit, as measured by accelerations in trial startup times, improving the site experience, and annual cost reductions, which include CHF 100 million of savings since 2024.
We expect, in the fullness of time, that this will deliver up to CHF 300 million in annual savings by 2030. That will provide additional resources that can be reallocated to support future transformative programs. Now, lastly, I'll say just a few words about how we're assembling a systems and data foundation to enable future R&D productivity enhancements. As you might imagine, we expect generative AI, agentic AI, and other automated platforms and analytic platforms to have a significant impact, really, across most elements of drug discovery and development. One specific use case from the development side involves content generation at scale. By now, it's self-evident how this kind of work can be enhanced markedly by generative AI. What you're seeing on the slide are multiple content generation elements where AI is actively being deployed to produce efficiency gains.
Of course, one can step back at a meta level and orchestrate all of this through agentification, for example. Now, we're moving far beyond content generation. We're mapping out many diverse workflows across our drug development continuum that might benefit in the future from agentic AI applications. In the fullness of time, these types of efforts could bring many efficiencies, and they also should augment the capabilities of our broader workforce. We have many AI and machine learning initiatives ongoing on the drug discovery side as well. One of these, which is called Lab in the Loop, has been championed by Aviv Regev, who leads gRED. The key concept behind the loop is the iterative learning that becomes possible when, for example, screening data or perturbation-based data at scale is leveraged recursively to train models.
In turn, the incorporation of such models can enhance target discovery, target enablement, lead identification, lead optimization, and other downstream efforts. Overall, these applications should lay the groundwork for a data foundation that can help drive improved productivity across the R&D continuum. All right. In summary, two years into our R&D excellence initiative, the majority of solutions seem well along the path to being embedded in a new business as usual. We still have a lot more work to do, and some of these are still closer to the beginning than to the final outcome. We believe this initiative could push us to top-quartile R&D productivity by 2030. Most importantly, R&D excellence is really fortifying our pipeline with many candidate medicines that truly have transformative potential. With that, I'll stop. Either we'll have the fire alarm or we'll have some Q&A first.
I want to ask you, we have now 40 minutes for Q&A. The speakers did an excellent job in keeping the time. We will be interrupted by the fire alarm at 11:00 A.M. Please stick to questions which were covered in the morning sessions. You still have the opportunity then to go drill down on details when it comes to pipeline or to data questions. Start here before Richard, please.
Thanks very much, Richard Vosser from J PMorgan. Maybe one question on the BAR on Zilebesiran and then one other. On Zilebesirab , you gave an example of all the criteria of the BAR. I'm wondering about competition. When I look at KARDIA-3, the blood pressure lowering is a little bit lower than some of the other agents, maybe the aldosterone inhibitors. How do you factor in competition when you're looking at that to go into phase III and push forward? One on R&D spend, clearly very good reallocation over the last few years. We're looking at a significant step up in phase III development going forward. Thoughts on how R&D spend can develop from here? Are we looking more at low single digit or growth in line with sales from now on?
Maybe I'll start. Of course, we'll have a lot more in-depth discussion on Zilebesiran this afternoon, but a couple of high-level points on the competition. The first point, and actually, I'm glad you brought it up because it's worth mentioning, the entire premise of Zilebesiran is that you can dose it twice per year. Because it's an RNAi, you get 24/7 coverage of blood pressure for that twice per year dosing, including nocturnal control, which is something that orals do not provide. The whole issue with orals is, of course, you don't necessarily get nocturnal control. You don't get that 24/7 coverage. The other issue is adherence. A major reason why many patients are not controlled is because it's hard for them to take two, three, four orals multiple times a day. We think that will set Zilebesiran apart. We'll talk more about that this afternoon.
In terms of big picture R&D investment, certainly, as you've seen, I think one important lesson for R&D excellence is that we have now really worked the discipline around making the trade-offs that are needed, but also maintaining overall fiscal discipline. That will continue to be a major effort here. To a first approximation, the idea is to make the trade-offs that we need within R&D or within other elements of the P&L, but to maintain tight margin discipline. I'm sure Alan Hippe will have more to say about that this afternoon.
Thank you. Yeah, Slash and Jane, Bank of America. One question on obesity and then one on the pre and post-BAR. On obesity, since you did the Carmot Therapeutics acquisition, the commercial landscape seems to have changed a fair bit as we observe it. Just two questions. One, the price point at which you expect to launch, has that materially changed given the changing landscape? Secondly, how do you think about the split of the eventual market, cash versus reimbursed, given that is also changing? On your blue dot sort of BAR, pre-post-BAR, I'll chance my arm. There is one pre-BAR asset, which is in the upper right quadrant, both large peak sales and high probability. Any sense of which that is? The one I'm more interested in, actually, is the post-BAR. You have one in the bottom left quadrant, so small and low probability. Why would you do that?
Thank you.
Yes, thank you for that question. The first part being the evolution of the market since the Carmot Therapeutics acquisition. I think we all agree that this is a very volatile and evolving market. We are well within the benchmarks that were part of the initial acquisition. The price point and the volumes are within what we have anticipated, even though it's evolving faster. To the split between cash and reimbursement, I think that will have significant differences across the different geographies. You will see all three ways of funding AOMs continue to grow with the growing market.
We are building in optionalities in our go-to-market plans, ensuring that we can cater for different future outlooks and make sure that we only make the decisions when really needed to ensure that we can meet the patients where they are and tap into whatever health care system evolution that we will see over the coming years.
Great. On the pre and post-BAR, first of all, for obvious reasons, we're showing directional to give a flavor of how the decision-making has changed. We're not going to comment on exactly which dot was where. I will say that one of the programs that we moved into phase III is an antibiotic, and we do that because of our commitment to society. It doesn't necessarily fit the path to value in the same way that the others do. I'll leave that with you, as you will.
Thank you. It's Matthew Weston from UBS. Two questions, please. Obviously, Teresa, one thing you highlighted was the excitement around the jurisdiction press release this morning with Avera. In the PR, you highlight that you saw efficacy in the ESR1 subgroup and in the total population. Can you give us confidence that there is actually some efficacy in the non-ESR1 patients or whether or not it's just those mutant patients that are driving the efficacy? I ask because we've increasingly seen the FDA focusing on subsets of patients and only giving a label for where the efficacy is. The second one also for you, Teresa, was the Vabysmo. Again, you highlighted in your comments the strong market share and market leadership.
One thing we've all been looking for from Roche is contribution to the Patient Charitable Access Foundation program so that you can cement that, help patients get access, and bring the Vabysmo to more people. Can you give us any comments as to when we can expect Roche? Can we expect Roche to contribute to the CAP? Could it happen in 2025? Would you see that as a way of accelerating the Vabysmo uptake?
Sure. Maybe I'll start with the CAP question and then I'll let you answer the Giredestrant question. I'm unfortunately going to give you a somewhat unsatisfying answer to your question because, as you all know, as part of our charitable contributions, we do provide donations to co-pay assistance funds. However, those donations are made by a separate part of the organization and are completely firewalled from the commercial organization. It would be inappropriate for me to comment what their plans are and how they plan to contribute because it is and has to be separate. That having been said, I think what we have previously communicated is that we will always attempt to do what's right.
What I can't do is comment specifically on the results of the Avera study. They'll be presented at an upcoming meeting, and we look forward to all of that. What I can say is, at a high level, everything is on thesis to what we have said actually multiple times, including I myself have said at this event in years past, which is that if a breast cancer is dependent on the estrogen receptor, Giredestrant can perform. That continues to be the case. That is the case regardless of whether or not there happens to be an ESR1 mutation. That is all on thesis. Of course, as you go through later and later stages, by definition, you can have reduced dependence on the estrogen receptor. If there's dependence on the estrogen receptor, Giredestrant can perform.
Thanks, Peter. James Gooding from Goldman Sachs has got two questions, please. First of all, on the balance between internal R&D and external R&D, of the 65 assets you have in the, or the 65 NMEs in the pipeline, how many of these were externally sourced and how has that changed relative to Q3 2023, I think it was? You had 81 assets in the pipeline. How will this then change or how will this develop further over time? What does that mean for your internal research spend? This is question number one. Question number two, picking up on the comment, Teresa, on new areas, and Roche has done this before. Across MS, [Avastin], Hemlibra, and obviously Vabysmo, I think it's fair to say with those three assets, you were head and shoulders above the competition. Moving into those areas maybe was made a little bit easier from that respect.
As you move into obesity, as you move into CVRM, are you confident that you have the same head start that you have relative to the other competition? Thank you.
Yeah, so I'll start. I don't, it may be that Bruno Eschli has the exact numbers and can speak to this. I can speak kind of higher level, which is that, as I mentioned in my talk, the concept of the BAR evaluative framework is that we will go after assets that clear the bar wherever they are. It's great if they're internal. If they're not and they're external and they clear the bar and they are otherwise a fit, then we'll go after those. To a first approximation, we haven't been sort of keeping tabs and using that as a guidepost to whether we go internal or external. Obviously, we certainly, by the way, Giredestrant is a homegrown molecule. Inavolisib is a homegrown molecule. Trontinemab came out of PURAD. We're very pleased with our internal pipeline and its ability to generate medicines like this.
We're not constrained by that to a first approximation in terms of where the exciting medicines might come from.
The ratio is very stable at 60-40. It has not changed despite the turnover. It's 60% external, 40% internal. What has changed, though, is that we have more late-stage assets. Therefore, it might become more visible. Normally, we have a lot of stuff which gets onboarded preclinic or phase I, and you will not recognize.
The question on best-in-class obesity, would one of you gentlemen like to take that?
I'm not sure I fully got the question.
The question was, when we entered prior disease areas, we entered with really best-in-disease areas.
We are having a growing portfolio of late-stage assets that we believe have the best in disease and can be differentiated when it reaches the market and the patients. We will do that based on some of the capabilities that Teresa talked to through combination opportunities and by being determined and curious about this growing market. Our belief is that many of the late-stage assets we have will translate into differentiated assets that have a clear role to play in the evolving obesity market.
I think if you sort of break them down more specifically, certainly CT-388 has potential. Petrelintide absolutely has potential to be best in disease. Pegozafermin.
Pegozafermin .
It'll roll off the tongue next time, I promise. Again, for MASH, it is the first to move into the F4 population, which is the most serious form of MASH. I think we have assembled a pipeline which, both in monotherapy and combination, has the potential to be truly differentiated.
Thank you. Conscious, I may have the fire alarm slot. I'll start. It's Louisa Hector from Berenberg. I have a couple of questions really on timing and efficiency. Starting with your three fast-track assets, which you highlighted last year, could you say a little more on how they have been accelerated versus other assets? Is three the right number? Might we expect to see more? On efficiency and timing, again, you have eight new NMEs entering phase III this year. Half of those don't start phase III until next year. Is there a reason for this? Is this perhaps not the best way for us to gauge timing, speed to market, etc., as you push through with the efficiencies? Thank you.
To the first question, we chose three programs that we felt had particular exceptional potential for impact for obviously the value of the company, et cetera. Actually, it's not as though those are the only three where we put all of our resources. The learnings, as I mentioned, really, I mean, we have many programs that are moving robustly. I will say that it was highly instructive to pick three and to ask our teams to really think outside the box of what would it take to accelerate. There are a range of, so there's not one single thing, but there are a range of approaches that we're taking. They range from, for example, very tight partnership between our Medical Affairs colleagues and our Clinical colleagues in parts of the geographies where we really took that to another level.
In other cases, there were close collaborations on the manufacturing side to make sure that things could be gated appropriately. In other cases, it was about can we take interim looks and have discussions with regulatory authorities and move things. There were a whole series of creative approaches that led to the acceleration. The second question that you asked, can you just remind me the.
Yes. One of the fast-track assets and then four of the eight NMEs you highlight for phase III don't start till next year. Why?
Historically, internally, we used to get very excited about when is the first patient in to a study. You would then move heaven and earth to get the first patient in as quickly as possible. Actually, it turns out that's not the relevant metric because very often you could say, OK, great, we've got the first patient in. You get through two or three months before you've enrolled enough sites. Really, the relevant metric is when do you get a critical mass of sites stood up. Once you have that, the hockey stick, you get to the long end of the hockey stick. That's really what we're focusing on. The time the phase III trial starts is less important than the time that enrollment finishes.
I just want to double down on something Levi Garraway said because I think it's really important. Every single one of the fast-track assets, those teams are actively sharing their learnings back with all of the other teams. The synergistic effect on the portfolio is actually pretty cool to see.
Maybe one add-on just to what confusion. When we show the appendix slides, for example, with the trial listed, we put it in there when it's first patient in. What we have communicated today is when we have taken the internal decision that we will move an asset on. Just a couple of months, one or two quarters in between normally. Over there. Michael.
Thank you. It's Michael Leuchten from Jefferies. Just if I could go back to the obesity question in terms of channels. Given the interdependence of pricing in the U.S. between the different channels: government, commercial, and cash, how much flexibility really is there in a DTC channel? Is there a scenario where you could price on the DTC side very low, say CHF 100, and then protect pricing in the other channels? Is that not possible because of the set interdependence? A question for Teresa on NXT 007. CHF 5 billion peaks on the slides. Can you just talk about how that fits with Hemlibra? Is that total cannibalization? Is that additional revenue potential in pockets? How do we frame that CHF 5 billion versus what Hemlibra does deliver?
I think maybe I'll just take that one to get it going. In terms of 007, we would anticipate cannibalizing all of Hemlibra. If we can beat Hemlibra, which is the current standard of care, we would clearly want to shift patients on to the most appropriate therapy. We should also remember there remains a significant number of particularly more mild and moderate patients that are not yet on prophylactic therapy. When you have a drug that potentially has the profile of NXT 007, not only do you sort of take the Hemlibra share, but you can then also very credibly think about expanding your market.
I think it's probably too early to comment on the exact price point. I'll refrain from that. What I do say I would like to comment on is the ability to also differentiate in a cash-paying segment. We clearly see that there is willingness to pay also for premium solutions in that channel. We will maintain, as I started out saying, the optionality to make sure that we are ready to offer where patients expect us to be.
Yeah, it's Rita from Morgan Stanley. Just a question on Prasinezumab. You mentioned the BAR evaluative framework across two trials, both of which didn't meet the primary endpoint. We saw a variety of findings: better efficacy in L-DOPA patients, better efficacy in MAOB-treated patients with diffuse disease, and running the trials for longer, over 104 weeks potentially. What drives the confidence that these findings across two trials, various findings, are not due to chance? A second question on Fenebrutinib in PPMS. Could you confirm if you've changed the endpoint to non-inferiority to OCREVUS in PPMS? Are you able to do so so close to trial ending? Thank you.
For Prasinezumab, as I mentioned, after the first study, we were not convinced that the findings that we're seeing were due to inefficacy versus chance. After the second study, which was much larger—number one. Number two, it was corroborated with additional biological correlates of activity of Prasinezumab . Then it looked like this is probably a real finding, and it's just a matter of can you power the study appropriately in phase III. Hopefully, that addresses that question. We'll talk a lot more this afternoon about the data. To the second question, we cannot comment right now on discussions around what we might or might not do in PPMS with Fenebrutinib.
Thank you for taking the question, Dmitris Papadopoulos, Deutsche Bank. Maybe just a couple of questions on your obesity strategy. Just interested to understand how you think the future market will segment in terms of oral, injectable, and then also in terms of incretin, amylin monotherapy versus combinations. I understand there's many things still to be determined. How are you expecting that will play out? How are you going to reflect that in your clinical development program, particularly in terms of timelines? Thank you. Yeah. Thanks for that question. I think Teresa, with her distribution of BMI, clearly shows that there are two ways to truly expand the market. It is treating more of the patients that are currently receiving GLP-1s or GLP-1 dips in the incretin market. The big opportunity to address an unmet need is to also engage patients much earlier in their disease.
Teresa called out that the average BMI for patients eligible and using AOMs today is 39. It means that we have almost 10 BMI increments where it's not sufficiently being used. Why is that? That was a heat map in terms of what is important to the different patient segments. There, clearly, we see that those with lower BMI in what we named and labeled prevention or early treatment, they value the tolerability and the convenience and are ready to trade in some of the last few percentage points on efficacy. We see both amylins with petrelintide and a more tolerable profile to have an opportunity for monotherapy there, as well as in combination with incretins and then play in the high efficacy. We definitely also see the opportunity for a significant share of the market, you can say, having a preference for daily orals over weekly injections.
The exact share, I think, is difficult to comment on. What we need to remember is that this market will be significant. Even a small share represents a large number. There's plenty of opportunity for oral GLP-1s to play in the early space and into maintenance, potentially for the amylins and petrelintide to establish itself. Do the combinations with incretins, etc. The market will be very heterogeneous. There is not one solution that will fit all patients. They are very different.
Maybe just to add one factoid on top of that, I think we generally, sometimes we assume that patients just prefer oral treatment. Many patients would actually prefer a once-weekly injection to an everyday oral because it's just more convenient for their lifestyle. There's actually only a relatively small subset of patients that are truly needle-phobic, that just won't touch a needle. The vast majority, particularly if it's a simple subcut injection, are more than willing to do that. It just is easier than taking a bunch of pills. We shouldn't always assume that oral is necessarily going to be the winner. I think you're right. It's just going to be a mix depending on preference.
I think Manu is also coming back with a little more details on how we see that market pan out.
There's one over in the corner. I don't know, but he's behind you.
Is there a question here in the CVRM area still?
Nope.
Can we go with that? Yeah.
Naresh Chauhan from Intron Health. Thanks for taking my questions. Just one, just going back to the R&D spend, please. You've got one of the highest spends in the industry. You've just shown that you've cut some of the assets and want to reduce costs per NME and drive efficiencies from timelines in AI. Help me to understand why we shouldn't expect R&D to fall in absolute terms over the midterm, please. Secondly, on your obesity programs, how has the evolving landscape or has the evolving commercial landscape reduced the size of the clinical program you anticipated maybe a year or two ago? Thank you.
Maybe I'll start on the R&D side. One major consideration over the next couple of years is the fact that we have indeed moved already eight NMEs into phase III. Some of those phase III programs could be robust, including CT-388. We haven't moved Petrelintide. These are significant programs, and we moved eight. We expect maybe a few more in the next several months. In order to make those successful, we have to invest behind them. That will be an important consideration that will require some additional fiscal discipline and trade-offs over at least the next two or three years.
On the perspective of how the perspective of the commercial ecosystem evolves, we are observing what happens. We know that patient segments start to fragment. It has very different patient preference and our CDP. Clinical development plans actually reflect this, and we'll use the portfolio we have to do the right combinations based on the patient seats we're observing emerging already there.
Thank you. Louisa Hector again from Berenberg. Maybe to follow up on obesity, have you debated simply trying to get to market on weight loss data as quickly as possible? How critical are the CVOT, the comorbidities, and will they just be assumed as a given given other drugs have that data? Thank you.
Yeah. Clearly, one of the lead indications will normally be chronic weight management. That's where the guidance to industry is relatively clear in terms of what is expected. You will probably also see in many of our assets that that's where we will have the first indication. Expanding into adjacent TAs and indications is really also a function of where we see that product play a role in that evolving landscape. If we are in the high-risk segment, you are expected to also demonstrate the benefits on comorbidities, whether it's CVOT or into MASH or chronic kidney, et cetera. You will probably see a growing, you can say, pool of evidence to support commercialization of those assets.
Whereas in the other end of the spectrum, it might be that it is not the, you can say, cardiovascular metabolisms that will drive uptake and preference for a certain product, but actually more being other endpoints. We are exploring what could those other endpoints. That's where we believe that many of the capabilities from other parts of our end-to-end DAs and TAs will help us make sure that we can make some strategic choices that will set us apart.
Can we capture some questions over there before we do a second round?
Thank you. Yes, Justin Smith from Bernstein. Just quickly on the BTK, Teresa, you used the word disruptive. Was that with reference to the entire market or just to tablets? If it's both, could you just help us understand where you would expect to take share from biologics and ABCs?
I think that fully depends on the data, right? If what we see in the phase II plays through to the phase III, certainly disruptive in the oral space, but potentially disruptive in the IV and subcut space as well. It looks like, at least in phase II, the efficacy is looking pretty good.
Today, just remember, today, more than a third don't have access to disease-modifying therapies in that space. If you can overlap, it would allow way more access for those patients.
Absolutely. Good add.
Thanks. Urban Fritsche from ZKB. Also on obesity, you talked about the patients are willing to pay a premium also in the cash pay market. Do you have already some understanding of what is really needed that the patient is willing to pay a substantial premium to cheaper solutions? A second question more on strategy. Would you assess that most of the internal transformation work is over now and that you are in full execution mode, which also could mean that we could see an acceleration of external deals being announced in the future?
Shall I go first?
I think we should try to look 10 years back and see what was cost for medicines and relative to effectiveness of those treatments and where we are today. That means that the price point is coming down per kilogram weight loss, et cetera. That gives room for optimizing the treatment journey through seamless engagement and patient support solutions that could be provided by some of our colleagues in diagnostics and other places that would give a holistic approach to care and thereby also warrant a premium to a generic version of an alternative product. I think there will be significant opportunities to explore that in the years to come. I think we have only seen the beginning of how patients will engage with telehealth, online pharmacies, and direct-to-consumer channels.
Maybe on the internal transformation question that you asked, certainly, there are several solutions that I described where I would say, done is always a tough term. We are very much into the embedding into this is just how we do business. Those things, the cycle, kind of the circle, comes to closure. There is one thing that if Thomas were here, he would remind us that productivity is never done. It always continues. Actually, there are still real opportunities that we see to continue to achieve productivity gains, and we're going to go after that. That's the first point. The second point on the internal versus external balance, certainly, we are, again, happy with the progress that we've made, including how harnessing these kinds of capabilities can boost our internal productivity.
It's also the case that the amount of external, the amount of innovation in the great wide world, is going to be far greater than what we can do in-house. That is one thing that's not changing. I would expect to continue to see a balance between external and internal. It may be that we don't have to do as many late-stage deals as we have done. Although if we see something that clears the bar, certainly, we'll evaluate it. Certainly, across the continuum of our pipeline, we would continue to have external augmentation.
If I may just add one question or one comment to your question. Obviously, we talk about getting ready for the obesity portfolio or the future portfolio. That work is at full swing, laser focus to make sure we understand how this market evolves, and we get the capabilities in place, as you've seen in the slide. You could argue there's still clear execution there, but there's still also capabilities to build.
Any questions from that end? Yes, please, hand on.
Thank you for taking our questions. Yihan Li from Barclays. The first question will be on your obesity franchise. A message from EASD conference last week is that the potentially evolving trial design standard with future obesity trials might likely require active comparator arms, for example, like semaglutide or tirzepatide, versus the placebo. I know it is still in early days. I'm just wondering what you think about it and any implications of your trial design as you are aiming to achieve the top three players in the obesity market. A second very quick question on your oral third. Congrats on the top line this morning. We note the preservera, like first-line data, is now pushed into the first quarter next year. Just wondering any commentary on this delay, please. Thank you.
I'll just briefly take the second one. All of these studies, given that they're event-driven, we have to wait for events to play out. There's nothing particular to read into that except that it's event-driven. On the first point, I would say we'll have time for a robust discussion on this in the afternoon. Suffice it to say, on the one hand, there's not a categorical requirement that we do studies against actual comparators. Certainly, if it becomes appropriate to do that, we are prepared to do that in certain settings. We'll talk more about that this afternoon.
Can we do a second round here on the front row?
Thank you. Thank you, Weston at UBS again. Teresa, MFN.
I thought I was going to.
You're not going to get away with that. I'm sorry. President Trump's letters required or requested a response from the pharmaceutical industry by the 29th of September. I'm not expecting you to tell us what Roche will say. I would be very interested in your view as to what investors should expect over the coming months. Do we think that this is a period where the industry has a clear view as to what it can offer or companies have a clear view as to what they can offer, I should say? Is this a period where investors should probably expect kind of noise, volatility, and some ongoing uncertainty before some very difficult or different views come together in a compromise in due course?
I think we are all aware of the significant conversations that are going on in the wider world today about MFN. I'd just like to say a couple of things. One, which is just to reiterate some comments that I made earlier in the morning, which is that we as Roche Genentech are committed to the U.S. We have a substantial presence there. We have over 25,000 employees. We have 13 manufacturing facilities, 15 R&D centers. We've made a CHF 50 billion commitment. We are committed to the U.S. market. We have also said over time that we share the goal of making medicines more affordable for U.S. patients. I think we all know that the complexities of the U.S. system mean that about 50% of the cost of innovative medicine actually goes to a middleman.
I think that the industry is in active conversations, as are we, with the administration to try and define what paths forward actually allow us to solve the ultimate goal, which is to help make sure that more Americans have access to the medicines that they need.
Is it going to be noisy, or is it all going to become clear?
I think it will all become clear.
Thanks. [audio distortion] . I'll take two on topics we've discussed. I want to follow on from Matt's question around Avera. I guess the simple question is, has it changed your view of the probability of success of persevERA? I guess was the background to the question. The reason I'm asking it is you say, whilst the data is on thesis, I think there's been mixed messaging on probability of success of persevERA across the C-suite. Just interested in your thoughts there. On FGF21 and 89bio, I wonder if you could talk about that relative to BAR. Again, following to James's question, a lot of commercial assets, competitive landscape at the time of your launch. How do you think your asset is differentiated? Thanks.
For Avera, I would say that the results that we're seeing reinforce the thesis, the biological rationale that we have believed in and talked about on many occasions for Giredestrant. We can't comment on a particular probability of success. Certainly, we're very pleased with the data, and we look forward to presenting it. That's what we can say now. On FGF21, I can speak to the scientific criteria. I'll let my colleagues speak to the business criteria. From a scientific standpoint, we have a very large unmet need in MASH, and actually, that will be true regardless of the penetrance of GLP-1. We expect that to remain a very large market. Now that there are therapeutic solutions coming out there, the diagnosis of MASH could actually grow, so the addressable market could actually grow effectively. Clear unmet need, a large opportunity.
The FGF21 data itself was, of course, a linchpin for us in terms of being enthusiastic about this opportunity. The phase II data that was seen, the effect on fibrosis, the ability to achieve resolution. Certainly, that data was for F3, but then also, we know that the class can have activity kind of across the board, including F4. That's a therapeutic differentiation that we don't really have. Particularly F4, the GLP-1s are not likely to play a major role in F4, and we can discuss more on that with Manu this afternoon. From a scientific criteria, it actually checked all the boxes from a BAR standpoint. I'll let my colleagues speak to the business side.
Which makes it relatively easy because the fact that this is a potential transformative medicine, which has a huge potential for patients, clears the bar. If you see just the numbers, the market right now is approximately CHF 2.5 billion. We expect it to go easily above CHF 10 billion-CHF 20 billion in 2030. There is opportunity for patients there.
To reiterate, I think the increment attempts to address this through addressing the underlying metabolic condition. The FGF21 analog actually goes straight towards the inflammation or fibrosis. It is a very different way of actually attacking the disease.
Maybe also, to let me add here again, we have in the appendix the updated epidemiology slides based per molecule. There you will see, for example, for Giredestrant and all the different lines of treatment with driving mutations on top, you will find the estimate for what Clobazam could do as the phase III trials are designed, what patient population they would go after. It's maybe worth to have a look there as well. For MASH, I think we'll find something as well. Assumptions in there, of course, that this will change over time. The standard of care will change.
Thanks, Bruno. Richard Vosser from J PMorgan. Just a question on the devices. You mentioned the pilot facility coming or being built now. What comfort can we have that there'll be devices for the GLP-1 and amyloid franchise, given we've seen, obviously, that's been the biggest bottleneck for current players? I can imagine NXT007, you can have a device for that for the future. Just thoughts there. Maybe aligned to that, obviously, CHF 750 million, I think, spent on a peptide facility in the U.S. You will have CDMOs. Thoughts on that capacity as well.
Absolutely. I think we've always said that with CT-388, our clinical trial and initial launch will be a balance of internal and external supply. That remains the case. We will ultimately bridge to a primarily internal supply chain eventually. That really was the purpose of building Holly Springs, to make sure that we had that large volume throughput device facility. I think you can be very confident that we will be entering with devices in the places where devices are necessary.
Maybe we take a final question before heading to lunch.
Hi, yeah. Kirsty Ross- Stewart from BNP Paribas. Just on the FGF21 deal that you've done, does that change the nature of your collaboration with Zealand Pharma, given their interest in MASH and survodutide? Just interested on the logistics there. Maybe a clarification on R&D spend. You've highlighted multiple new phase III programs requiring investment. Can I just clarify what you mean and what you can commit to in terms of R&D spend on an absolute basis? Can the current rate be maintained, or is it fair to expect this to grow in absolute terms over the midterm? Thank you.
On the FGF21, sorry, can you just repeat the first part of the question?
The nature of the partnership with Zealand Pharma will change.
Oh, yeah. At a high level, we are really excited about our partnership with Zealand Pharma. We're excited about the FGF21. We actually think that there's certainly no fundamental disruption or alteration. If anything, it just opens additional opportunities, including additional combinatorial opportunities. That gives me a chance to emphasize something that I didn't in the last question, which is that the characteristics of pegozafermin are very safe. A little bit of nausea, diarrhea, but not a lot of dose-limiting toxicity. That implies, we don't know for sure, but that implies the possibility of combinability with other assets. We think overall, this is a net add for all parties. Now, on the R&D side, I think once again, this is probably not the place where we can say specific numbers. What we can say is, number one, we've gone out and done these deals. We've made these investments.
We've applied the BAR evaluative framework. We're certainly committed to driving these programs through phase III. We're also committed to fiscal discipline. We have evolved practices to do that. We see other opportunities to do that. We'll work together to make that happen. I don't know, Teresa, if you want to say anything from a P&L standpoint on that one.
Yeah, no, I think that's.
We have been saying before, we want to defend the margins. I think there's more room for relocation of resources. You should not expect, because we have now a wave of phase III studies, that you will see the R&D expenses go forward.
Yeah, I mean, as Levi Garraway pointed out, we've been planning for this. This isn't.
OK, I think with that, we end our first session. We're heading into the 50-minute lunch. See you later.
OK, thank you. I
Lead Hematology Oncology Product Development. I'm here to kick off the afternoon session where my colleagues and I will be sharing with you the highlights of the portfolio across therapeutic areas, beginning, in my case, for oncology and hematology. Roche has a long history of 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 our PI3K inhibitor, ipilimumab, and our KRAS G12C inhibitor, rituximab. We're advancing high-impact combinatorial therapies. As you'll see shortly, we have a growing number of combinations to address non-Hodgkin's lymphoma, as well as our growing portfolio of combinations in hormone receptor breast cancer. We're investing in new technologies and novel modalities such as next-generation off-the-shelf allogeneic CAR T therapy, as well as molecular glue degraders.
We're focused on seamless end-to-end investment from discovery science through commercialization in key disease areas, namely lung, breast, hematologic malignancies, and hemophilia, to deliver differentiated, high-impact, high-value therapies to patients across the globe. Our organization also has a strong legacy of pioneering new drug targets and technologies. Today, we have a highly diversified portfolio in hematology oncology, ranging from small molecules, antibodies, antibody-drug conjugate, fusion proteins, peptides, gene therapies, and next-generation CAR T. We also recognize that innovation in cancer therapeutics requires a constant hunt for novel modalities being developed externally. Highlighted here are some of the key deals we've made over the last couple of years. Mentioned earlier, the CDK portfolio acquired from Regor, the HER2/neu TKI partnered with Zion Therapeutics, the CAR T program through our acquisition of [IGNYTA], and antibody-drug conjugates from MediLink and Innovin.
This broad array of technologies is reflected within our portfolio of agents in development for solid tumor malignancies from phase I through registration, with a particular focus on end-to-end development in lung and breast cancers. Turning specifically to breast cancer, our organization really is proud to have launched the field of targeted therapy for breast cancer and transforming the lives of patients with HER2 positive disease. We continue to address the unmet needs of patients with metastatic HER2 positive breast cancer. Specifically, 50% of patients with HER2 positive disease will ultimately develop brain metastases. We're therefore advancing ZN1041, a highly potent, well-tolerated, brain-penetrant HER2 TKI that has shown high response rates both systemically and within brain metastases in phase I investigation. Today, though, a major focus for our organization, as you heard earlier, is hormone receptor positive breast cancer, which represents 70% of patients.
There remains an important unmet need to reduce the risk of disease progression or recurrence and foster greater tolerability of these therapies. We're tackling HER2 positive breast cancer by targeting well-validated signaling nodes that are critical for tumor development and resistance, with our best-in-class SERD, Giredestrant, our recently approved PI3K inhibitor, ipilimumab, and our acquisition of the next-generation CDK inhibitors from Regor Therapeutics. These novel CDKs have the potential to become best-in-class molecules, overcoming resistance mediated by CDK2 adaptation and reducing toxicity often mediated by CDK6 inhibition. Our lead molecule, GDC4198, is a potent inhibitor of both CDK4 and CDK2. Among patients who have progressed on a CDK4/6 inhibitor, 4198 monotherapy demonstrated durable objective responses with acceptable tolerability, favorable PK profile, and sustained target coverage of both CDK2 and CDK4. At upcoming scientific meetings, we look forward to sharing our ongoing work and plans for this program.
As I alluded, our strategy in HER2 positive breast cancer focuses on three fundamental pillars: next-generation endocrine therapies and CDKs, and novel targeted therapies. Within these three pillars, endocrine therapy, as you know, remains the backbone of treatment for HER2 positive disease across both early and metastatic disease until, of course, resistance develops. Despite progress in endocrine therapy, there remain limitations. In the adjuvant setting, 50% of patients discontinue due to tolerability issues, and 30% will go on to develop progressive metastatic disease. Our ambition is to improve the standard of care across all three pillars through novel agents that both meaningfully improve efficacy and reduce toxicity. Let me turn now to our next-generation SERD, Giredestrant, as well as our PI3K inhibitor, ipilimumab.
As compared to other SERDs currently in development, Giredestrant demonstrates the highest potency, is combinable at full dose with CDK4/6 inhibitors, and has not been associated with ocular toxicity, an important adverse event for patients now seen in up to 20% of patients treated with an alternative SERD in development. Our development plan for Giredestrant aims to replace current standard of care endocrine therapies across early and metastatic disease as the next-generation best-in-class endocrine backbone. We expect first results, as you know, from the phase III persevERA trial in first-line endocrine sensitive disease in early 2026. We anticipate an additional readout in the first-line endocrine resistance setting in 2027, which, by the way, allows physician choice of CDK4/6 inhibitors. Additionally, we are the leading SERD trial in early disease with a head-to-head comparison in the lidERA trial, comparing Giredestrant to an aromatase inhibitor in the adjuvant setting.
We're also evaluating combinations of Giredestrant with CDK4/6 inhibitors as a sub-study in lidERA. Several other studies are ongoing in other lines of treatment, including a phase I/II study in combination with our CDK2 inhibitor and a trial in ER-positive HER2-positive metastatic disease in combination with Phesgo. This morning, as you heard, we announced the positive results from the phase III acelERA trial in second-line HER2-positive metastatic breast cancer, comparing physician's choice of an AI or fulvestrant plus everolimus to the combination of Giredestrant plus everolimus. Of note, 100% of patients had received a prior endocrine therapy and all had received a prior CDK4/6 inhibitor. The study met its co-primary endpoints with Giredestrant and everolimus, demonstrating a statistically significant and clinically meaningful improvement in progression-free survival in both the intent-to-treat population and the ESR1 mutated population.
Overall survival remains immature at this time, but there is a positive trend in both the ITT and ESR1 mutated cohorts. Consistent with prior studies, treatment was well tolerated, and we did not observe any new safety signals. The acelERA results reinforce our confidence in the Giredestrant clinical development program and show the potential for this Giredestrant combination to improve patient outcomes in the second-line setting. Full data will be presented at an upcoming medical meeting, and we are actively sharing these results now with health authorities. In the wake of these positive results, we're looking forward to the Persevere readout in Q1 of next year, followed by our trials in adjuvant therapy and endocrine-resistant disease. We believe that this compendium of studies will make Giredestrant the standard of care across all estrogen-dependent breast cancer indications. Complementing Giredestrant is our best-in-class PI3K inhibitor, ipatasertib.
For decades, we've realized the potential to target PI3K mutated in 40% of HR-positive breast cancer and 30% of HER2-positive breast cancer. Nonetheless, the available molecules previously in development and currently approved demonstrated limited efficacy and poor tolerability, with a high rate of treatment discontinuations due to adverse events. In contrast, ipatasertib is differentiated as a highly potent and selective inhibitor of PI3K alpha. A unique feature of the molecule is its selective degradation of the mutant PI3K alpha subunit, conferring greater efficacy and far greater tolerability when compared to the alternative PI3K inhibitors. Moreover, ipatasertib can be combined at full doses with endocrine therapies and CDK4/6 inhibitors. In the INAVO120 study, the combination of ipatasertib, palbociclib, and fulvestrant demonstrated a near 60% improvement in progression-free survival in the first-line endocrine resistance setting and served as the basis for our approval in the U.S.
and EU, with additional approvals on the way. At the recent ASCO meeting in June, we shared an update of INAVO120 demonstrating a statistically significant 33% improvement in overall survival for the combination, making ipatasertib the first PI3K inhibitor to improve overall survival. At that update, the time to subsequent chemotherapy was delayed by two years among patients receiving ipatasertib. Importantly, ipatasertib continued to be well tolerated, with discontinuations in the single-digit range. Based on the strength of these data, we're conducting additional studies in PI3K mutated breast cancer, including INAVO121, a head-to-head comparison of ipatasertib versus alpelisib in the post-CDK setting, INAVO123 in the first-line endocrine sensitive setting, INAVO122 in the HER2-positive disease. We recently initiated a phase II trial of ipatasertib in combination with ribociclib and letrozole as neoadjuvant therapy for patients with stage II and III disease.
We have other trials in the adjuvant setting currently in design. As well, we're conducting studies in multiple other tumors that possess PIK3CA mutations. Turning now to lung cancer and our KRAS G12C inhibitor, rituximab. In preclinical studies, rituximab is 25 x more potent and 50 x more selective than the current G12C inhibitors on the market. These features translate into robust, durable clinical activity. In our phase I-B studies in second-line metastatic non-small cell lung cancer, tiruzumab monotherapy achieved an objective response of 56% as compared to 30%- 40% for soterastine or adirastine. At the same time, tiruzumab documented a median progression-free survival of 15.3 months as compared to roughly six months for the other molecules currently on the market. Based on these highly encouraging results, we have an ongoing comprehensive phase III program.
First, we have the phase III KRAScendo-1 trial, which is a head-to-head study comparison of rituximab versus the choice of soterastine or adirastine in the second-line non-small cell lung cancer setting. We have FDA breakthrough designation for this indication, and the trial will read out next year. Next, we have the phase III KRAScendo-2 trial in first-line non-small cell lung cancer, which we're initiating, comparing a chemotherapy-free regimen of rituximab and pembrolizumab as compared to chemotherapy and pembrolizumab. Finally, we're expanding our phase III program into the early curative setting of non-small cell lung cancer, initiating the KRAScendo-3 trial, which will test tiruzumab in the adjuvant setting. Moving on, Tecentriq continues to deliver positive results across tumors and indications.
At ASCO, we shared the results of the IMforte trial, demonstrating a statistically significant and clinically meaningful overall survival benefit for the combination of Tecentriq and lurbinectedin as a first-line maintenance therapy for extensive stage small cell lung cancer, establishing a new standard of care for this difficult-to-treat form of lung cancer. At the ASCO plenary session this year, we shared the results of the ATOMIC trial in the adjuvant setting of DNA mismatch repair deficient colon cancer, demonstrating that the addition of Tecentriq to postoperative chemotherapy conferred a 50% improvement in disease-free survival. This regimen has now been incorporated into NCCN guidelines in the U.S. Additionally, at next month's ESMO conference, we'll be presenting results from the IMvigor011 trial. In this trial, patients underwent serial ctDNA testing following cystectomy for muscle invasive bladder cancer.
Those testing positive and therefore at a high risk of recurrence were randomized to treatment with either Tecentriq or placebo, whereas those testing negative remained on observation. Among patients with positive ctDNA testing, Tecentriq demonstrated a statistically significant and clinically meaningful improvement in both disease-free survival and overall survival. Additionally, ctDNA negative patients experienced excellent outcomes without adjuvant therapy. This is the first prospective phase III trial using a personalized ctDNA-guided approach to identify patients who will benefit from adjuvant therapy with Tecentriq and has the potential to change the postoperative management of bladder cancer. We believe these positive trials of Tecentriq across the three domains of small cell lung cancer, colorectal, and bladder cancers will translate into continued stable sales for Tecentriq through the decade.
Now turning to hematology, we're advancing novel molecules targeting both malignant and non-malignant conditions across the spectrum of development, all designed to meaningfully improve the lives of patients with hematologic disorders. Over the past 25 years, Roche has transformed the landscape for patients with non-Hodgkin's lymphoma, which accounts for almost half of all blood cancers. We have a comprehensive program of clinical trials across the range of NHL subtypes. The list on the right is not an exhaustive one, but it is a strong representation of the breadth of our clinical program in NHL. Our CD79B antibody-drug conjugate, Polivy, has had strong uptake in the first-line DLBCL setting with over 50,000 patients treated around the globe. At this year's Heme Summer Congresses, we presented the positive results for the POLARGO study of Polivy and Argemox in second-line DLBCL.
Prior to that, we shared the five-year update for the POLARIX trial in the first-line setting of DLBCL. We launched [lansoprazole] monotherapy in over 60 countries. Last week, the CHMP for the European Medicines Agency recommended approval for subcutaneous [lansoprazole] for the treatment of follicular lymphoma. We're moving [lansoprazole] both into the second and first-line treatments of follicular lymphoma. We look forward to the readout of the second-line Celestamo trial of [lansoprazole] and lenalidomide in the first quarter of next year. Additionally, the SUNMO trial of lansonib and pivekimab in second-line DLBCL was reported out this summer, and I'll review those results with you. Similarly, for COLUMVI, the third-line launch of this highly efficacious CD20/CD3 bispecific is going well, with over 6,000 patients treated in 60 countries commercially.
STARGLO in the second-line setting of DLBCL has been approved in over 45 countries, including the EU, and is a category I recommendation by the U.S. NCCN. Our first-line SKYGLO trial of COLUMVI is almost fully recruited. In July, we shared the positive results of the SUNMO trial of [lansoprazole] and pivekimab in second-line plus DLBCL. Patients randomized to [lansoprazole] and pivekimab experienced a 59% improvement in progression-free survival, with a median PFS of 11.5 months for [lansoprazole] and pivekimab, and 3.8 months for argemox. The combination of [lansoprazole] and pivekimab also conferred a robust and statistically significant improvement in objective response, with a 30% absolute improvement in ORR, 70% versus 40%, and a doubling of complete response, 51% versus 24%.
Of note, this chemotherapy-free regimen of lansonib and pivekimab was delivered entirely as an outpatient and was associated with a manageable safety profile with a low incidence and low severity of cytokine release syndrome. SUNMO is the first positive phase III study of a chemotherapy-free regimen in DLBCL, providing an important fixed duration, well-tolerated, highly efficacious outpatient regimen suitable for the community care setting, where more than half of patients in the U.S. now currently receive their care. Also, this summer, we shared the phase I-B data for the combination of COLUMVI with polatuzumab in first-line DLBCL, demonstrating an unprecedented response, a 100% response rate, and a 96% complete response rate. These responses were highly durable, and treatment was well tolerated, with relatively low rates of cytokine release syndrome. The results further enhance our confidence in the ongoing phase III SKYGLO trial.
SKYGLO is the only phase III trial in which a bispecific is being added to the more effective pola-R-CHP regimen, offering patients the best chance for cure for diffuse large B-cell lymphoma. Of note, recruitment for SKYGLO is now nearly complete, and we're expecting the results from this trial in 2027. Turning to multiple myeloma, we're advancing a unique CD3-engaging bispecific, cevostamab, into pivotal phase III investigation. Cevostamab is the first antibody in the clinic that targets FCRH5, which is expressed on essentially 100% of myeloma cells. Cevostamab offers the potential to address an important unmet need in multiple myeloma. Emerging data in myeloma is now moving anti-CD38 antibodies, immunomodulatory agents, and proteasomes with dexamethasone, all collectively now into standard first-line therapy, often now referred to as first-line quad therapy, as the standard of care. Nonetheless, myeloma remains incurable, and virtually all patients will eventually develop refractory disease.
This highlights the need for additional safer and efficacious options in the second and later lines of treatment. At the International Myeloma Society meeting last week, we reported the efficacy data from our phase I trial of cevostamab in combination with pomalidomide and dexamethasone in relapsed refractory multiple myeloma. The combination with the cevostamab demonstrated deep and durable responses, with an objective response of 86% to 88% and a VGPR rate of 74% across the two doses tested. Equally notable, the safety profile was quite manageable. On the basis of these exciting results, we're initiating the phase III EVOLUTION trial for the combination of cevostamab and PomDex in second-line patients.
Beyond EVOLUTION, we believe the unique target of cevostamab, FCRH5, and the documented efficacy and safety for the molecule enable this agent to be a partner of choice with a range of multiple myeloma therapies across the industry, and we're now actively exploring those combinations with various potential companies. Further building on our portfolio in hematologic malignancies is our entry into cell therapy with the acquisition of Poseida Therapeutics. CAR-Ts have transformed the landscape of hematologic malignancies, but current autologous technologies are highly complex, and only about 25% of patients who are technically eligible for CAR-T actually receive the therapy. Our approach developed with Poseida leverages healthy donor-derived stem cell memory T cells, enabling durable anti-tumor protection. As well, Poseida's non-viral gene editing technology allows stable integration of multiple CARs, as well as high-fidelity knock-ins and knockouts to both enhance efficacy and reduce adverse events.
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 relapsed refractory multiple myeloma, demonstrating high response rates in heavily pretreated patients for which the FDA has granted RMAT designation. Beyond BCMA, we have a CD19/CD20 dual CAR program, currently in phase I in B-cell malignancies. We're also leveraging this technology in non-oncology indications, and my colleagues will share some of that work with you this afternoon. Finally, switching gears to non-malignant hematology, we're initiating phase III trials of NXT007, our next generation bispecific that promises to enable patients with hemophilia A for a life free of bleeding complications. Hemlibra has set a high bar in terms of efficacy, safety, and convenience. NXT007 builds on Hemlibra to enhance potency, half-life, and allow for low-volume, infrequent sub-Q injections.
NXT007 is 30-fold more potent than Hemlibra, and as you can see on the left side of the slide, an in vitro assay indicates that NXT007 promotes thrombin generation within the range of people without hemophilia. In July, we presented our dose escalation trial of NXT007 in cohorts B3 and B4. Patients experienced zero treated bleeds during the observation period, and there were no safety concerns. These data support the growing body of evidence that NXT007 has the potential to become a new standard of care. We're now initiating three phase III trials, including a head-to-head comparison of NXT007 to Hemlibra, reflective of our confidence in this program. This ends my presentation. I thank you for the opportunity to share our portfolio in HemOnc, and I look forward to your questions later this afternoon. Now, let me turn to my colleague, Hideki Garren, to review the work in neuroscience. Hideki.
Thank you, Charlie. I'm super excited to talk to you about our neurology portfolio. We're one of the leaders in neurology, both on our all-market medicines as well as in the deep and rich portfolio. In fact, I was a little bit of a misguided soul. I left Roche for four years, and one of the main reasons I came back is because of our portfolio. It really is the envy of the industry, as you'll see in a couple of slides here. How do we get to that portfolio? It's through critical capabilities. One is we are looking at multiple therapeutic modalities. The one you already heard about is brain shuttle, brain shuttle anti-ABETA for Alzheimer's disease, which we call Troncinemab. We also have a brain shuttle for multiple sclerosis. It's one of our many modalities we're looking at.
As you heard multiple times already, we have this unique collaboration with pharma and dye. In fact, neurology is one of the areas where we have really used that to our advantage. One example is this traveler pre-screening program for Alzheimer's disease, where we're using a blood-based biomarker to identify patients as early as possible and to roll them into the study. I'll talk about that in a little bit more detail. Further, we're taking that one step further. Using the same blood-based biomarker, we can identify patients for prevention of Alzheimer's disease. This is pre-clinical Alzheimer's disease. Pre-clinical meaning there are no signs or symptoms of Alzheimer's. These are patients with biomarker-based amyloid pathology who are walking around perfectly normal, maybe one of us as well, and therefore we may be able to identify patients and treat them, prevent Alzheimer's disease with a molecule such as Trontinemab.
Finally, as you heard earlier this morning, we have made end-to-end investments in both MS and Alzheimer's disease, and we're doubling down on our R&D capabilities there. Let me show you the pipeline I've been talking about. Here's a pipeline. As you see, there are multiple different modalities. The index is on the right lower corner where nearly every modality you can think of is within our pipeline. The other thing you should notice is the color coding. Across the board, through development, we have neuroimmunological molecules across the board in development in purple. Neurodegenerative disorders, we also have molecules in development across the board in green, and in neuromuscular disorders in orange, we also have molecules throughout development. A broad and deep pipeline in neurology with industry leaders.
One other thing you should note is that this pipeline looks a little bit different from what you saw early in the year because two molecules have moved into phase III. That's at the bottom on the phase III column. Bottom Trontinemab, as you heard, has moved into phase III, as well as Prasinezumab for Parkinson's moved into phase III. We're also looking forward to some exciting phase III readouts of zanubrutinib and PPMS later this year and relapsing MS next year. The other phase III molecule, NSPRING in MOG antibody disease and autoimmune syphilitis, we expect readouts next year. Let me give you one example of our neuroimmunology pipeline molecule, Fenebrutinib, which you've heard about many times already, but let me dig down into some details about why we're excited about this.
It is the only BTK inhibitor that achieves a dramatic CSF concentration greater than IC90 for B cells and microglia. BTK inhibitors have a dual mechanism of action as shown in the far left panel in terms of targeting B cells as well as macrophage and microglia, and therefore they can reduce relapses as well as disability progression. In the middle panel, our particular BTK inhibitor, Fenebrutinib, has an optimized pharmacokinetic profile. What that means is if you look at that red line in that graph, there is a high bioavailability because of the free plasma AUC, and the reason that's important is that it will lead to increased concentration of Fenebrutinib in the periphery as well as within the CSF. Speaking of CSF, CNS penetration that's in the far right panel, you see that we have a dramatically increased CSF penetration compared to the other BTK inhibitors.
Therefore, because of this profile as well as CNS penetration, we have a high confidence in the outcome of Fenebrutinib in relapsing and primary progressive MS. The other aspect of Fenebrutinib that's unique is that it's very highly selective, and that's shown in the left panel where the selectivity is compared to the other BTK inhibitors in development, and you can see that based on this graph, there's very high selectivity to the appropriate BTKs that we're targeting. It's a non-covalent molecule, meaning that potentially we could have a beneficial benefit-risk profile. It's the only non-covalent BTK inhibitor in development. We've completed the phase II study called Fenebrutinib in relapsing MS versus placebo, and I'll show you that in the next slide.
We will have two studies reading out early next year with Fenebrutinib versus teriflunomide, and then on the bottom, we have a study called Fenebrutinib, which is in PPMS versus OCREVUS, which are laid out toward the end of this year. Let me show you the phase II study that's been completed. Here we see a really dramatic decrease in relapses and GAD lesions. The analyzed relapse rate is shown on the left. We're doing the double-blind period, which is that blue grayed-out part of the graph. You see really zero relapses within that double-blind period. Patients roll over into the open-label extension, and you can see that the relapse rate is dramatically low at 0.06 out to week 96. Further, 97% of patients remained in the open-label extension through week 48, speaking to the tolerability of the molecule. On the right panel is the data on GAD lesions.
T1 GAD lesions are measured by MRI, and it's indicative of active acute relapses and acute disease in the brain. The double-blind period, again, is that grayed-out period in the first part of that graph. You see a rapid and dramatic decrease in GAD lesions with over 90% reduction by week 8. If you follow that out into the open-label extension, we have zero new lesions at week 96, so no new GAD lesions. This is really a dramatic decrease in both relapses and GAD lesions, giving us a lot of confidence in the relapsing MS study. Let me switch gears to our neuromuscular pipeline. The first example is ELEVIDYS, which is a microdystrophin gene therapy for Duchenne's muscular dystrophy. The most important message to take away here is that we have a positive benefit-risk profile in ambulatory DMD patients. The reason that's important is the diagram on the left.
These patients, over time, have a loss of their ambulatory skills and motor skills such that roughly around age 13, most patients are wheelchair-bound. There's a huge unmet medical need for these patients. On the right are data that you've already seen from our EMBARC phase III study. What you see here is a two-year extension in that study where we're comparing to external control because the placebo period is over. In every instance, in every measurement of motor function, ELEVIDYS is favored on the right-hand side of the graph with significance. We demonstrated a stabilization of disease progression with durable effects in DMD patients. It's important to note that over 850 patients have been treated with ELEVIDYS . Ambulatory DMD patients have been treated with ELEVIDYS across clinical and real-world settings.
Another example for my neuromuscular pipeline is imioglobar, previously known as GM329, and we expect phase II results in both SMA and FSHD later this year. Imioglobar is an anti-latent myostatin inhibitor, and it has a unique sweeping and recycling technology. This allows for every four weeks sub-Q dosing. Preclinically, imioglobar has been shown to have an enhanced benefit in mouse studies compared to other anti-myostatin. These are the two studies that we're waiting for readouts. Phase II studies we're waiting for readouts: the MANITY study, which is imioglobar on top of EVRYSDI for SMA, and the MANOEUVRE study, which is imioglobar in FSHD. It's important to note that in FSHD, there are no disease-defying treatments available. Changing to the neurodegenerative pipeline. First of all, you've heard a lot about Prasinezumab, but let me give you one slide on the crown of Parkinson's disease.
In Parkinson's disease, there is a steady progression of neurodegeneration and loss of motor and non-motor signs and symptoms, such that by the time of diagnosis of clinical Parkinson's disease, it's already about 40% - 60% of the dopamine-producing neurons within the brain have been lost. Let's diagram the burden on the healthcare system with about 1% of the population over 60 affected by Parkinson's disease, resulting in a... We do have symptomatic treatments, primarily L-DOPA and MAOB inhibitors, but it's important to note that they do not change the course of disease and that there's a wearing-off phenomenon as patients stay on these symptomatic treatments over time. Prasinezumab is our anti-alpha-synuclein antibody, and as you heard, we have achieved a phase III gold decision with this monoclonal antibody.
The pathophysiology of Parkinson's disease is shown in the left panel where alpha-synuclein, which are the red items diagrammed in the left panel, causes neuron degeneration by accumulating in neurons, as well as interferes with synaptic transmission. Prasinezumab, which is shown in green in that cartoon, is designed to bind to aggregated alpha-synuclein in order to reduce that cell-to-cell transmission of alpha-synuclein. We've conducted phase II studies, Pasadena and Petova, and these are unique in the sense that they're large phase II studies and that we have a primary endpoint of a clinical endpoint as opposed to a biomarker endpoint. The wealth of that data, the clinical data from those two studies, has led to the phase III gold decision.
Pasadena's first phase II study started many years ago, and the advantage of that is that now we have long-term data on patients on Prasinezumab , and that's shown in the left panel. What you see is that whether patients started with PRASI from the very beginning, that's the early start in dark blue, or they switched from placebo to Prasinezumab , and that's the delayed start in light blue, you see almost flattening of the measurement, which is called MDS-UPDRS part 3. One word about the endpoint is it is clinical, and part 3 is a motor examination by the clinician. In other words, it's an objective measure of disease progression. You see near flattening of that curve over the four-year course of the open-label extension. The question is, what happens if you were not on Prasinezumab ? What you see there is in an external control, the gray line going upwards.
That external control is a robust clinical external control called PPMI, where data were collected very carefully, and the same endpoint was collected. Therefore, it's a robust comparator to Prasinezumab during the open-label extension. You see this wide separation of about 65% reduction in progression. The more proximal study is Petova on the right, the phase II-B study, where again, it's that same endpoint, the same measurement, MDS-UPDRS part 3, but we have evolved that into a time-to-event. The reason we evolved it into time-to-event is because these patients were treated with Prazinicumab on top of their symptomatic treatments. What we found there is in the L-DOPA subgroup, we see a separation of the curves, blue and gray, in terms of time-to-event, which achieved a hazard ratio of 0.79 and a P-value of 0.04. This is a subgroup that's quite large.
About 75% of the patients were on L-DOPA, so it's a large subgroup of a large phase II study. That result, along with multiple secondary endpoints, which I'm not showing here, all favored Prasinezumab , as well as a biomarker endpoint, which is the MRI endpoint looking at neuromelanin and iron, show that Prasinezumab has biologic activity and is very robust. That led to the phase III gold decision in the context of no disease-modifying treatments available. Another molecule early in the pipeline that we're excited about for Parkinson's disease is NLRP3. The NLRP3 inflammasome has been shown to be associated with inflammation across various therapeutic indications, and in particular, Parkinson's disease. The idea is with an oral molecule called Selnoflast to reduce the activity of NLRP3, and therefore reduce the brain inflammation and microglia activation and progression of disease.
Phase I's completed, and we're waiting and analyzing the data from the phase I. There have also been studies in coronary artery disease and asthma, as this inflammasome has been implicated in those diseases as well. Moving on to our other neurodegenerative indications, Alzheimer's disease. As you know, there have been two molecules approved for Alzheimer's disease, Lecanemab and Donanemab, but there are limitations with what's available to Alzheimer's patients. Those limitations are shown in the left-hand side of this slide. Number one is that there's limited blood-brain barrier penetration of these large monoclonal antibodies. Number two is the rapid and deep reduction in amyloid load has been shown to correlate with clinical response, and that's shown in the right-hand side of the cartoon, that we want to reduce that amyloid load much more rapidly in a much deeper manner.
The third item down on the left is the overall safety profile. There is a side effect with the anti-amyloid therapy called ARIA, amyloid-related imaging abnormalities, and that causes brain edema as well as potentially brain bleeding and, in rare cases, death. We want to try to avoid that as much as possible. Finally, biomarkers indicative of change downstream of beta amyloid is another area that we want to look at. How are we addressing that? We're addressing that with Trontinemab. Trontinemab is our brain shuttle coupled anti-ABETA monoclonal antibody, and we believe this antibody addresses all the limitations that were outlined in the prior slide. Trontineumab crosses the blood-brain barrier through a TFR receptor-mediated transport mechanism, and that has been shown in humans to have an eight-fold increase in the CSF plasma ratio versus standard antibodies.
On the right-hand side are data that was shown earlier this year at AEIC, where we see a dramatic decrease in amyloid. What you see on the y-axis is the centiloid scale. Centiloid is a 0- 100 scale, and with Trontinemab in the milligram dose, which is the purple line, you see a dramatic reduction such that by day 196, roughly six months, the sedimentation level in amyloid. Percent of patients below the amyloid positivity threshold at 28 weeks to six months. Further, all patients had a reduction in amyloid. In other words, there were no non-responders. We also had a pronounced effect of fluid biomarkers downstream of amyloid on CSF PTAP, which decreased by 27% at 25 weeks. In terms of safety, that's shown in the right-hand table, there was less than 5% incidence of ARIA-E, so much lower than what's been shown by the competitor molecules.
We're excited to announce that we have started the phase III study called Frontier 1 and 2, and we have achieved first patient enrolled in that study. Frontier 1 and 2 is diagrammed on the right-hand side. What I'll point out is what's in the green box. We have a prescreening program called TRAVELLER, where we're using a blood-based biomarker PT217 to identify patients for this study. In TRAVELLER , we already have in the first 60 days 3,000 patients enrolled in this prescreening study. There's clearly a lot of excitement about this study. The study design of Frontier 1 and 2 is diagrammed here, where after the prescreening, patient-centered screening period, followed by induction with Trontinemab every four weeks for six months, followed by a maintenance period every 12 weeks. The maintenance period is important because it reduces any pathologic burden that the patient might have within the brain.
Amyloid is one thing we can measure, amyloid plaques are one thing we can measure by PET, but we can't measure the other amyloid species that might be toxic, like protofibrils. That's why it's important to keep that every 12-week dosing schedule. Frontier 1 and 2 have started with first patient in. We also announced that we have a preclinical study, which is in the lower left part of this diagram, and that we plan to start shortly. Again, this is in preclinical Alzheimer's patients with no signs or symptoms of Alzheimer's, but with biological evidence of amyloid pathology, and those patients are also going to come from Traveler. A really robust prescreening program to identify patients. A brief word about our DYA collaboration. Diagnosis of early Alzheimer's is, of course, important. It's a major unmet need. Over 55 million people have dementia.
The majority of those have Alzheimer's disease, but the majority of them remain undiagnosed. PET is not available broadly, and measuring CSF ABETA is invasive because you have to do a lumbar puncture or spinal tap. Therefore, we're really excited about the developments at DYA with the Alexis PT217 assay, which should be launched next year, and which is the same assay we're using in the TRAVELLER prescreening study. They result directly from our collaboration with DYA. My last slide, because the timer has now been at zero for a while, is an early-stage molecule called Nebivolol, which is a potential first-in-class gamma secretase modulator orally administered for Alzheimer's disease. Prior iterations were gamma secretase inhibitors, and what's unique here is it's a modulator.
What we've already seen in the phase I study, which is in the middle panel, is a decrease in the pathologic ABETA 42 and 40 species, and an increase in the non-pathogenic ABETA 37 and 38 species, which may also be protective as well. The phase I study is complete, and we're looking forward to the phase II-A GABRIELLA study, which would have interim data hopefully by next year. With that, let me turn it over to my colleague, Larry Tsai, to talk to you about our exciting immunology portfolio.
It would seem I'm being encouraged to use the podium. Is that okay? Fantastic. Thank you so much, Hideki. Hello, everyone. Good afternoon. I guess it's afternoon. My jet lag buddy isn't entirely sure what time of day it is, but I am Larry Tsai. I do know that, and I am the Global Head for Product Development Immunology. Happy to be here this afternoon to give you an update on the immunology strategy and pipeline. Hopefully, you are familiar with the One Roche Immunology Strategy, which we rolled out last year, and which is really an extension of the One Pharma Strategy, which Teresa rolled out last year and which we spoke about a little bit earlier this morning.
Roche has a long legacy of innovation in immunology dating back more than two decades at this point, and the strategy really aims to build on that legacy using four strategic levers. First of all, optimizing pathways, both novel and validated pathways that are known to play foundational roles in immune-mediated diseases. Second, looking for rational combinations of novel and validated pathways to raise the efficacy ceiling for immune-mediated diseases. Third, using biomarkers to break down patient heterogeneity and identify endotypes, which may predict a better response to specific therapies. Finally, where the science is mature, seeking functional cures using deeper B cell depletion and potentially immune reset. The strategy also centers around two end-to-end disease areas: inflammatory bowel disease and chronic obstructive pulmonary disease, while recognizing that there may be opportunities in other disease areas where there is the potential for breakthrough innovation.
This is particularly important in immunology because the immune system tends not to obey anatomic boundaries, and often you do have to follow the science wherever it leads you to other areas of unmet need. When we look at our clinical stage pipeline, we can see that there is a good balance between programs that are relevant to our end-to-end disease areas and to areas of potential breakthrough innovation. I'll spend the rest of my time today taking a little bit of a deeper dive into some of these programs. Okay, microphone's working, but clicker's not. There we go. One area of breakthrough innovation is that of immune-mediated kidney diseases. Immune-mediated kidney diseases are a common cause of chronic kidney disease and are, in fact, the third leading cause of end-stage kidney disease.
Chronic kidney disease is obviously very common globally, affecting about 1/10 people worldwide, and is associated with high healthcare costs, including about a quarter of the U.S. Medicare annual budget and about CHF 140 billion annually in Europe in healthcare-related costs. The Roche development pipeline includes several programs which are relevant. That are relevant to immune-mediated kidney diseases, including lupus nephritis, membranous nephropathy, idiopathic nephrotic syndrome, and IgA nephropathy. GAZYVA, of course, is our next-generation anti-CD20 monoclonal antibody, which has been glyco-engineered to be less dependent upon complement for cytotoxicity, therefore making it particularly well-suited to diseases where there may be depletion of complement levels, such as advanced lupus. In the phase III Regency study, GAZYVA was shown to be associated with a 46.4% complete response rate compared to 33.1% for placebo. Those results have now been published in the New England Journal of Medicine.
The results have also been submitted to health authorities earlier this year with a U.S. PDUFA target date set for next month. In addition, international and national lupus nephritis guidelines have already been updated to include GAZYVA as part of first-line combination treatment for patients with lupus nephritis. Beyond lupus nephritis, phase III data in extra-renal lupus in the Allegory study and in idiopathic nephrotic syndrome in the InSURE study are expected before the end of the year, and phase III Majesty in membranous nephropathy data are expected in 2026. With success in these disease areas, we expect that GAZYVA can become the treatment of choice for immune-mediated kidney disease. In addition, Roche is helping to write the next chapter in B cell depletion with its T cell engaging B cell-directed bispecifics. Lunsumio is a CD3, CD20 bispecific antibody that's already been approved for relapsed and refractory follicular lymphoma.
Lunsumio has been tested in a phase I study in lupus and lupus nephritis and showed deep B cell depletion in the top three dose cohorts with an acceptable safety profile. Accordingly, Lunsumio has now been entered into a phase II study in lupus and lupus nephritis as of earlier this year. In addition, our CD19, CD3 bispecific program is in an ongoing phase I study in lupus and lupus nephritis. Beyond our T cell engaging bispecifics, our CD19, CD20 alloCAR T cell program filed for an IND in lupus and lupus nephritis and should be entering a phase ISefaxersin study this year. With these treatments and with other B cell-directed therapies in the pipeline, we believe that Roche can continue to build a leadership position in the emerging field of immune reset for autoimmune diseases.
Moving beyond B cell depletion, Sifaxersin is our first-in-class antisense oligonucleotide for selective complement suppression in IgA nephropathy. Globally, IgA nephropathy is the most common primary glomerulonephropathy and can progress to chronic kidney disease and renal failure. High levels of complement factor B have been associated with IgA nephropathy, and Sifaxersin aims to treat IgA nephropathy by downregulating complement factor B production by inhibiting mRNA translation. Sefaxersin was shown in a phase II study to have met its primary endpoint of a change in 24-hour urinary protein with a 43% reduction in mean proteinuria at week 29, as well as meeting secondary endpoints and showing stabilization of kidney function. The phase III imagination study of Sefaxersin in IgA nephropathy is ongoing, with an interim analysis readout expected in 2026 that could lead to an accelerated approval.
Shifting gears to talk about GI, and in particular our end-to-end disease, inflammatory bowel disease. IBD is a very serious problem that affects about 8 million patients worldwide, and despite significant advances in treatment over the past decade, still only about 40% of patients respond initially to standard-of-care therapies, and only about 20% achieve a lasting remission. Afimkibart is our anti-TL1A monoclonal antibody that's now being developed for inflammatory bowel disease, atopic dermatitis, MASH, and as announced this morning, rheumatoid arthritis now as well. TL1A sits upstream of and is a key amplifier of several different inflammatory pathways and tissue remodeling pathways, and cells that express TL1A and its receptor DR3 are known to be drivers of different immune-mediated and fibrotic diseases. We believe that Afimkibart has the potential to become a pan-immunology pipeline in a molecule.
As I mentioned, the studies are underway in inflammatory bowel disease, atopic dermatitis, and MASH. We have also initiated, as of this year, registrational studies in ulcerative colitis and Crohn's disease, and we are continuing to look at additional indications that could help to realize the full potential of Afimkibart as a pan-immunology molecule. The phase II study that I mentioned in rheumatoid arthritis is expected to begin later this year as well. Of course, Afimkibart's lead indication is inflammatory bowel disease, and in the phase II Tuscany study, Afimkibart demonstrated strong proof of concept in ulcerative colitis and also demonstrated its potential to be a best-in-disease molecule. The phase III Amitrin 1 and 2 studies in ulcerative colitis are well underway, and we are very pleased to report today that enrollment is about 3-6 months ahead of target.
That is due in large part to the fast track designation that Levi Garraway spoke about earlier this morning, which has enabled expedited enrollment and execution. In addition, the phase III SIBRITE studies in Crohn's disease are underway, as are the studies in atopic dermatitis in phase II and MASH in phase I, as I mentioned earlier. We continue to collect biomarker data, which will help us to explore the endotypes that I mentioned earlier that may predict better response to treatment. Since IBD is an end-to-end disease area for us, we're already thinking about the next generation of treatments, including bispecifics built on a backbone of TL1A combined with other validated mechanisms of action, such as IL-23. Towards that end, we have initiated a phase II study in ulcerative colitis of our P40 TL1A bispecific molecule, and we have additional bispecifics in preclinical development at this time.
Let's not forget, although not technically a part of our immunology strategy, Roche's contribution to the fight against global antimicrobial resistance, which is part of our commitment to global health security. Zosurabalpin is a novel macrocyclic peptide molecule that targets the LPS transport system in gram-negative bacteria. Zosurabalpinn has been shown to have potent activity against Acinetobacter baumannii, including carbapenem-resistant strains, which are the highest threat pathogens according to WHO and CDC from a bacterial pathogen standpoint. Acinetobacter baumannii, in particular carbapenem-resistant strains, are becoming a more common cause of nosocomial infections, including hospital-acquired bacterial pneumonia and ventilator-associated pneumonia, which are associated with high morbidity and up to 40% mortality. A phase III study of Zosurabalpin in HAPVAP is getting underway and is expecting to enroll its first patients in 2026.
With that, I will end, and I will pass the baton on to Chris Brittain, who will give us an update on what's going on in ophthalmology.
Okay, so good afternoon. Thanks for the introduction, Larry. I'm aware that I'm the last person standing between you all and an exciting update on the cardiovascular, renal, and metabolism franchise. However, I really want to make sure that you learn a lot about the ophthalmology business because there is so much exciting stuff going on. Give me my 15 minutes, please. Just as a reminder, ophthalmology, our strategy remains threefold. Number one, we continue to treat patients who have suffered vision loss, and we have the great example of Vabysmo, which you heard from Teresa and Levi this morning, which is doing really great work for patients globally.
We also want to treat earlier in disease still, in order to prevent that vision loss happening in the first place, because even though Vabysmo does great, the majority of patients, once they have vision loss due to the structural damage, cannot achieve the vision which they were used to before that disease impacted them. Thirdly, we aim to have truly restorative therapies for those patients who have more end-stage vision loss, and this is the graph which you see at the bottom right. Examples of these will be our OpRegen cell therapy program. Our critical capabilities remain key to our success. We have a number of novel mechanisms of action, which you'll hear about, and these include bispecific antibodies, of which we now have two in clinic and two declared novel MOAs, which you'll hear about. We have a concrete and strategic approach to extended durability and novel technologies.
Examples here are the port delivery system implant and also, again, our OpRegen cell therapy, very innovative, very novel technologies. In terms of our digital capabilities, we have, over the years, brought in-house tens of thousands of retinal images on top of thousands of biosamples from patients and hundreds of intraocular fluid samples. We've been using all that data to develop algorithms. We have a remote monitoring system. We really have this robust digital capabilities system set up. Finally, end-to-end investment. We're really using our end-to-end disease areas, which are geographic atrophy and intermediate AMD, and then the retinal vascular disorders, which you group together to diabetic macular edema, neovascular AMD, diabetic retinopathy. We're really investing in those heavily. What that is enabling us to do is have this seamless transition through the stages, and then at the end, we have the opportunity to reverse and to back-translate.
We provide those data from our aqueous humor samples, our ocular samples which have taken the phase III, to identify new markers of disease and new potential targets for new therapies back to our research groups. In terms of our pipeline, it's exciting to share. First of all, I'll start to the right-hand side. Central is metabolism, thyroid disease, you've heard of this program for the last couple of years. We'll be able to share some data at the American Society of Ophthalmic Plastic and Reconstructive Surgeons. That's in the middle of October as ASOPRS. I'm not going to be able to share any specific data today. That data just came in-house in the last few days. The Vabysmo phase III program in uveitic macular edema, that data will be presented.
The two phase III studies there, I'll talk a little bit more in a moment, but that data will be presented at the Scientific Congress of the American Academy of Ophthalmologists in the next few weeks. We'll be sharing that data with the regulators, and those two programs together we'll be discussing, as Bruno mentioned this morning, the investor relations call specifically for ophthalmology after the AAO meeting. Thirdly, today we'll be talking a little bit about showing some first-time data from our Vabysmo in DME program, and we are proud to say that we now have a new asset in phase I, which is a VEGF/IL6 bispecific molecule.
Starting with Susvimo in neovascular AMD, just as a reminder, this is an intraocular implant which is designed to continuously release a customized formulation of the anti-VEGF ranibizumab, and the actual implant enables us to have as infrequently as every six monthly refills of that device. The exciting data which we've been sharing recently is this on the left-hand side, which shows that over seven years since the implant, about 1/2 of patients maintain driving vision. I'll compare that to a previous study, which was seven years of ranibizumab, and over that seven-year time period, about 1/4 of patients were able to maintain driving vision. The advantage of having this continuous release of ranibizumab through the implant has really doubled that number. Quite remarkable results. Sometimes I like to share kind of patient anecdotes, which are quite interesting. We're here in the clinic.
One of our physicians was talking about a conversation he overheard, and one patient was saying, "How often do you come into clinic?" The one patient was saying, "Every four weeks." The next patient says, "Oh, I come in every 10 weeks." The Susvimo patient says, "Oh, I just come in twice a year." That is a real strong patient benefit for Susvimo. The next piece is that the port delivery platform itself, the implant, we actually have now two bispecific molecules which are ready to be used in that platform, and a large number of additional preclinical assets. Moving on to Vemicubart, just as a reminder, IL-6 is a cytokine which is very pro-inflammatory. You will know it from many other systemic diseases, but it's also involved in the pathogenesis of uveitis and a number of retinal diseases.
Vemicubart is designed for intraocular use, and it was first used, and it's an intravitreally delivered product. We're kind of excited to say that we've now got the uveitic macular edema phase III data in-house, and they've shown that we have a favorable benefit-risk profile in the patients that have undergone treatment, and the data will be shared with the regulators. We'll also be sharing the clinical data at the AAO, and we'll be able to discuss more clinical data on October 21 in our investor relations call. Secondly, I'll talk a little bit about the DME study. I'm delighted to say that we are moving forward with a VEGF IL-6 bispecific in DME. Dwelling on that for a moment, this is the diabetic macular edema study, phase II study Vabysmo plus ranibizumab versus ranibizumab alone.
This is a superiority study, and what we see here with this data is that the overall outcomes were a 3.4-letter improvement in visual acuity when Vabysmo was given on top of ranibizumab versus ranibizumab monotherapy. More importantly, which is the FDA-approvable endpoint, which is a 15-letter gainers, we saw a 44.7% versus a 28.6% percentage of 15-letter gainers if you take Vabysmo on top of anti-VEGF monotherapy. That's exciting data from the Bardenas superiority study. As you note in the second bullet, we did note that there were two cases of occlusive retinal vasculitis, but when you take all this data together, we believe that there's a strong and robust proof of concept for the role and the benefit of adding an anti-IL6 mechanism of action on top of VEGF, and therefore we'll be proceeding, and we're in the middle of an expanded phase I program.
We'll be accelerating this VEGF IL6 bispecific in DME. The additional benefit of this bispecific, obviously, is it's a Fab-sized molecule based on the DutaFab platform, and therefore it's compatible with the port delivery implant. Going back to Vabysmo and UME, I've already made the comments that we're excited that we've seen robust improvements in vision and anatomy in the two identical phase III studies, which you've just read out, MEERKAT and SANDCAT. As a reminder, uveitic macular edema is the leading cause of vision loss in patients with uveitis, and despite a plethora of systemic immunosuppressive therapies available for this condition, there is a significant unmet need for a safer option for patients. We are looking forward to sharing this data more in the American Academy of Ophthalmologists, as I say, in about three weeks' time.
Moving on to Zithibansomab in neovascular AMD, this is the second molecule which went into the port delivery implant. This is currently in the phase I/II Burgundy study. As a reminder, Zithibansomab is our bispecific, which targets both anti-VEGF and ANG2, and is much more potent in terms of both VEGF and ANG2 than the intravitreally delivered furosemide molecule. Therefore, we believe that Zithibansomab will be able to provide us with an option in the port delivery implant, which will give us infrequently as once every year dosing. This is proceeding very rapidly in our phase I/II study. Now moving on to Satralizumab. As a reminder, Satralizumab is a subcutaneously delivered IL6 inhibitor. IL6, as we know, is a key mediator of disease in thyroid eye disease. There is a significant level of unmet need that remains despite a single available treatment in thyroid eye disease.
Thyroid eye disease is a painful, disfiguring, and potentially blinding condition, which people often forget about. Although there is an available treatment, there is a need for a treatment which is more safe. The available treatment has issues such as it's teratogenic, it causes significant disruptions in the menstrual cycle, it causes deafness, it causes muscle spasms. There is a significant opportunity there for a safer treatment. We have the data just brought in-house. I'm not going to be able to share any today, but what I can say is that we're looking forward to, again, sharing the clinical data in the ASOPRS conference in just two to three weeks' time. Next on is OpRegen, one of my personal favorite programs. This is the allogeneic RPE cell therapy injected under the retina for patients with geographic atrophy.
This is delivered, as I say, subretinally, and what we're starting to see is over the years, we've got longer-term data from our phase I study, and on the left-hand graph, you see the visual acuity remains stable over that three years compared to the fellow eye of these patients. Fellow eye controls aren't always optimal, but what I can say is that in the large trials, what we see consistently is that patients with GA generally lose about five letters of vision every year. What we're seeing is stability of vision, so this is really exciting. This is replicated in the anatomy on the right-hand side, whereby the size of the geographic atrophy lesion is remaining stable, and we see that is not the case in the fellow eye here, and we know from natural history of geographic atrophy that the lesions do get bigger.
We are excited about this program. It continues in phase II, and with extended follow-up, we're continuing to see a really robust and acceptable safety profile. Obviously, this is delivered through a transvitreal approach currently, and therefore there's an opportunity to improve the delivery. Teresa talked this morning about a number of devices, so we're excited that we've acquired two additional devices which have the potential to even further improve how we deliver not just this therapy, not just this cell therapy, but other future cell therapies or other future gene therapies or other technologies that we need to deliver to the eye. The left one is a transvitreal subretinal injector with a dual lumen. This means that instead of injecting, you go through the vitreous, through the jelly in the eye, make a hole in the retina, and inject your therapy.
Instead of pulling out and making a second hole, because it's got two lumens in that injector, you can just simply inject the drug without taking it out and putting it back in again. This has a significant advantage. The device on the right-hand side is the orbit subretinal delivery system. It goes through what we call a transcoroidal approach, which is between two layers, between what we call the retina, which is the seeing part of the eye, and the choroid, which is the vascular support of the retina. It goes between those two layers, and then a needle comes and the cells are injected between the retina and the choroid. You don't need to make a hole in the retina. That's really important. These have the potential to make the delivery of these technologies easier and safer for patients, and we're excited to report these technologies in-house.
This program carries on in its phase two, and we're looking forward to sharing more data over in future meetings. With that, I'm delighted now to hand over to our last act of the day, Manu Chakravarthy, who will talk through our cardiovascular, renal, and metabolism pipeline. Thanks, Manu.
Thanks, Chris.
Great. Good afternoon. Can I stand here or do I have to... It's good? Okay, perfect. It's an honor to go after all of my esteemed colleagues, so hopefully we'll have another 15, 20 minutes of engaging discussion and then open up to questions. You heard a lot from Teresa this morning about the obesity strategy. In case anybody's still wondering why is Roche in CVRM, hopefully, you know, this is a slide that can remind us as to why this is so important in a way that there's an obligation in some ways to really address this incredible burden to society. You heard earlier this morning that 51% of the globe is going to be either overweight, with people with overweight or obesity.
What we know from the epidemiology is that obesity transects and touches the lives of almost, you know, I wouldn't say everybody, but you know, a great majority of the people in the world. You can see in this graphic the incredible overlap with many of the diseases. That's why when we really think about CVRM at Roche, we're thinking about these intersecting, highly interdependent diseases. We see this as one continuum, whether it's CV, whether it's renal, whether it's MASH, whether it's diabetes, all of that underpinned through a common pathophysiological thread. In order to address that level of heterogeneity, we really need to be thinking very broadly and very holistically about how to actually position our portfolio to really try to tackle this challenge. It's really around the four pillars that we had introduced last year.
Just to reiterate some of the forward momentum that we've had since the last year, you can see with the first box, it's not just incretins, it's incretins and beyond. We believe that our portfolio will obviously have a foundational backbone with incretins, but there are other foundational targets too. That was one of the reasons why we did the deal with Zealand Pharma, you know, with Petrelintide. Most recently, a couple of days ago, with 89bio with Pegozafermin, which is FGF21. Both Petrelintide and FGF21 are foundational targets, just like incretins are. In order to really address that level of heterogeneity you saw in the previous slide, we need combinations. Without combinations, it's nearly impossible to really tackle this multi-pathophysiological spectrum of interdependent diseases. You heard a little bit about the comorbidities. We are singularly focused on improving the health of the society.
In order to bend that trajectory, it's not possible to do that without addressing comorbidities. The key comorbidities, of course, a lot of people think about are CV, renal, but you can also easily imagine other things like MASH and many other areas where there's a true unique synergy with other therapeutic areas. You heard from my esteemed colleagues, they presented the work from neuroscience, immunology, oncology. These are potentially transecting areas where Incretens and our portfolio can be synergizing. The final piece is the end-to-end solutions, without which we cannot really bring all these things to bear. Holistic solutions include a very close partnership with diagnostics, with our devices, as well as with our digital apps, and then ultimately to monitor, diagnose. The final piece, very, very important as a physician, I can tell you that patient empowerment, especially in a chronic disease setting, is critical.
People with chronic disease don't like to be reminded that they have chronic disease. How do you really address all of these things? This is kind of what we have really spent a lot of time and effort and thought thinking through. You heard a little bit from Teresa this morning about how we've taken a more patient-centric approach. We also have taken an approach that we also listen to our KOLs, our key opinion leaders and other thought leaders in the field. Here is just a smattering of things, and you can see that many of these things intersect with what Teresa shared with us this morning. Patients really are looking for obviously superior weight loss, but also improved tolerability.
They're also looking to improve not only 10%-15% of their weight loss, but improving their whole, the comorbidities, better maintenance of their weight loss, better quality of their weight loss. These are all things that we actually take very seriously. This is the reason why, when we get asked the question, why do you need so many different things? This is the answer to that, because there is an intrinsic heterogeneity and the incredible fragmentation of this marketplace. We need to be in a position to really meet patients where they are, and chronic weight loss management is a chronic weight loss journey. We have to meet patients wherever they are, whether it's in a preventive mode, in an early treatment mode, or in the high-risk, comorbidity mode. This is why you need the armamentarium that we have, which is orals, Incretins, non-Incretins, combinations.
All these things are actually required to really compete and to be successful in addressing the needs of patients that are living with obesity and its comorbidities. This is the backdrop in which we have taken a lot of pain and care to construct the portfolio that you'll see today. I was here a year ago and shared this slide. This is actually 2023, there was only one, right? It was Sylvester, and in 2024, we added four more to our pipeline. This is what we had showed just approximately a year from now. I'm really proud and gratified to be able to share with you today the portfolio as it stands in 2025.
This is the forward momentum and the progress that we have tried to articulate by learning about the market, knowing what it takes to compete, and to pull together a portfolio that will address these kinds of heterogeneous needs. What I'll do in the next few minutes is give you snippets and highlights of the three phase III programs. Very happy to announce that we're moving CT-388 into phase III, and we'll cover those top three phase III programs. Then I'll give you quick snippets of the remaining four phase II programs with Petrelintide, CT-996, Emuglobart, and then we'll end with CT-868. Let's start with Sylvester. We believe that this is a paradigm-shifting first-in-class opportunity that is truly unique. Why do we believe that? The first is the way that it addresses the target. It's way upstream of what is called the RAS pathway. That's the renin-angiotensin-aldosterone system.
It really addresses angiotensinogen, which is made in the liver, and with an siRNA approach, you can have near a complete knockdown of this gene. When I say near a knockdown, it's like over 95%. It's completely flattened out, and we know that the suppression of angiotensinogen directly correlates with blood pressure control. We know that we definitely hit this target. The siRNA approach allows us to silence this for a long duration of time, and that's really critical. That's one of the core reasons why you see here that we are able to reduce blood pressure, not just for, you know, a few hours in the day, but 24 hours in a day, seven days a week, for all the way up to six months. One shot every two years will give you 24-hour control and gives you nocturnal control. We know from epidemiological baseline.
When you have nocturnal control, you will improve outcomes. That's been a direct link, and that's one of the core reasons why we've been so focused on getting sustained blood pressure control over a long time. Here are some data to actually prove that, right? One, it's easy to say, we have nocturnal control. We have a very comprehensive phase III program. Levi Garraway shared with you how robust this program is. It was actually heartening, to be quite honest, to see three phase II studies before we actually decided to go to phase III. That shows the rigor of the program. KARDIA 1 and 2 were in mild to moderate hypertension. They're relatively healthy people with one or two antihypertensive meds. One could have taken the view that, you know, we could have actually gone to phase III at that point in time.
We actually took a little pause to make sure that we truly understood what is the dose, what is the population, and how do we actually want to study this. That's why KARDIA 3 was actually designed. KARDIA 3 is a population that is much sicker. They're all people with established CVD or those with high risk of CVD, the exact population that we wanted to study, with at least two, if not maybe three or four background meds. These people are actually very poorly controlled. That's why we call it uncontrolled hypertension. The majority of them were on a backdrop of diuretics. What you see in the middle panel is this very nice reduction, about 7mm-9mm of mercury, in the population that is ultimately of interest to us.
Those that are uncontrolled, those that are on diuretics, those that have a CVD risk, those are the people we want to take forward. On the right, you see what I've been talking about is the importance of nighttime control. In there, you can see clearly in the nocturnal period, you are able to really see profound suppression, both doses, 300 and 600, relative to placebo. This gave us great confidence that we are able to achieve what we set out to do. I think we already had made this announcement prior to today, but just to reiterate, very happy to announce the initiation of ZENITH, which will be our phase 3 11,000 person cardiovascular outcome study. This is not a small study. It's as robust as it gets.
A large population with a primary outcome of the composite of the essentially the four-point, what we call the four-point MACE, right? CV death, non-fatal MI, non-fatal stroke, and a heart failure event. Many secondary events that we will look at in all the different forms and components, including nighttime control, etc. All in all, very happy that this is advancing forward. We feel very confident that this will then, given the results that we have, it should translate to outcomes because the one thing that we know about blood pressure control is that that's a significant predictor of cardiovascular morbidity and mortality. Now let's transition from hypertension, CV, to more obesity. Really, on the left side of this thing, you had seen some of the work that we had presented last year.
To build on the work from the incretins, which by design, all of our incretin molecules have been what we call signal biased, because we believe, based on our existing data, both preclinical data as well as early clinical data, suggests that having a biased signaling pathway enhances pharmacology. More efficacy, potentially longer duration of action. We will see all this borne out, hopefully, in the phase II studies, but that's our approach to incretins. On the right side, you'll see now that we've added to this armamentarium, as I said, with Petrelintide, which is a long-acting analog. It is suitable for once weekly dosing. We believe, based on the preclinical characteristics and the preclinical data set, this is a molecule that would be differentiated because it has no fibrillation. It's stable at the neutral pH, has better potency and stability, and has the pharmaceutic properties for potential combinability.
All are important attributes and differentiators. I'm going to start with CT-388 because that's in our phase III now. Again, very happy to advance this forward. We had shown you a lot of the phase I data from the weight loss. I'm not going to repeat that, but just remind us that we had seen up to 19% weight loss in six months in a cohort of people that had obesity and non-diabetes. Here, what you're seeing here is a cohort with obesity and type 2 diabetes. On the middle panel, there are the curves of the A1C. This is just over 12 weeks glycemic control on people that are on monotherapy of metformin. If you treat people on a placebo with metformin, you get that gray line, but if you treat people with metformin plus CT-388, you get the blue line.
That's a delta of around 2.8% relative improvement in A1C in as little as 12 weeks. On the right, it basically underscores how potent the metabolic benefits are with CT-388. This is the same cohort from what we call the phase I-B study, over 24 weeks, obesity, again, non-diabetes. We looked at MRI PDFF. What was striking to me, having looked at the MASH field for a while, is that almost 85% of people achieved a 30% relative risk reduction in PDFF. For those that follow the MASH field, you know that 30% reduction in PDFF means that you actually have one stage improvement in fibrosis, or at least 1-2 point improvement in the MAFLD activity score. Very potent effect, even as little as six months. We are very excited about the metabolic benefits here.
For all those reasons, along with all of the data from the totality of the data from phase I, because as I said, we've done it in people with and without diabetes, overweight and obesity, and looked at it in all different ways. Consistently, we're seeing a very comparative profile of the weight loss. From all of that, along with the ongoing safety monitoring, with two existing ongoing phase IIs, which are fairly large, between 350- 450 people across the population, we feel very confident to be able to move this now to phase III, which is planned to be initiated in the first half of 2026. Quickly about Pegozafermin, because that's our third phase III asset, very quickly. For those that have followed the field, you'll appreciate that not all FGF21s are created equal. Everybody says, oh, it's another FGF21.
Again, having worked in this area for a little while, I can tell you that all FGF21s are definitely not the same. It depends on how and what the receptor potencies are, what receptors they bind to, et cetera. We believe that Pegozafermin certainly has the characteristics to be best in disease for MASH. What was really exciting to us is that actually not just in between two panels, but the panel on the right. In the phase II study, it so happened that there were about 11 people that actually had a diagnosis of cirrhosis. When we actually looked at those 11 people, I know it's 11, but again, the point here is that it's a proof of principle. In nearly 1/2 of them, in as little as six months, we were able to see a fibrosis stage improvement.
That is very hard to see, by the way, in as little as six months. To see that in an F4 population was, again, further reaffirmation of the properties of the FGF21 molecule. In between there, you can see the more formalized analysis from the 24-week study and Leiben study, where there's about a 27% response rate for fibrosis improvement and roughly the same, you know, between 27% - 37% response rate for MASH resolution. All in all, very excited about this, and we're looking forward to integrating with the company and continuing the great momentum with two additional ongoing phase IIIs that's ongoing with data that is to be expected in the first half of 2027. Moving on to our phase II assets, I'm going to talk about four very quickly. Let's start with Petrelintide. Many of you have already seen this multiple ascending dose data.
Currently where we are with the program is that we have two ongoing phase II studies, what we call Supreme One, that is in people with obesity and non-diabetes, and then Supreme Two is people with obesity plus diabetes. Both are going really well, very happy with the progress. Just a reminder here that in as little as 16 weeks, you know, we see a clinically meaningful weight loss of about 8.5% with Petrelintide. What was, again, very reassuring to see this, even though we had hypothesized that the tolerability would be better, always nice to see data that supports it. You can see no vomiting in Petrelintide, except for the one case at 9 mg, which is very mild, and then very little to no diarrhea. These are the two things that really annoy people when they take incretins, for example.
The nausea is manageable, but vomiting and diarrhea are really, you know, life-disturbing kind of events for most people. We're very excited about this profile. We continue to push forward to get this into completed the phase II so that we can get to the phase III again sometime in 2026. Now, very quickly on the 996, just as a quick update. Again, many of this we have already presented last year, especially the exciting data from the multiple ascending dose cohort. This was just a four-week study in people with obesity, non-diabetes, and you can see up to a 7.3% weight loss in about four weeks. That set of data was the reason why we actually initiated two large phase II studies, which you see on the right. Again, roughly between 250 - 350 participants in both with obesity, with and without diabetes. These two studies are now underway.
It's being conducted, and the data to be expected in 2026. Very excited about this oral program because this is, we believe, has the potential, again, to be quite differentiated in at least from the oral space. You heard a little bit from my colleague Hideki about imuglobard. I'm not going to talk about the biology. He's already covered that really nicely. Just as a reminder that this is a sweeping technology and it removes what we call the anti-latent myostatin. It's really all of the ligands that bind to the activating receptor. Not just myostatin per se, but a little bit more of the broader swath of ligands that impact the receptor. The overarching hypothesis here is that we would get more significant or deeper weight loss with a clear preservation of lean mass.
We're excited about what we call the Jeminda study, which is the study that we're doing in combination with Tirzepatide. These are in people, again, overweight or obesity. A 48-week study with Tirzepatide by itself and Tirzepatide with various doses of imuglobard. We will have this data again in 2026. Last but not the least, we're also very excited about the ongoing developments and work that's going on with CT-868. CT-868 has been designed, again, as a once daily dually biased GLP-1 GIP and specifically for type 1 diabetes, again, a very underserved high-end need population. We had already demonstrated the proof of concept of glycemic control reduction in people with type 2. You might recall, but I'll just quickly remind us that we had seen about a 2.3% reduction in A1C in people with type 2 diabetes. We feel really good about the glycemic control potential.
We have done two studies with type 1 diabetes, both ongoing near completion. One was a mechanism of action study, and the other is a formal phase II study, you know, dose range finding study, both of which are ongoing and will have data from the phase II study, actually, you know, in the fourth quarter of 2025. Just as a reminder, why are we excited about this is that people with type 1 diabetes need to actually still lose weight, are still insulin resistant, still have a very high insulin burden. The hyperinsulinemia actually predisposes to a very high cardiovascular risk.
This set of data in type 2, which we fully believe will translate to type 1, indicates that you're able to reduce glucose while also reducing the insulin burden, which is really, in our minds, the proof of principle that, you know, improving insulin sensitivity in people with type 1 diabetes will improve their overall outcomes as well. Very excited to see what those results bring us. Again, quite happy with the progress there. Let me conclude with this slide, which is the slide that Teresa showed, which to me is an encapsulation of why it is what we're doing. Let me end before I hand it off to Teresa to bring us home with three things.
The first is we've taken a lot of thought and effort to understand what are our market needs, what are our patients' needs, you know, and what is the holistic way to approach this extremely complex and very heterogeneous disease. I hope you at least can leave with the impression that we have that understanding, that it is a segmented and fragmented market. The second is we have made significant progress with forward momentum in our pipeline. Right. The way the pipeline has been constructed and designed is really to try to address this intrinsic heterogeneity and the interdependencies of CVRM. The third, which is what I'm most excited about, is the fact that we are confident that we can actually execute this because of our capabilities and what unique opportunities are available at Roche. That confidence then translates to commitment because we have to do this all in.
This is not something where we can just sort of dip our toe in the water and see how it feels. We are all in into this. We feel confident, we're committed, and I am really excited to see how this will evolve in the coming months and coming years. With that, let me hand it off to Teresa to bring us home, and I think questions after that.
Wow, what a day. We've covered a lot of information. If there's one thing I hope you take away from everything we've discussed today, it's actually the word that Manu used a couple of times, momentum. We have spent a considerable amount of time over the last number of years focusing on what it is going to take in order to change the trajectory of our future. We have thoroughly embedded the pharma strategy in our everyday operations. We are investing in strengthening the capabilities along our enterprise from end to end to ensure that we can not only deliver to patients today, but we are setting ourselves up to deliver for patients around the world in the future.
We are optimizing our investments and our commercialization capabilities, not only to ensure that we can reach maximal potential with our on-market products, but they're ready to launch into these new disease areas when we get there. We are maintaining and will maintain a stringent cost discipline to ensure that every dollar, whether it's an R&D dollar or an M&D dollar or an SG&A dollar, is going to the thing that will deliver the highest return for the patients, for our people, and for business. If there is one thing I'm proud of over the last couple of years, it is the change in our portfolio. We are in a 180-degree different position than we were in a number of years ago.
We have a significantly evolved phase III portfolio and a robust phase I, II portfolio that really well position us to deliver on our ambition of 20 transformative medicines by the end of the year and beyond. R&D excellence is helping us figure out how to do this more efficiently, with more rigor, and with higher success rates. Partnering supplements our impressive internal activities. I'll leave you today with the same commitment I made to you a year ago. We will continue to operate with rigor in the science and discipline in the business. We will continue the momentum that we've generated. With that, thank you very much for your time and attention. I'm going to call all my colleagues back up on stage, and we can start grilling Manu with questions.
Thank you.
Something cozy.
I forgot they were.
Okay. Michael, go first.
Thank you. It's Mike Leuchten from Jefferies. Maybe two questions. One on Cevostamab. Just taking that asset straight into phase III, given what we know about multiple myeloma, is quite an aggressive decision. Just wondering how you feel comfortable about those being to do that, make that decision. The second question on Vabysmo. Why would a five specific targeting the same targets get around the adverse effects you've seen?
Your microphone seems to be fading in and out. Can you just repeat the latter part of your question on Cevostamab ? I'm sorry.
Yeah, so you're taking Cevostamab straight into phase III, as I understand it. We've seen dose range work become more important with recent history on the regulatory side. Just wondering how you feel comfortable with the dose ranges out of the phase I straight into phase III.
Yes. I think that, as you saw, the two doses we focused on both are showing excellent tolerability and deep and durable responses. We are finalizing the choice of dose for the phase III with health authorities, but we're honestly comfortable with both. With regard to the decision to go from phase I-B to phase III , the strength of the data for Cevostamab , Pomdex, and just to be aware, we've now treated 700 patients with Cevostamab in aggregate. The strength of that triplet data and realizing the opportunity in second line, because of the evolution of the field where all the drugs are now moved into first line and patients really need new and different, more effective and safe therapy second line, we see that, and realizing what's now available, we believe that our probability of technical success based on these data in second line is worth moving forward on.
Okay, so on the Vabysmo question, we're prioritizing the VEGFR6 bispecific over Vabysmo for a number of reasons. Safety is not the primary reason. The primary reason is actually because having a single molecule, which is a bispecific, is much easier to deliver in clinic. Instead of giving two separate injections, you can give one injection. You can just get away with a single injection. That's the primary reason why we're moving forward with the bispecific. In terms of, is the VEGFR6 bispecific safer than Vabysmo? What we've seen in the early stages is that it really improves our confidence that that specific VEGFR6 molecule is looking really good. We're very confident with that. I hope that helps. Question?
Hey, it's Sarita from Morgan Stanley. Just a quick follow-up on COLUMVI. Have you had confirmation from the FDA post the negative ODAC that the phase III SKYGLO trial serves as confirmation for converting the accelerated approval? I noticed in the data in the SKYGLO trial, the OS benefit in, it was actually detrimental in the U.S. patients. Are you confident that we won't see the same trend in the frontline trial? Has the frontline trial recruited enough patients from the U.S.? If I could just squeeze in another question, sorry, on the FGF21, do you expect this to move to a combination market with GLP-1? If so, are you initiating those trials? Perhaps you could speak to the ease of co-formulation and administration. Thank you.
Yeah, I can start. The ongoing discussions with the FDA, we have not yet finalized the confirmation. Obviously, the accelerated approval for COLUMVI remains and we are finishing our discussions with the FDA. With regard to your questions about SKYGLO , that we're completing enrollment, I can tell you without getting into the details, there is robust U.S. enrollment in that trial. I don't think we should be running into problems in terms of U.S. enrollment within that particular first-line study.
FGF21 combinations?
You mean, just to clarify, GLP-1 just generally or specifically to FGF21, sorry?
MASH being GLP-1 with FGF21, will you start combination trials?
We haven't basically provided that level of information yet, but as shown on the slide, we fully anticipate that there will be some kind of combination that we would need to do, but the exact timing we'll come back to you on.
We need to close the formulation.
In terms of co-formulation, that's been a general topic of importance for us because as you saw, combinations is a critical part of our pillar. All of our assessments have always included early CMC assessments to see many of the things that we have in our portfolio combinable. Happy to say that while we're doing our phase II study in parallel, we are also looking at co-formulation feasibility for Petrelintide and CT-388, for example. Similarly, we've looked at early for FGF21 and GLP-1 feasibility studies, for example. That's part of our thinking in terms of feasibility of co-formulations.
Can you please pass it on to Lisa?
Thank you. It's Louisa Hector from Berenberg. I had a question on the TL1A, just interested to hear where you see that fitting into the treatment paradigm. Perhaps for Manu on obesity, could you talk a little bit around how to mitigate some of the risks of running trials today, given potential dropouts on placebo arms and perhaps the expectation around the GI tolerability profile and how that could impact. Maybe just a comment on the obesity market and how you think pricing might work in terms of maybe an induction price and then a maintenance price, whether that's something you're thinking about. Thank you.
Maybe I can start in terms of the TL1A. I'm assuming the question has to do with where it fits into the treatment paradigm for MASH. Is that the question?
No, sorry, in IBD.
Oh, in IBD. Okay. We believe that [vixarelimab] has the potential to be best in disease for ulcerative colitis and Crohn's disease. Therefore, we fully expect that it will be early in the line of therapy as a best in disease therapy.
Yeah, in regards to the trials, thank you for asking that. We are acutely aware that the world that we live in now is very different than when those trials were designed five, six years ago. One of the things that we've been paying a lot of attention to is patient retention, because that's one of the core challenges, as you can imagine, right? Running against placebo, yes, it's important from a regulatory perspective, but it's not the most patient-friendly perspective. For that reason, in our trials, what we have decided is to actually allow for what we call long-term extension, meaning after a certain defined period, you collect your primary endpoint, then you convert all those that were on placebo to active. That allows for motivation, for retention, for doing what is right ultimately. We believe that can be a substantive benefit.
The second is partly related to your question, if I understand it, is in order to keep patients in the trial and motivated, ultimately, we fully recognize that we would need to go head to head. Differentiation is going to be important, and that is very much something that Morton and I think about every single day. I can't get into the details of exactly what a competitor, in what trial and what population today, but suffice to say that is the forefront of our thinking in the design of our trials, that we would need to differentiate and we would need to go head to head against the right and the appropriate competitors. Your third question was to Morton, I think.
I think this thing about a weight loss and maintenance phase is starting to evolve. Of course, the question is, will you use the same agent and the same dose and the same everything to induce the weight loss and maintain it over time? If that's the case, then you could also argue the price will be the same for the two. If you can use two different, you can say, agents or doses, then you would have the opportunity to charge a price for the weight loss phase and a different price for a different agent on the maintenance. I think the jury is still out if that will become the way obesity is treated over time. I think it's too early to comment on specific price points there. I think there are some underlying dynamics that need to play out to really consider such an approach.
Could we move here back to the front, please?
Thanks. Richard Vosser from JP Morgan. Maybe a question on Fenebrutinib to start with, please. There's been discussion on lots of the BTKs about changing the endpoint towards a disability endpoint. I just wonder whether you've had that discussion in terms of your phase III. Also wondering on the baseline characteristics, because as earlier patients are recruited, it's much more difficult to show a difference to a placebo. Thoughts there, please. Second question on 996. Lots of discussion on CT-388. Just wondering what's going on with 996. It seemed to have got lost in the presentation. Thanks very much.
I can address the Fenebrutinib question on relapse MSDs, which is what I assume you're asking about. At this point, we're not going to change the, we don't have plans to change the endpoint from analyzing relapse rate. We will, of course, look at disability progression as the secondary endpoint. We have high confidence that based on the phase II study, we should be able to show difference in relapse rates.
Do you have a follow-up?
Baseline characteristics, how similar are they to phase II? Are they early patients? Just wondering how that might impact the result.
Yeah, the baseline characteristics are relatively similar to other phase IIs. What's happened is, over evolution in time, the relapse rates just generally have decreased. Nevertheless, because of what we see in the phase II study, we still have high confidence that we'll see a difference.
On 996, yeah, I mean, it's true, and there's only so much you can pack into 15 minutes. While it may have been buried, it's certainly not in our mind space. It occupies a significant portion of our energy and time. We believe that 996, as I said in my presentation, has the potential to be differentiated and has the characteristics based on the data that we currently have to support that. We're currently in two phase II studies. Just to reiterate, again, it's both in people with obesity, with and without diabetes. All in all, it's about between the two studies, roughly 600 - 650 participants. It's a very robust phase II-B program.
We believe that data from that program will inform on the dose, on the regimen, and also, of course, trying to really creatively think through what are the other areas we can start to really differentiate from an endpoint perspective. All of that will then inform our phase III decision, which we, as I said before, anticipate in 2026.
Sachin Jain , Bank of America. I'm two on CNS and one obesity. On Fenebrutinib, whilst we're focused on efficacy, could you just update on the liver safety and your total package? I think there's been one confirmed case of Hy's law. Does that impact your regulatory sort of discussions if you get the efficacy? Secondly, on Trontinemab, I think the primary completion of the Trontinemab studies is mid-2028. Have you had any discussions or potentially an earlier look in the study on amyloid for a potential earlier filing? And then just one on obesity on CT-388. Any high-level commentary on the phase II interim that's driven the phase III start? Did you sort of get your dose maximization relative to safety? And have you told us what dose and titration regimen you're going to phase III with?
Thanks. Let me start with Fenebrutinib.
Yes, we've seen slight elevation in liver function. It's only in a couple of patients. They were mild to mild plus in nature. They were reversible and did not lead to any consequences. We did have one Hy's law case as you pointed out, but it is not of great concern. On the TRONTI, yes, as far as earlier filing, we of course are open-minded to really get this drug, promising drug to patients as soon as possible. Currently, we don't have plans to accelerate filing of that study. Having said that, the FDA has stated that amyloid PET is a validated surrogate biomarker.
Firstly, very important for us all to be reminded that the studies are still ongoing. The study remains blinded. What we have made the decision on is the extensive totality of the data. That's what I was trying to emphasize during the presentation. We've done a fairly long and extensive phase I, I-B program that has gone up to six months, essentially. Much of that data, you've seen it either in previous meetings or at the ADA this year. That totality of the data gives us a lot of confidence in terms of what do we really think is the trajectory, where do we really believe are the safety tolerability issues. We also believe that, which is a known fact at this point, going lower and slower in the titration will actually help us.
There's ongoing safety monitoring in any study that you would do, and that further reassures us of the profile that we anticipate. When you take it all together, that's the totality of the information on which we've made the decision to go to phase III. It's not because we've looked at the data or anything like that. Again, I want to emphasize that data remains blinded, and we need to keep that so for data integrity.
Has dosing been decided yet, or are you waiting for the phase 2 to decide the dosing in phase III?
Based on the PK data, the PKPD modeling, the information that we already have gives us confidence of what the doses, at least the dose limits, ought to be. It's not that we have to specifically wait, but we do want to wait to see what the final dose is, if you will.
Let me start around the mid-section. Is there anyone in the back? No, then we go to the front.
I call my UBS. My first question was on FGF21. In the 89bio studies, it seemed the placebo rate was quite low compared to some of the other studies that we've seen. I just wondered if you could comment on your thinking about the reasoning for that. You know, what gave you confidence when you look at all the data that's been presented that your FGF21 is differentiated from the others? The second question I had was on Fenebrutinib and the FENtrepid study. It was designed originally to show superiority. I was just wondering when you look at the data from FENopta on disability, and obviously, you know, the effect of OCREVUS from your studies, if there's anything you've seen in the clinical data to give you reason to believe that on 12-week disability progression, it might be faster acting.
I got the first part of your question about the placebo response, so I'm happy to answer that. What was the second part?
On FGF21, what makes you think your FGF21 is differentiated from the others in development?
Okay. The placebo response, one thing to keep in mind again is that's why it's kudos to the 89bio team in terms of how they conducted this study. It was very rigorously done. It's a biopsy-based study, the biopsy endpoint, and the way that the biopsy endpoints were read were very rigorous. That rigor allows to basically get to what would be a true treatment effect size. Really kudos to them for designing a trial that allowed us to get to that very clear result. In terms of the differentiation with others, I cannot get into the nitty-gritty, obviously, for obvious reasons, but on a broad level, it does matter whether you take the approach of targeting based on a ligand-based approach or a receptor-based approach. These are all ligand-based approaches.
We believe, again, that based on the data that we have seen and the data that's available, that's in the public domain, we do think that the data speaks for itself. It does look quite robust. The nausea and the vomiting rates are there, but it's very low. In fact, lower rates of diarrhea than others may have seen. When you take the totality of the efficacy, the tolerability, the safety, the convenience of dosing, when you put it all together and then the targeting modality, it gives us a lot of confidence that this will be differentiated and the potential for best in disease.
On the question of Fenebrutinib and impact on disability progression, because of the mechanism of action, where it's a dual mechanism of action, targeting B cells as well as microglial macrophages and the high CSF concentration we achieve, potentially this could have a very strong impact on disability, even potentially higher than OCREVUS. Nevertheless, if it is as equal to OCREVUS in terms of impact on disability progression, it's an oral molecule, so we think this would be a benefit for patients.
Thanks, Bruno. James Gooding from Goldman Sachs. Two questions. One on, again, not to belabor the point on the phase III design or potential phase III design for CT-388, but one of your competitors has gone down the traditional route in terms of escalating up to the highest dose for maximum weight loss. Another competitor has taken an approach in phase III of a more flexible dosing design. Where are you landing in terms of how you're thinking about that for the phase III design for CT-388? Are you going to start a cardiovascular outcomes trial straight away as well? The second question, on Fenebrutinib, the PKPD data that you've shown today highlights a stronger profile, but when you look at the phase II data for Evobrutinib, they also had an annualized relapse rate of 0.08 at the highest dose.
Have you interrogated that analysis to work out why they can still get such a low relapse rate? Similarly, given the baseline characteristics are similar, as you mentioned, have you run any analysis of where you think the Fenebrutinib profile will come versus the placebo or the BAJO arms in the failed trials for Evobrutinib and Tolebrutinib? Thank you.
I can take the CT-388 question first. We haven't, as I said before, disclosed the exact details, but we will in the coming months when we actually start the phase III program. What we have today disclosed is the fact that we are going to phase III. We're finalizing the designs. I cannot speak to the specificity of what you're asking, but in terms of principle, I can tell you that those are all very much front and center of our minds. Just as I mentioned to Louisa, which is that the long-term extension part of the design, the head-to-head component, the regimen is equally important for us. Providing the appropriate level of flexibility, appropriate level of maximization or optimization, if you will, of the tolerability profile, because that's another way we believe we can be differentiated. These are all going to be key considerations in the design.
At this point in time, not able to give you more details than that, but that's the general principle in which we would want to do these designs.
In terms of Fenebrutinib impact on relapses, as you saw, a really low annualized relapse rate, 0.06 at week 96, translates to one relapse every 17 years or so. It is a really dramatic reduction in relapses. The important thing to remember about Fenebrutinib is the benefit-risk ratio is a highly selective BTK inhibitor, which is the advantage it has over the other BTK inhibitors, and that is non-covalent. Potentially, it has a better benefit-risk profile.
BK, question from the right side. Yeah.
Thanks, yes. Justin Smith-Bernstein, two please. Firstly, on Zilebesiran, given the outcomes data, you said it's 2030. Could you just remind us on the LOE? The second one on Octove B. I know it's not an exact comp, a true cap, but can you just help us understand if we should be expecting the sales to inflect and if so, when?
You want to do the sales one?
Do you want a question?
Yeah, I can. You want to know the sales for October B?
When we’ll see the inflection.
I mean, as you remember, we have an entire program in the whole PIK-39 mutations, and we start with a very small patient population. That's probably for that population in a smaller CHF 100 million set. Once the other trials read out, which you're going to have in the course of this decade, we'll see those inflection points when we move further into the front line. We'll see the potential of it hopefully being in that CHF 1 billion -CHF 2 billion range as we have anticipated, coming then through once those trials come through.
Would you mind repeating the LOE part? We didn't quite get it.
There'll be a strong LOE, yeah.
There'll be a strong.
Sorry. I guess I kind of struggle with why Astra aren't doing an outcomes trial. You're doing an outcomes trial. You said today your outcomes data is 2030. Could you just remind us when the patent exclusivity expires on the drug? Or if I've got the wrong end of the stick and why you are, you obviously believe in outcomes and Astra don't, I'd love to understand why.
I don't want to misspeak on what the exact data is, but we can get that information for you. I think in terms of where we think the data will read out, just given the number of people that we just alluded to, 11,000 people, four-point MACE, it would have to be, they would have to be followed for at least 2.5 years minimum. That's the earliest, but it's event-driven, right? We would have to wait to see it. That's that kind of the end of the bookend, if you will, that we have provided, just to make sure that we have a sufficient number of events. We can get back to you on the exact LOE date.
It's front.
Hi, thank you for taking our question. Yihan Li from Barclays. Our first question actually is a general question on Alzheimer's disease. We saw the Trontinemab map showed a very promising and differentiated profile in Alzheimer's. We also know your competitor is running a trial for GLP-1 in Alzheimer's. We're just wondering what is your view on GLP-1's potential in Alzheimer's in prospective trials? Do you see a rationale for GLP-1 plus anti-amyloid combo for Alzheimer's disease? Our second question actually is a very quick clarification question on XTW7. You noted in your slides that you will run the phase III head-to-head trial with factor 8. We're just wondering, can we know which specific factor 8 will be used in the trial, like potentially L2B? That's our question. Thank you.
I'll take your last question first while people work through the early ones. We haven't provided yet the details. As you know, we have three phase III trials for NXT, one in the pediatric population, one comparing to factor 8, and one comparing to MLIBRA. All three are critical to establish the basis of evidence for this to become a standard of care. We do look forward to providing those additional details, but that's probably as much as I can say right now.
While Manu and Hideki are starting to draw at a high level, we have to see the data on the GLP-1 and Alzheimer's. If it happens to look good, we of course also believe that we have potentially a competitive set of assets in that space. We think Trontinemab could be very much competitive in that space. It will be interesting, but everything depends on the data and whether this, in fact, plays out.
Yeah, I couldn't have said it better. I mean, I would only add to that is that it's always good to remind ourselves that, you know, sometimes Alzheimer's, while it's called Alzheimer's, it's also called type 3 diabetes. Because the pathophysiology is very, very similar. You know, it's insulin resistance, neuroprotection, neuroinflammation. One of the other things that we had highlighted, worth highlighting again, is the synergy that we have within our own TAs. It's a very unique opportunity for Roche to be able to mix and match the portfolio to go after the most unmet needs. I think we'll all agree that Alzheimer's is an unmet need. Having that opportunity in a data-driven way is kind of how we will approach it.
Next question goes to Emmanuel.
Thank you, [audio distortion] Berkeley. Maybe follow up on NXT, but this time on the safety side. 2/ 30 patients in phase II seem clinically significant. Anti-drug antibodies is a fairly meaningful rate. Could you just talk a little bit about the potential impact that could have in the real world setting? How do you think that would be monitored? Obviously, the risk of a patient losing response could be pretty catastrophic.
Of course.
Sorry, maybe.
Go ahead. No, finish your—you have another question.
I just have a question on SUNMO in light of what's happened with STARGLO. Have you had any agency feedback yet on the lack of OS benefit at interim analysis and the potential importance of showing that at the final? Could you comment on the potential for an early readout on SKYGLO at interim? Thank you.
Sure. I think your first question was on the antibody drug antibodies for NXT. As you rightly point out, we've seen two patients with ADAs that influence PK. One patient was on the lowest dose in the dose escalation study and did go off study. The second actually remained on treatment and has had zero bleeding events. In fact, we're going to have an additional data cut of more patients to be shared at a future medical meeting. What I can say is the totality of events gives us continued confidence to move into phase III with that robust portfolio that we think will establish this as a standard of care and best-in-class treatment. With regard to the discussions, you asked about the feedback about STARGLO and the OS. I couldn't quite make it.
You mean CT-388, which I think you're planning for.
Yes. You're asking specifically about, the study was designed to look at PFS. That was its PFS. PFS was the primary endpoint as discussed with health authorities. It did achieve that robustly with a 59% improvement and a marked improvement in terms of months. The OS is a secondary endpoint. It's certainly going in the right direction. That's historically been what the health authorities have looked for. I think you ask about U.S. data. One thing that was presented in the presentation in July was the PFS within North America, which was a hazard ratio for PFS of 0.15. Certainly a result that looks like it's going in the right direction. We are moving forward with our plans and discussions with health authorities. Your third question was on.
I think interim of CT-388.
For SKYGLO?
Yeah.
To the first line?
I think you said the readout would be 2027, and any chance of an earlier interim?
Yeah. I don't think I'm really able to share more details other than the fact that the study is finishing enrollment. It's enrolled robustly. The feedback we get from TAEs was that they, you know, they're very impressed with the phase I-B data with a 96% CR rate, which gives us greater confidence. Right now, what we can say is we're expecting a readout in 2027.
Thank you very much.
Okay, I think just waiting final questions. We have to stop here, but I think all our key management will be available for the upper row, so you have another 30 minutes to drill down on whatever's on your mind. Let me quickly use the occasion here also to thank a couple of people because this event would not have been possible without the contribution of many. Just to call out here for the people from the IR team who have been working here since four or five weeks, I think day and night, some of them, to make it work. It's Jan Philipp Schwarzhand and Jan Bayar, who were responsible for both morning sessions and also managed the overall slide deck, and who were working, really, I can say, tirelessly day and night and throughout the last few weekends. It's Raphael Pavlovsky, who was responsible for the oncology deck.
It's Lauren Calm, who was responsible for the neurology slide deck, also preparing macro topics and keeping Q&A up to date for speaker preparation. It's Anita Tang, who was responsible for the immunology and ophthalmology slide decks and speaker preparation, and also managed the epidemiology slides, which you can find in the appendix. Julia Broyer and Sabine Born-Graeber, who were responsible for the CVRM decks and also all the alignment needed around it with all the external partners as well. This was quite a task. Last but not least, I want to thank the IR back office team, that's Melanie Wolf, Beatrice Hau, and Eva Losart for all the excellent organization. Of course, there are many other colleagues from within the organization and different departments who have contributed, which I simply could not all, you know, call out by name. This would be a long, long list.
We really want to say a big thank you from our end here as well. With that, I think we are closing the session. As such, you're welcome to stay for an upper row and get additional answers, whatever is on your mind. Thanks.