Welcome to our annual Pharma Day in London. I have to say it's a great pleasure to be here again on site and meet all of you in person. I'm looking forward to many lively debates and discussions which we will have, and several opportunities during the event here with the investor and the analyst community. However, I will go through the agenda and some housekeeping items. However, before we start, I would like to say the following. We at Roche would like to extend our greatest condolences to all the people in the U.K. for the loss of Queen Elizabeth, and we are with you in these very special days. Moving now to the first slide. Just taking you quickly through the agenda.
Our event, as you can see here, will be kicked off by Bill Anderson, our CEO of the Pharmaceuticals Division, who will provide his update on the ongoing business transformation, summarize past achievements, but most importantly, also outline our vision and show you the future building blocks which we need for success as an R&D-driven company, which is driven by the credo, wherever science will take us. The second session goes to Teresa Graham. Teresa is our Head of Global Product Strategy. Teresa will take us through the existing portfolio, summarizing the most recent event with regards to our key growth drivers. The most recent launches, which we are very proud of, first-in-class launches for Vabysmo in ophthalmology and Lunsumio in the hematology.
She also will mention, I think, some of the commercial opportunities which we might have ahead of us. We have a combined 30 minutes Q&A for the two morning sessions. This will be on stage with Bill and Teresa, and before we go into lunch at 12:00. At lunch, we will have all our key managers here, our key senior managers, present. Also, I think all our IR officers are around. I'm looking forward to taking any of your questions. I think after lunch, we will then start our deep dive into the pipeline. I have to say we have a focus, as always, on the late-stage pipeline.
However, we will also flag some earlier projects this time, as we are developing certain R&D focus areas. Let me also make a more general comment here on the totality of our pipeline. I think overall pipeline has hit a record high, in terms of the depth and the breadth which we are having now. We have like an industry-leading pipeline, just to point out, with 85 NMEs currently in clinical development, thereof 10 NMEs currently in late stage. I think what is also interesting to see is the growing portfolio of platform technologies. As you see, the latest additions to this platform to these technologies are either in-house developed technologies, but also, I think technologies which we acquired for business development.
If we go to the first afternoon session, this will be given by Levi Garraway, our Chief Medical Officer and Head of Global Product Development. Levi will take us through the oncology pipeline, providing updates of key late stage products. Among these products, there are Tiragolumab and Giredestrant. We just presented the update on the ESR1 mutant data at ESMO two days ago. He will also take us through some of the more recent additions to the pipeline, to the late stage pipeline, such as our PI3 kinase inhibitor inavolisib or our KRAS inhibitor. The second section for the afternoon will be held by Paulo Fontoura. Paulo is our Head of Clinical Development for neuroscience, immunology, ophthalmology, infectious and rare diseases.
Paulo will provide us with updates on both the neuroscience and the immunology pipeline. There is, I think, topics in there, like for example, the six monthly subcutaneous formulation for Ocrevus, which is to come, and also, an update on our gene therapy program in Duchenne. These are both projects where we expect pivotal data actually to come in next year. Finally, for the third and last session, we will end on ophthalmology and providing you an in-depth look on our growing ophthalmology pipeline. This will be handled here, over here by Nilesh Mehta. Nilesh is our Global Franchise Head Ophthalmology, and we will also use this occasion here to, you know, he will give a presentation and recapitulate, some of the, designs of our pivotal Vabysmo studies.
He will also, I think, point out some recent external real-world data which are coming in on Vabysmo. Of course, he will also go into the pipeline, some interesting assets, we recently added, like for example, our IL-6 anti-IL-6 monoclonal antibody. After the second round of presentations, we have then a second Q&A. This will be with all speakers on stage. Basically we have the end of the event, but you are of course invited to stay longer. We have a buffet reception afterwards, so there's at least another 30 minutes where you can ask any questions, which have not been answered by then. I think at the buffet reception, everyone again will be available, I think with the exception of Bill. I think you have some other appointments.
One final comment here from my side. Please let me point out that we have prepared also a short feedback survey. The link to the survey will be shown to the participants in the webinar at 10 minutes before the end of the event. Participants in the room will receive a message in the app with a link to the survey. We would very much appreciate if you could provide us your feedback, as this will always, you know, we always strive for improvement and this feedback will help us to for setting up future events. With this actually, I would like to hand over to you, Bill, and to provide us the update on the strategy.
Thanks, Bruno. Welcome everyone. Really great to see you all in person. Many of you, I haven't had a chance to see in person since 2019, and so it feels really good after so many Zoom calls and sort of such distance. Bruno, I appreciate your comments about the passing of the Queen and I think, obviously, our condolences go out to all of our British colleagues. But I think it's fair to say that not only was the Queen a pillar of strength and resilience for the British people and for the Commonwealth, but I think she also stood as a real sign of integrity and character and peace in a world where many leaders are not following that model.
I think for that reason, we all mourn her loss. Okay. Today, you're gonna hear a lot of exciting details, a lot of cool science, a lot of, I think, really interesting things about what we're doing at Roche to prepare for the future and to deliver for patients. But in the midst of all of that, I wanna make sure that we don't lose sight of the big picture. Let me just propose three key takeaways that I hope you'll see over the course of the day. First is just the tremendous growth we've had in our portfolio. Growth and, at the same time, diversification over the last years.
We have been able to not only absorb CHF 13 billion in losses biosimilars , but we've actually been able to grow over that same period 9% by adding CHF 15 billion from new products. In fact, that has basically made us the number one company in the industry in terms of the value in our portfolio from new products, and I'll show you some evidence of that. We've also got major readouts. We've got momentum. We have major readouts coming for breakthroughs in major neurological diseases like Alzheimer's, like muscular dystrophy. In the next five quarters, we're gonna see phase III readouts in both those diseases, as well as major potential breakthroughs in adjuvant cancer, and in many other diseases.
I think that not only have we come through this era of biosimilars with strength in the top line, but we've got a portfolio that is really well positioned for both the short, mid, and long terms. Secondly, we've made a once-in-a-generation additional commitment to R&D during the same period. I think that's really remarkable. I don't think going back, say, five years, people thought, "Oh, we could weather the biosimilars, we could grow sales, and we can make a major additional investment in our commitment for the future, for patients." We really feel great about that. Almost CHF 3 billion in new annual investment in R&D over that period. We're securing the future, not just for patients, but also for our shareholders.
Third, we've made a major transformation in how work gets done, and that relates to everything from what the individual jobs of employees look like. They've gotten much bigger, much broader, and more interesting and fulfilling. That's led to much greater productivity, but we've also implemented digital tools and new techniques all the way from R&D through the whole value chain. We'll talk about that as well. I think the bottom line is, we believe we're extremely well positioned for the future, better than ever, and we look forward to making that journey together and for having you all as part of that. Let me get into the content. I'll start with a bit of an overview at the high level.
I mentioned this fact that we've been able to grow and diversify. Again, if I was with the company in 2012, and I have to say, I don't think we pictured that we could be this successful. We were committed, and we had passion, but we've translated that into continued growth and, again, amazing revitalization of the portfolio. I would point out that from 2012 to 2017, as a total Roche, we grew 17%, and then we had the biosimilar impact, and we grew another 23% in the next five years. I feel really good about that. I think that's amazing delivery on our strategy. We set out an ambitious strategy. We've delivered on it. You can see we're much better positioned with respect to the breadth of the portfolio now.
HR went from being over 40% of our total, and it's now less than 10%. You can see really advances in every other area. At the same time, as I said, we managed to grow pharma 18% in that first five-year period and 9% in the next five-year period, despite absorbing CHF 13 billion in biosimilar losses. That I think is the power of a strategy that you execute with diligence and persistence. I think that, you know, hopefully you know us for that we're looking far out ahead, we absorb the speed bumps along the way, and we keep marching. This is a little more detail in what that's meant.
As I mentioned, we've plowed additional CHF 2.9 billion per year in R&D in pharma alone, and this is basically what that's paying for. You can see on the left, our projects in phase III in registration, which is kind of the best indicator of what's coming for the midterm sales dynamic. You can see, you know, it goes up and down because, mostly because projects graduate. Sometimes they fail, but they also graduate into the market, and they come off the list. In the last year, we've graduated three into the market, and as you can see, a nice upward trend over time. We've got more coming.
If you look down and along the bottom in terms of additional indications, we're at 51 right now that are in phase III in registration, which is an all-time record for us. You can see also the number of NMEs in phase I, phase II, phase III, and across the whole portfolio. I think we're incredibly well-positioned. Not all of those are going to be big breakthroughs, but some of those are going to be major breakthroughs and are going to be what's fueling the future of our financials and our ability to invest. Now, some people are asking, "Okay, you've weathered the AHR storm, what about other biosimilars and other losses of exclusivity?" We put this together. We hoped it would be helpful. Let me explain this slide because it's a little bit complicated.
On the left, the bar on the far left is a listing of all of our medicines that potentially could have biosimilars coming in the period between now and 2025. You can see the total sales. This is basically the consensus numbers for 2025 for those products. You can see that there's sort of a gap, a loss of sales potential in those products of about CHF 7.5 billion. The list kind of in the middle there is the list of basically all the in-market products and then some of the pipeline, and you can see that adds up to growth of about CHF 18.6 billion.
Essentially, we have about CHF 18 billion, CHF 19 billion of sales projected to offset the CHF 7.5 gap, which I think we feel really good about. We have an opportunity even to beat that. Let me point out a couple of other things. If you look, for example, at the pipeline, a total of CHF 4.2 billion from the consensus numbers, Gantenerumab in the consensus is CHF 1.1 billion, okay? We're really excited about Gantenerumab, and we're going to be talking about it today, but we are not dependent on Gantenerumab. If Gantenerumab goes away, then the model goes from CHF 18.6 to CHF 17.5, all right? I think that's important to note. We are not a one-trick pony.
We have a rich pipeline, and we have lots of opportunities to benefit patients beyond Gantenerumab. Likewise, you can see Tiragolumab is in at 0.3, so CHF 300 million out of CHF 18.6 billion. Obviously, those are nearer-term readouts, and they garner attention. This is, I think, the long picture. There's also a lot of potential upside. If you look at the NMEs that really aren't playing any significant role in that CHF 18.6 billion, you can see a number of things, bispecific antibodies, our KRAS molecule, which has the potential to be best in class, and we'll be talking about all those in more detail.
I think at the big picture level, we believe there's a lot of room or a lot of reason for optimism for strong growth in the immediate years ahead. All right. Let's now back up a bit to the fundamentals. You know, what is our big picture view of the world, and how are we going at sort of capturing the opportunities we have to help patients? I think most of you have been along with us on the journey enough to know we set out a very bold vision several years ago. We said, we're going to deliver twice as many medical advances to patients and which by the way, that's saying something. That's not easy to do. R&D is not getting easier.
You know, advances, fundamental breakthroughs are not easier to come by, but we're committed to doing this and doubling our rate of breakthroughs over the next decade compared to what we did in the past decade. But we said, that's not good enough. We also need to deliver at a lower cost to society. We're targeting internally, we're targeting half the cost to society, and we're going to do that by having more breakthroughs. Some of that can be through price, and we'll talk about our responsible approach to pricing. But a lot of that can be delivered by doing things like targeting diseases early, stopping diseases, curing diseases, instead of, for example, requiring lifelong treatment. These are the opportunities that we have, we believe that Roche can make the biggest difference in healthcare.
Kind of peeling that back a little and saying, you know, what are the fundamentals? You all know about the big trends in healthcare. You know, the needs are only getting greater. The fact that healthcare systems are under strain, budgets are under strain, and so we believe there's a compelling need both for better therapies, but also that economic bottom line. Patients are demanding more information. They're taking more action themselves. Telemedicine is a new reality. That also means there's a lot of opportunities. For example, we're using telemedicine to improve the possibilities for patients in the poorest countries in the world to get access to our medicines. You know, often in poor countries, the only barrier is not things like price. It's the lack of specialists who are qualified to administer the kinds of therapies that we're producing.
We're using innovative partnerships between developed countries and emerging countries to create sort of virtual specialists in the poorest countries in the world. This is a whole range of things we can do, ranging from the most developed countries to the poorest. This is part of our access commitment. Again, I'll talk a little more about that. COVID and the pandemic have really just put all of these underlying trends; they've sort of accelerated them and made them even more important. As I mentioned, our vision of doubling medical advances, of providing more patient benefit, we believe is exactly what the world needs, and to do that at a reasonable cost.
In order to achieve that, because when we set out on this vision three years ago, we sort of said, why should we believe we can do this? Do you know, why is this reasonable? It's not like we weren't trying to work hard in the last decade. How are we gonna double things? We believe fundamentally that large organizations can be made much, much better. Many of you, and I've talked to many of you over the years about this, and I've asked you, like, how is it at your firm, right? You know, do you have bureaucracy? Is everyone able to punch at 100% of their weight, or are people held back by the system, by the processes, by the hierarchy? We've made a huge commitment on this.
Again, I think this is something that's characteristic of Roche. We are not a flavor of the month company. You've been hearing me. Some of you, I've been talking with about this for six years. When I was CEO of Genentech, we began this journey of transformation. We called it a transformation because we knew we could get much better. We didn't know how to do it. We said, "You know, we're gonna have to start by understanding, like, what are the best companies in the world doing?" We didn't find examples of that in life sciences, but we found a handful of leading companies in other industries who were trying really fundamentally new organizational approaches. We began that journey about six years ago. It has swept across all of Roche, and it's making a major dividend.
We'll talk a little bit more about that, but I wanna share some of the results of this. For example, one of the first places we started was in our technical operations group, and we've now increased sales volume growth. If you look at that period from the first half of 2022 or from 2016 to 2022, so that's six years of transformation. We've grown sales volume 76%, and over the same period, headcount is down 19%. All right. If you do the math on that's a doubling in productivity per employee. And again, that's great for the bottom line.
That's great for our ability to deliver for patients, but it's also great for the people because, you know, we believe if someone's gonna invest their whole life at Roche, we deserve or they deserve to make that a good investment of their time, and they're not wasting time in a bureaucracy, but they're able to deliver the full impact of their talents. 200% increase in productivity in PT. At Genentech in the U.S., sales growth of 25%, headcount lower by 22%. That's a 60% increase in sales per person. Again, this is about helping people invest their lives in things that matter. Pharma International, a 50% increase in sales per employee. In pharma in China, over 200% increase in sales per employee.
In PD, this is one of the areas that's the hardest to tackle because drug development doesn't lend itself to simple solutions. You know, when you're developing medicines in you know, 30 or 40 different diseases with all different kinds of requirements, but we're chipping away at it. So far, we've made about a 9% increase in productivity, and I think you should expect more to come there because we're really excited about our opportunity to deliver higher productivity also in product development. What's that meant in terms of bottom line and our ability to invest? This is a comparison. I used 2017 as the base year because that was the last year before the major biosimilar impact on AHR. In fact, that was peak sales year for AHR at about CHF 20 billion.
Basically what you can see is we've managed to weather that CHF 13 billion in sales of AHR, CHF 13 billion loss. We've been able to grow sales 9%, but at the same time, we've been able to increase R&D by 32%. Again, this has been a major lift for all the leaders and all the people at Roche. This was our commitment, and we told our employees then, we said, "Look, this is gonna be hard. We're gonna be changing everything. We're gonna change the way we do business. You're gonna have a different relationship with your manager. You're gonna see your manager a lot less." We have a lot fewer managers, okay? We hire the best and brightest people in the world, and they don't need a lot of management.
You need to have, you know, you need to have clear frameworks. People need to understand the vision, and then you need to get out of the way and let them go. We've been able to increase that R&D investment in that major substantial way while absorbing the biosimilar loss, and I think we're really proud. This is just numbers, but what that took to deliver, we're really proud of not only what we've learned along the way, but how that positions us for the future, and we're not done with this. I mentioned digital. It's also becoming an increasingly important contributor to how we do things. I won't go into this in detail right now, but I will just say this is happening in research, major changes in the way we develop, invent new drugs, new pathways.
It's happening in clinical development. We're working on virtual clinical trials on much more streamlined data flows from investigation sites into the databases at Roche. It's having a big impact in the production and supply chain as well as our medicines and enabling us to do things like truly personalized therapies, like our cancer vaccines, that's our partnership with BioNTech. Every vaccine for every patient is different, but it's not autologous. You know, it's not. In other words, we're not using patient tissue to create a drug, but we are using patient tissue to determine the composition of each vial, which is really extraordinary. In the future, we're also looking at things like digitally assisted therapeutics. I think this is a big part of what we're gonna be in the future, and it's starting to deliver already. Customer engagement.
I mean, we have totally flipped this on its head. Starting in Genentech, where we made a major change. We said, "Hey, the old model, the old push model, where pharma has just got, you know, multiple sales forces in doctor's offices and in major institutions like Memorial Sloan Kettering or MD Anderson, where there might be literally over a hundred employees from the company, we've taken that way down, you know, reduced that by a factor of three to five and really put a focus on what does the customer need, not what does the company want to convey." That's also paying off in big ways, and I think you can see that in the success of our launch products over that period. We're also spending a big investment to rejuvenate our manufacturing sites.
This is a global network that's very resilient. It steadied us incredibly well through the pandemic, where we were able to deliver millions of doses of Actemra, of Ronapreve, at the same time that we basically kept all our core products online. I mean, we did not have any major stock-outs in the whole portfolio, other than being short on COVID medicines at the worst of the Delta surge. This is something that we believe is a vital part of who we are. We had that capacity that allowed us to do those partnerships and allowed us to step up that COVID production, and we wanna now invest for the future to make sure we're ready in for whatever comes. I mentioned our funding for R&D.
Let's talk a little bit about what that looks like. For example, we have, as you know, we have a lot of these innovation engines. We think that's really important. A company our size, it can never be monolithic. The trick is, how do you have a bunch of independent R&D sites, but how do you capture kind of the best of everything? Again, this is a major change, because if you go back five years ago, we had a number of innovation engines, but those innovation engines had, I would say, pretty big walls between them. They didn't collaborate. They didn't talk. That wasn't even necessarily seen as a virtue, collaboration. We have totally changed that. We brought in new leaders that are both, you know, leading scientists in the world, but also highly committed to collaboration.
What we're doing now, you can see this in things like our big investment in computational biology and analytics at gRED, which will be used to benefit all the other innovation centers. Likewise in pRED, we have a major investment in human tissue modeling. This is like organoids and doing preclinical work in organoids instead of animal models, so that we have basically lower cost, faster development, and hopefully, more accurate. That investment will benefit not just pRED, but will be used in gRED, in Chugai, at Spark. I think this is a key part of why we believe we can be successful and even more successful in the future. This is also leading to an incredible diversity of approaches.
I think we probably have the most platforms of any company, and you can see now probably some of the latest additions I would point to. If you see sort of in the middle on the top, the cyclic peptides. This is the Chugai Center of Excellence in Cyclic Polypeptides. This is a class of drugs that was basically. Well, they're not even I can't even call it a class of drugs because they don't exist. This was something that a lot of scientists and chemists hoped would be an important contributor to medicines over the last, say, 50 years, but it was never attained. You know, the potential was never realized because we couldn't make drugs. We couldn't make molecules that hit the targets and had drug-like properties. That's all about to change, I believe.
Chugai, this is kind of characteristic of, maybe of Chugai in particular, and the Japanese in general. They have an incredible stick-to-itiveness. You know? They're not willing to give up, and they've been working in this for well over a decade, and now they've got a whole line of molecules for a number of different disease targets. The leading one is a pan KRAS inhibitor, and it is now showing drug-like properties, and we're super excited about this. For the science geeks in the audience, I hope you can appreciate how important this is, because to have a cyclic polypeptide that's highly bioavailable and is hitting the target is a really exciting development, and there's many more of these to come.
Another one I'd point out in the bottom right, and Levi will say more about this. Or actually, where is it? No, top right. Allogeneic CAR-T-cells. Many of you know, we've sort of stayed out of CAR- T for the most part up until this point. We got a lot of questions about this. You know, are you missing out? We always said, "No, we think it's really important to be able to put the medicine in a vial and ship it, as opposed to bringing patient tissue in and processing it and hopefully getting it back in time for a patient to actually receive the benefit." We believe now is the time to invest because of the maturing technology around allogeneic CAR-T, which basically doesn't rely on patient tissue.
We've made a significant investment just this year in a company called Poseida, and look forward to hopefully bringing some promising therapies there. All right, this brings us to our partnering approach. I think you all know that Roche, I'd like to say we have partnering as a key part of our strategy, but we're not partnering-dependent the way some other companies are. We have massive internal innovation, but we know that 95% of the innovation in life sciences is not happening inside Roche, and we need to tap into that.
This is sort of a list of some of the more important deals that we've made over the previous years. What I want to highlight is this is sort of on the right, you can see this is kind of the evolution. We had a flurry of deal-making activity in 2019 and 2020. This was in large part because of our big infusion of new R&D funding. We said we're making a generational investment, a once in a generation move to significantly step up the early research and development. Those investments in 2019 and 2020 will be paying off in 2023 and 2025 and 2027 through the course of the decade. Last year we exercised, I think, extreme discipline.
I hope you know that of Roche, is we're not gonna chase after whatever the industry is doing. We were patient. We used discipline. Last year, the prices, the asset prices were crazy. We would go into a deal thinking we'd be willing to pay 100, and the biotech company would say, "It's worth CHF 1 billion," you know? We're like, "This isn't gonna happen." We did two significant deals last year. We did nin e the year before and eight the year before that, okay? That's discipline. This year to date, five, okay? We're pretty much back on track towards our historical average because asset prices. I would put it this way. It's not a bargain.
This is not bargain hunter time, but we actually have the ability to find reasonably priced deals, partnerships that make sense, and we're doing that. On the right, I think is a very important chart, and I'll explain why. It's probably no surprise that you'd see we're the leading investor in R&D, and that's borne out on the chart on the right. On the left, in the gray bars is the M&A activity, okay? What you can see, and this is over five years, so it's kinda averaged out. You can see, I think maybe a way to think about this is the difference between paying it up front versus paying in arrears, okay? Because when you do M&A, it's not hitting your P&L immediately.
It's hitting your P&L over time in the form of amortization. That amortization takes up space on the P&L that is not available for future investment, okay? As you can see, we have really the smallest proportion of M&A spend of any of the major pharmas, and this means we have the lowest amortization. So when we're spending, if you look at that total, that's all paying it forward. You know, we're not paying for stuff that's already in the market. We're paying for the stuff that's coming in the future. For longtime investors, I think this is a really important fact. Again, we're not always gonna hit on every medicine, but over time, with our discipline, we're gonna hit on a lot of big medicines.
I think you'll see that we can, because we've paid it forward, we can then invest for the next generation. We're not paying for the stuff that's bringing in revenues today. I mentioned the major step up. I think this is an important chart. If you look, before we started this in 2017, we were spending 53% of our operating expenses on R&D and 47% on everything else, okay? Already last year, we were at 60/40, and we're continuing that trend, all right? You could say, "Okay, great. That's great, Bill. You're spending lots of money, but what's that getting you?" I think over time, again, we've shown that we will deliver innovation.
The chart on the right, I think is a really interesting one because this one is showing, in the blue, what is the NPV of recently approved NMEs. NMEs approved in the previous five years, what is the NPV of those. You can see we have by far the biggest number on that, and that's out of a share of total enterprise NPV. I think, well, hopefully, that's useful to you all in terms of the way you look at Roche, but maybe the way you look at some of the other companies and how we stack up in terms of strategically and over time.
Let's talk briefly about some of those new focus areas in R&D, and you're gonna hear a lot more about these, so I won't take any length of time. Hematology, this is an area of great strength and depth for Roche, and we believe there continue to be some very important opportunities to benefit patients. You can see we have a really broad pipeline. I mean, we have in-market molecules, small molecules, antibodies, ADCs like Polivy, Bispecifics like Lunsumio. As I mentioned, we've now entered the CAR-T space with an allogeneic CAR-T partnership. Again, Levi will talk more about that. Ophthalmology. This is an area where we think there's an opportunity to really change the way patients are treated. Right now, you basically have a few medicines.
They're all targeting the same diseases, and they have very similar MOAs. Now, with Vabysmo, we've brought a new MOA to bear. We have excellent data, and as you'll see, as we continue to roll out data over the quarters, Vabysmo is being adopted very rapidly, not just in America, but in many countries in the world, in Japan, in the U.K., and the rest of Europe rolling out very soon. We have an opportunity to change the paradigm to bring in biomarkers, which we're very active in, and these can be biomarkers that are based on tissue, and aqueous samples, but also based on basically optical biomarkers that can advance the treatment choices both in terms of the timing, choice of treatments, and frequency. Moving on to Alzheimer's.
We're very pleased to have the opportunity to get the data. You know, this is something we've been waiting for. I've been involved in our Alzheimer's programs extensively since 2012, so 10 years. Believe me, you know, we've got a lot of heart and soul tied up in Gantenerumab, not because we're financially dependent on it, but because the same reason many of you care. Personally, I've lost an aunt to Alzheimer's disease, my mother-in-law, and it's time we did something for our parents, our grandparents. We've got an opportunity with Gantenerumab. We're following that up Brain Shuttle Gantenerumab. For those of you who aren't aware, Brain Shuttle technology, which has been pioneered in pRED, is something to assist getting.
Basically getting the active part of the protein across the blood-brain barrier so that we don't have to dose so much systemically in order to get the necessary concentrations in the brain. We have promising phase I PK data with our Gantenerumab Brain Shuttle, and we're looking forward to bringing that also to other therapy areas like MS. We have other MOAs, for example, anti-tau antibodies. You know, we'll have to see, but we're still hopeful that there could be an impact for tau. We're also pursuing with the diagnostics division, both blood-based and CSF-based diagnostics, that could be companion diagnostics or at least lead us to know, you know, who is likely to benefit from treatment and who can be screened out. Sustainability, I know many of you are particularly interested in this.
This is something that's in our DNA at Roche. It dates back to the founding family's involvement with entities like the World Wildlife Fund, and we've been, as you know, number one or number two in the Dow Jones Sustainability Index for many years. This is something that I just want to highlight one angle on this. The biggest thing we can do for sustainability, by the way, is deliver that vision of better medicines, earlier treatments at less cost to society. I hope we could all see that that is the most important contribution Roche can make to sustainability. There's also a how we do it.
For example, in pricing, I think we have a really good balance of price for funding tomorrow's innovation, but price that ensures patient access. Recent examples of that, you know, I think in the U.S., these are our average discounts on some of our most important products we've launched in the U.S. compared to the standard of care, usually a standard of care that we've beaten. You can see average discounts between 20% and 50% on major products. Also price increases, which are important, and we've been at or below inflation in almost every year. I again, I think it's just part of who we are. We believe we want to deliver great medicines, but we need to do that at reasonable prices that allow for broad access. All right.
Let me finally turn to the kind of near-term outlook in terms of readouts. There's a lot on here, so I'm gonna be brief. Some of the things that are remaining this year, three adjuvant or neoadjuvant readouts for Tecentriq, important to watch. We've got an opportunity, obviously Gantenerumab to change the world in Alzheimer's. I'll remind you, not only is Gantenerumab potentially a breakthrough in Alzheimer's, but it's a sub-Q injection, which can be done in the home. That's a big deal. I mean, monthly IV infusions for elderly people who you know may have issues getting into a clinic to get an infusion, I think that's a very important thing. Three major readouts in ophthalmology with Vabysmo and Susvimo, so continuing to bring it and we're.
That's not the end of the sight on ophthalmology. In 2023, a couple of important Tiragolumab readouts, including SKYSCRAPER-01, which we'll have an additional interim and final readout on OS for SKYSCRAPER-01. Tecentriq and Alecensa, more adjuvant readouts next year, including the Alecensa readout in adjuvant ALK-positive lung cancer. Alecensa is the leading therapy for ALK-positive patients, and now we'll have the first data in a major adjuvant study in that setting. Moving down, you can see Venclexta plus azacitidine in first-line high-risk. This is myelodysplastic syndrome, which is an important indication and another opportunity for Venclexta to expand its impact. Crovalimab, this is our medicine targeting PNH. It's a complement inhibitor, and these are the first global studies.
We had a positive study with Crovalimab in China this year, readout. Now we'll have the phase threes and the global studies next year. Two bispecific antibody readouts in second line and later DLBCL. This is a big deal, a sizable indication. We have two shots at it, and it may be that we have one as a clear winner, and it may be that we have basically differentiated drugs based on efficacy and safety. We're looking forward to that, and we believe we'll be the first with these indications. There's competition here. We think we have a good shot at being first. I mentioned muscular dystrophy with our partnership with Sarepta. A big readout late next year will be the full phase three data, highly anticipated. This could be the biggest breakthrough ever in muscular dystrophy.
We have rights to outside the U.S., and I think this is. If this works, this will probably be the largest gene therapy. Maybe for a long time, and so we're really excited about that one. Ocrevus, which is our MS leading therapy, we have our first sub-Q phase III data next year. That will be the data we can file. This will be the opportunity for patients to have a twice-a-year sub-Q Ocrevus. So I think we can all understand how important that is. Finally, I would highlight TNKase, which is one of our older medicines. We have a study to extend the window. Right now, patients with stroke can only get TNKase if they get it in the first four hours.
This would take it from 4.5 to 24 hours, which is more than a doubling of the size of that opportunity. Really exciting pipeline in the near term. Teresa will talk more about some of the readouts that are beyond that, but I wanted to tee that up. In summary, as I mentioned, we continued to drive growth and diversification. We got major readouts in the near term. Second, we've made a once-in-a-generation step up in R&D, and that is fueling a high level of innovation across our early R&D engines, which is going to fill the pipeline for the second half of this decade. Finally, we've had a major transformation in how work gets done that's leading to high fulfillment for our people and acceleration of progress.
I hope you agree that we're very well positioned for the future, and we look forward to sharing more of that. Now I want to welcome my distinguished colleague, Teresa Graham, our Chief Marketing Officer and-
I just got a really big promotion.
Head of GPS. Teresa.
Thanks, Bill. Thank you. Well, you took a lot of my talking points, so maybe we can make up a little bit of time here. As Bill mentioned, my name is Teresa Graham, and I'm the Head of Global Product Strategy, and it's actually really exciting to be back in London in person with all of you and to see so many familiar faces actually three-dimensionally. I didn't know some of you had legs, so that's actually really nice. I'm going to start by just introducing a little bit about where our portfolio is at the moment. In 2022, we had the opportunity to launch two new molecular entities, both Vabysmo and Lunsumio.
This is important not only because of the benefit that these two drugs actually provide to the patients that they treat, but also because it's our second and third first-in-class bispecific molecules following Hemlibra. Soon we'll be launching our fourth with the filing of Glofitamab. This really entrenches us as leaders in the bispecific space and continues to give us more information about how this modality can help patients in additional indications. Bill talked about the diversification of our portfolio, but I wanted to take a little bit of a step back here and just really tell you what that means for the near and midterm outlook for Roche. You can see by half year 2022 where our absolute growth was coming from, and this is actually really important. Our growth is coming from Hemlibra, Ocrevus, Evrysdi, Phesgo, Tecentriq.
These are drugs that we have approved that are in the market today that we are currently commercializing, and really execution and future growth is in our hands. That's where you want to be. You also note that we are increasingly less dependent on Herceptin, MabThera, and Avastin, as Bill pointed out. I can confirm guidance. We're looking at about an additional CHF 2.5 billion in erosion this year. For the most part, we've now got the AHR biosimilar cliff behind us, and we're really looking forward into a new era with a much more diversified portfolio. In 2022, we have hit an all-time high of 15 blockbusters annualized revenue in the portfolio with an additional two coming in, both Phesgo and Vabysmo, which is just sort of on the uptick here.
If you look at the right hand of the slide with the half year 2022 sales split, again, this is the diversity that we've been talking about coming for quite some time. Oncology is now 48% of our overall sales, followed by, neuroscience at 17% and ophthalmology and immunology at 16%. We will continue to see that diversification happening as all of the new molecules that we'll talk to you about start coming online. Just a really exciting place to be. Now let's actually look at some of our individual treatments, and I'm going to start, not surprisingly, with oncology. It is Roche's goal in oncology to be the leaders in bringing a cure to cancer. Our goal is to take groundbreaking science and to turn it into medicines that can actually materially advance patient care.
We currently have 20 marketed products in oncology, but we've got a significant number of oncology products that are currently marketed. Last year alone, we helped 1.25 million patients around the world, which is just staggering. We have 150 clinical trials currently ongoing in oncology. 60 of them are in the late stage, and 24 of them are in early-stage cancers, which is important because that's where we have the best opportunity for cure. We have a tremendous investment here, and I think as Bill mentioned earlier, one of the things that's so exciting about that is it means we're not overly dependent on any given molecule or any given modality. We really have a lot of opportunity across all of oncology.
Let's get started with Tecentriq, because I think Tecentriq actually shows you that strategy in action. You see on the graph on the left-hand side of the slide that we continue to grow, very favorably with Tecentriq. Double-digit growth, 13% growth so far this year. Our sales breakdown is very much as you would expect. We have our biggest sales where we have differentiated data. The expansion of small cell continues, as does HCC as we continue to gain approvals and reimbursement in both the E.U. and Japan. Much of our near-term growth is driven by adjuvant non-small. We'll actually talk a little bit more about that in a minute. Bill did touch on the positive readout for Tecentriq subcut.
This is very important for the molecule overall, reducing that treatment time from 30 to 60 minutes down to three to eight minutes. Think about what that means for the office, think about what that means for the patient, particularly as you start moving into earlier lines of therapy, that becomes really, really important. Now let's spend a little bit more time on Tecentriq in adjuvant. We were obviously the first-in-class treatment in adjuvant non-small cell, and that launch is going very strong. The U.S., which was our first launch market, where we have the most data, has about 60% market share to date, and that is growing at 20% quarter-over-quarter in the last two quarters.
Testing rates are exceeding our expectations, up from 40% to greater than 80% since Tecentriq was approved, which means a lot more patients are getting the opportunity to get into that funnel. We're approved in more than 55 countries, with E.U. approval achieved June first, and that means that we're gonna start seeing reimbursement come online, and we'll start seeing adjuvant grow even more significantly. Where we're excited about taking Tecentriq next is actually into this peri-adjuvant setting. What is peri-adjuvant treatment? We're all familiar with neoadjuvant treatment before surgery. We're all familiar with adjuvant treatment, which is treatment after surgery. That's where IMpower-010 sits. Peri-adjuvant treatment is an area of great interest for the physicians right now, where you actually treat both before and after surgery.
It's four courses before surgery and 16 courses after surgery. The thought is that will actually allow you to get the best possible outcome for patients. That data, IMpower030, is expected to read out later this year, and it gives us the opportunity to be first in class in peri-adjuvant, which would be a really exciting step forward for Tecentriq. Again, this is an area where the subcutaneous formulation would be really meaningful. Now, one of the reasons that we're so excited about our investments in early cancer is it actually gives you the best opportunity to have a great outcome for patients. That is similarly true when you talk about targeted therapies. We've been very intentional about building a leading portfolio in multiple oncogenic drivers within oncology.
You can see in non-small cell lung cancer, we currently have eight of the most common modalities represented in our portfolio. Also within targeted therapies, we continue to move into early disease. Bill mentioned the ALINA trial for Alecensa and adjuvant ALK-positive non-small cell lung cancer. Alecensa is the standard of care in ALK-positive treatment today. This would be an important new extension for patients. We continue to think about how all of these molecules could be further enhanced in a pan-tumor environment. We have a TAPISTRY basket trial, which is currently ongoing, and then our investment in developing the most common mutations. We've talked about KRAS. Levi will talk more about that this afternoon, as well as the PI3 kinase, which is in 17% of cancer patients, which are two considerably larger opportunities.
I think many of you are aware that commercializing in some of these smaller opportunities can be more difficult, but we're very encouraged that NGS testing rates are actually dramatically increasing globally. As new kinds of testing starts to come online, hopefully we'll be able to identify these patients with increasing frequency and allowing them to get on therapies which potentially allow them to have the greatest outcome for their treatment. The FMI liquid biopsy was approved. This again is groundbreaking, as about 30% of patients have insufficient tissue for testing. It means you would never even know if you have a tumor that could be treated with one of these medicines. The B-FAST trial utilizes that liquid biopsy that's underway, and again, we've talked about the fact that we see NGS testing rates increasing dramatically, which is a really positive sign.
Now let's talk a little bit about the Tiragolumab program. We've talked a lot about Tiragolumab over the course of the last couple of years, and so I'm only going to touch on it relatively lightly today. Because the TIGIT space is so competitive, what I'm about to tell you is pretty much what you're gonna hear from us today. You can send Bruno questions, but chances are we're probably not gonna answer them because this is a highly competitive space. As you know, we made a significant investment in our TIGIT program with one of the most comprehensive clinical development programs out there. We did this very intentionally, taking some smart risks.
We wanted to try and get what we believed is a very promising treatment algorithm or treatment set of treatments into the patients that had the highest unmet need as quickly as possible. When we saw the results of SKYSCRAPER-01 and with that very early readout, unfortunately, we did not meet the co-primary PFS endpoint, but the co-primary endpoint of OS was still immature at the time of that reading. We did see numerical improvements in both, and that study does continue until the planned analysis. The regimen is well-tolerated, just as we had expected, and no new safety signals were identified.
What we saw in SKYSCRAPER-01 makes us continue to believe that the science here is quite promising, and you'll see that we expect to see results in 2023. I wanna give you a couple of other updates on the TIGIT program. In SKYSCRAPER-06, we had a planned futility analysis. That has happened, and we are now expanding that into a phase III trial. It is important to note that we remain blinded to that data. We do not have any additional information. In first-line esophageal, this is SKYSCRAPER-08, this is our China-only study. We had a planned interim analysis. That trial will now continue until its final results in 2023. We are also planning to present the data in cervical cancer in the first half of next year.
Lots of activity in the TIGIT space, and we look forward to continue to bring you readouts as those data continue to mature. Now let's switch over to HER2 positive breast cancer. We see continued growth in our HER2 franchise, specifically in a couple of really key areas. The global Phesgo launch continues to go exceptionally well. You see here a 27% conversion rate in launch countries. If you actually take the US out of that number, and for lots of reasons, we all know the U.S. has a slight bias towards IV treatment. That number for global conversion actually goes up to 40%. You can see that Phesgo is actually gaining quite a bit of traction. Why would that be? It cuts healthcare costs significantly.
Up to 80% of non-drug related costs are actually addressed with Phesgo conversion. We also importantly see 85% of patients prefer Phesgo treatment over their prior administration. This is important again when you think about continuing to expand more and more into early breast cancer, where that patient experience with patients who are gonna be on treatment for a long time, something like Phesgo, makes a really big difference for them. We continue to see growth in Kadcyla in the adjuvant setting. Despite competition, we expect Kadcyla to continue to grow in the low single digits.
The majority of that growth and the majority of sales is coming in the adjuvant setting, with the expansion of Kadcyla's launch in Europe and other key markets around the world, and we have additional phase III trials ongoing, with both KATE3 and the Stefania. Moving over into the hormone receptor positive breast population, I'm not actually gonna spend a lot of time on this because Levi is gonna do a significant deep dive on both of these programs, Giredestrant and our PI3K program. What I will tell you from a commercial perspective is this. These are really compelling drugs. We have the opportunity to reach a large number of patients, it's two best in class with two best in class therapies.
They have broad development programs and that high potency, that well-tolerated profile, and the fact that they are combinable means that we have the opportunity to help a lot of people in some very significant areas of unmet needs. As I said, Levi's gonna talk a lot more about both of these going forward, but I think these are two areas to watch, particularly when you see how many patients could potentially be impacted by either one of these therapies. From there, I'm gonna switch us over to hematology. Hematology, again, is an area where Roche has a long legacy of leadership, and we are sort of taking two approaches here.
We both wanna build in those areas where we've historically been strong, such as DLBCL, as we expand into areas of significant unmet need, like multiple myeloma, which Bill mentioned earlier. Let's start off with Polivy. Polivy is obviously the first new treatment in more than 20 years in first-line DLBCL. We've talked about this a lot, but I think it's important to underscore the unmet need that remains in this market. As effective as R-CHOP is, about 40% of patients still do not respond, and those patients that do not respond, that relapse, actually have worse outcomes over time. This is a significant market opportunity in first-line since we have about three times more drug-treated patients than we do in the later lines of therapy.
Importantly, there's no new competition expected in this area, no new options for patients, for about the next 3.5 years. Polivy is currently approved in the E.U., U.K., and Japan. It files now in the U.S. and China, and we've seen strong uptake in those markets that have already launched. Germany, in particular, had it entered into its guidelines, and we saw a doubling of sales within a month. I think what's important as people spend more time with the Polivy data and really begin to understand what it can mean for their patients, we're seeing more and more physicians become enthusiastic about the opportunity of having Polivy in their armamentarium and having it as an option for their patients. We continue to believe that this is very compelling data and data that should be changing the standard of care in first-line DLBCL.
Moving on to Lunsumio and Glofitamab. Bill talked about both of these as well. I think what is important to note here is, again, we have two best in class molecules in Lunsumio and Glofitamab. What's important is our ability to actually tailor who gets what treatment depending on the setting, whether it's the disease that the patient have, or the setting in which they're being treated. Lunsumio, as we know, is sort of ideally suited to the community setting. In those places where it is currently launched, that is exactly where we see it being used. Glofitamab has that best in class efficacy potential with very high CR rates, very durable responses, and particularly in first-line DLBCL, we're seeing very minimal CRS observed, so it also may be eligible for treatment in the outpatient setting.
Certainly, we have more to discover with these two drugs. We'll talk about that in a moment. I think what's also very unique about both of these two is the fixed duration and the very easy to understand dosing, which for physicians we've heard is extremely important. Again, I'm not gonna spend a ton of time on this slide because Levi will cover all of this in his section as well. Again, both of these have the ability to be first in class and best in class. You can see that we have significant development programs against all of them, both in monotherapy and in combination.
What you can see is that while the first indications that we're going after in third-line DLBCL and third-line follicular represent relatively small patient populations, those populations get significantly bigger over time, particularly as we get into first-line DLBCL. Two molecules, again to watch. We think that these could have transformative potential, for patients. We don't tend to talk a lot about Venclexta, but we should. It's a really, really remarkable molecule. It is revolutionizing treatment in CLL and AML. We are soon to see the long-awaited CANOVA results, which builds off of the phase II that we saw in BELLINI on patients with the t(11;14) translocation. This is a relatively small patient population, but depending on what data we see with this trial, it could actually open up, a lot of opportunity in multiple myeloma.
Then Bill also mentioned the first-line trial, the VERONA study in MDS, which is expected to read out next year. I think a lot of really interesting data coming on Venclexta and another one to watch. Finally, no conversation about hematology would be complete without talking about Hemlibra. Hemlibra is head and shoulders, the number one prophylaxis treatment for hemophilia A in the U.S and the E.U. You can see that we continue strong double-digit growth in this patient population with 35% share in the U.S. and the E.U. 65% of those patients are on greater than two-week dosing.
We expect further penetration, both by additional countries coming online in our inhibitor and non-inhibitor indications, but also as new data continues to become available, including things like the phase III HAVEN 7 in infants zero to one-year-old. The growth in the rest of the world is really driven by reimbursement and approvals now starting to come online. You can see that the non-inhibitor indication is approved in 98 countries, but only reimbursed in 52, and so that's a tremendous amount of additional upside for Hemlibra. Why do we remain so confident in Hemlibra? We remain so confident because Hemlibra has really redefined the bar for treatment in hemophilia A. We have infrequent sub-Q injections. Up to 90% of patients are bleed-free in a year. We have an incredibly positive experience with patients on Hemlibra.
It is not to be underestimated the importance of the safety profile and having a well-characterized safety profile in this patient population. We have over 18,000 patients currently treated with seven years of safety data. That is absolutely fantastic. We think that the bar that Hemlibra has set for patients is just incredibly significant. That having been said, we always like to press ourselves and step over our own bars, so we continue to think about how we might be able to make a difference for hemophilia patients going forward. We have the gene therapy for Spark and the next generation bispecific that's coming from Chugai.
Our hope is that this may be able to further reduce or eliminate the frequency of administration while maintaining that very high efficacy and safety bar, providing significant ability to improve the quality of life of these patients. Just another drug to watch because while we've had great growth, there's still a lot of growth to come. Now, ophthalmology, I'm sure is on lots of people's minds. Bill, you mentioned line of sight earlier, no pun intended, so I'm gonna give you a little bit of insight into what we're seeing with ophthalmology at this point. I'm sure that you guys have lots of questions.
We do have Nilesh Mehta coming a little bit later this afternoon, so I'm just gonna quickly ground us in what Vabysmo is and what we're seeing in terms of the early launch performance, and then we'll have the opportunity to take a deeper dive into Vabysmo later. As you know, Vabysmo is the first bispecific that has been approved in ophthalmology. It simultaneously binds to the Ang-2 and the VEGF arms, which potentially allows us to improve vascular stability and retinal inflammation. That is in fact what you see when you look at the outcomes from our clinical trials. The updated two-year data continues to underscore the durability that we see with Vabysmo, and you see from the left-hand part of the screen that the need for longer-lasting therapies is where the highest level of unmet need is in the ophthalmology community.
We continue to see real-world data that reinforces our belief in Vabysmo. Nilesh is gonna talk a little bit later about the TRUCKEE study, which is currently ongoing. We've seen multiple cuts of this data, all of which demonstrate consistent efficacy and safety in many different kinds of patients. We are observing evidence of anatomical benefit when we switch from other VEGF therapies, which again, is very encouraging when you think that in the beginning of a launch, who do you get? You tend to get the most severe patients, and that's who we're seeing, and we're still seeing great benefit. Importantly, since this slide was done, we actually have an update.
We're now at 130,000 vials that have been shipped with no new safety signals observed, which again gives us increasing confidence in the safety of Vabysmo. Probably top of your mind is how is launch going, and launch is actually going extremely well. We're seeing high initial uptake in high unmet need patients. We're seeing many of our patients switching from Eylea. We have uptake across both AMD and DME patients with more AMD patients, as you might expect, given the epidemiology of this disease. We're also seeing broad access in reimbursement. We do expect that to accelerate with the receipt of the permanent J-code, which we anticipate on October first.
You may not know that Japan is actually the second-largest retina market in the world, and they are seeing extremely quick uptake of Vabysmo. Here in the U.K., NICE actually covered Vabysmo just one week after MHRA approval, which is quite unheard of. We are just hearing a lot of excitement from our E.U. retinal specialists who are awaiting the approval of Vabysmo. As Bill mentioned, we are continuing to invest in additional indications and formulations, including a prefilled syringe, which for any of you who's spent time in a retinal physician's office, you know that they really value the convenience of having that prefilled syringe. We're excited to see that come online as well. We don't wanna forget about Susvimo, which is also launched now in the U.S.
This is the first and only eye implant with a Q six-month drug delivery option. We have always told you that the launch of Susvimo was going to be a purposeful launch, and that is very much how we've approached it in the U.S.. The focus has been on providing the best possible experience for our surgeons and for our patients. We have over 350 patients who have been. I'm sorry, 350 surgeons who have been trained, which is fantastic. We did receive a permanent J-code on July first, which has given us a corresponding increase in scheduled surgeries as we would have expected. We are anticipating E.U. approval next year, and we continue the platform delivery for port.
We continue the development for the port delivery platform, both in studies in DME and DR, extended dosing studies, and importantly, the next generation of DutaFab bispecifics, which Nilesh will talk about later this afternoon. Finally, neuroscience. Ocrevus remains far and away the number one treatment in the U.S. and the EU5 for MS. You guys are probably tired of hearing me say this, but we are the only drug that has robust, consistent, sustained disability and sustained delay in disability progression and the kind of safety that we have, the kind of safety database that we know people wanna see in neurology. That makes Ocrevus really just a very hard drug to unseat. Ocrevus is the first and only therapy that approved in both RMS and PPMS, and that high persistence compared to other therapies is really important.
We're still seeing around 90% of patients remain on therapy over time, which again, in a chronic disease is quite unheard of. Paulo will talk a lot more about what we're seeing in our MS investments over time, but Bill mentioned the Ocrevus subcutaneous data, which is expected next year. This is really important for Ocrevus. It both allows us to expand the patient population in IV centers where there might be some capacity constraints, but also potentially expanding into the community setting. The higher dose Ocrevus studies, again, will help us continue to expand on the efficacy for Ocrevus. Both fenebrutinib and brain shuttle programs are ongoing and have the potential to really revolutionize the care of MS. Lots going on in the MS space.
Evrysdi is well on track to becoming the global market leader in SMA. I think it's just always important to Levelset us in the data that we see with Evrysdi. On the left side of the slide here, you see the RAINBOWFISH data. This is the data that the FDA approved in less than two-month-old patients. That approval was achieved in Q2. It's important to note the Evrysdi is the only DMT that actually doesn't require baseline monitoring or labs, and that enables patients to get on treatment very, very quickly. Again, this is extremely important, particularly when you're dealing with infants, because the faster you treat, the better result you're going to see.
Since RAINBOWFISH approval, we've actually seen a number of babies treated within 24 hours of birth, which again is just incredible and gives them the opportunity to have the best possible outcome. We have over 7,000 patients treated worldwide. We're well on our way to becoming market leader in our most significant markets. We have rapid growth that is primarily being driven by switching. About 60% of new patients are coming from switching. About 50% of those are adults. We have high treatment satisfaction and again, very high retention rate. That lasting motor function approval is incredibly important and we're continuing to see responses maintained or improved over three years.
Again, Paulo will talk about this more in the afternoon, but we are continuing to invest in SMA and in particular the MANATEE study, which looks at the combination of Evrysdi along with an anti-myostatin, which could again be a really important advance for these babies. Finally, Gantenerumab. Bill mentioned this already. We will finally see this data in Q4 of this year. The world needs a solution for AD. It just does. We are going to learn a lot with the GRADUATE data when it reads out. These are large well-powered studies. They are significantly long enough that we should be able to see benefit. They've been well designed from a safety perspective. Probably what I'm most proud of is actually how we have incorporated a patient-centric approach to the design of these trials from the beginning.
Having the first sub-Q administration actually in embedded in our phase III development. As Bill mentioned, the ability to be able to do that at home is really significant and important for these patients. Finally, we are also looking at how we can continue to provide access to patients all around the world for Gantenerumab, including the development of an auto-injector, which will really help with the ease of administration over time. Finally, I'm going to close with a quick outlook of what's coming more in the midterm. Bill mentioned what was happening in 2022 and 2023. I'm gonna cover a little bit of what's happening in 2024. There are some very significant trials that Bill actually called out in 2022 and 2023.
The HCC adjuvant trial is definitely one to watch as the head and neck trial is with Tecentriq. As you look into 2024, there are a couple of things that are very significant. I'm gonna start in the line extensions with Gazyva and lupus nephritis. Lupus nephritis is an area of incredibly high unmet need where we saw some very compelling phase II data. This is the phase III reading out, and this could really be quite transformative for patients with lupus nephritis, and it could really help us understand the role of Gazyva in immunological disease. That is definitely a trial to watch.
In terms of our new molecular entities, again, Levi will talk more about both of these in his section, the PI3K, we see our first phase III readout here with our frontline HR-positive trial in metastatic breast cancer, potentially a very significant population and a place where we could really do a lot of good for patients. We see the Giredestrant first-line trial in ER-positive metastatic breast cancer. This is an interim analysis, one that could potentially be fileable and that would allow us to actually be the first oral SERD in this patient population.
I think that's gonna be a really interesting trial and one to watch because again, patients in this setting really do need additional options in Giredestrant, for all the reasons that we've talked about previously, could be a really great solution, for those patients. At this point I'm gonna stop. I tried to make up a little bit of time so we wouldn't be quite so late to lunch. I'm gonna invite Bill back and I think we can. How do you wanna do this, Bruno? 'Cause we're pretty close.
You come back on stage and then we have the first Q&A session. Very good. Also to just remind the people who join via the web, there's the possibility that you send us questions via the chat so we can then I can read them aloud. We'll take the first few questions from the room. Simon, please. Do we have a mic, please?
Thank you. Simon Baker from Redburn. Two quick questions, if I may. Firstly, Bill, the drug negotiation provisions of the Inflation Reduction Act mean that certain types of drugs and certain types of development approaches are disincentivized, whether it's small molecules or kicking off in small indications and expanding. Can you give us some thoughts, at this still fairly early stage, how this is gonna affect what you develop and how you develop it? And then secondly, going back to the productivity slide, you showed how you've capped pharma development headcount at 14% since 2016, which is very impressive achievement. Doubly so given that the figure was +27 on the slide last year. Could you tell us what's changed and what's driven that shift, over the last 12 months? Thanks so much.
Yeah, sure. In terms of the Inflation Reduction Act, I'd say the good news is that I don't think there's really significant effect on Roche, even, I mean, I don't know if you wanna define long term, but certainly in the next five years, we see minimal impact. Just sort of the nature of how the provisions are structured and the nature of our portfolio. The bigger impact is on small molecules. Of course, most of our major medicines are large molecules. Where we have our older products, they often would have biosimilar competition before the provisions would kick in, and of course, those provisions don't apply to products with biosimilar competition. For various reasons, we see really minimal impact in any reasonable horizon.
I mean, I think long term, this is obviously not a good development for innovation in the world. I mean, the idea that small molecules would essentially have a nine-year life, which is. I'd say that's the bleakest way to look at it, but maybe not wholly unreasonable, because we all know government negotiation isn't really a negotiation. The government basically says what the price is, and yeah. I would put it this way: I don't think we plan to do anything differently in our portfolio today, but over time, that would have certainly a disincentive, particularly on small molecules, which would be unfortunate. I would say we and our colleagues across the industry certainly plan to do everything possible to influence policy in a better direction in the future.
In terms of PD, I maybe I'll let Levi talk more about that when we're in the afternoon. I would just say that, we're just getting going in terms of understanding how to employ some of these new models for leadership in the realm of product development, which is not only in Levi's space, but also in areas like GPS and in process development. We're really excited about the prospects. In this case, whereas in the commercial organizations and in PT, we found ourselves often with too many people.
In the case of I think in late-stage development, it's more of a case of we have a rapidly growing portfolio which we think we can largely handle with the people we have.
Maybe the next question comes from Matthew.
Thank you. It's Matthew Weston from Credit Suisse. Two specific product questions, please. Teresa, you called out the adjuvant Alecensa data, excuse me, but you flagged that the ARIA trial was an interim read. How confident are you that we're actually gonna see. Is there some reason why you're calling out an interim next year as the, you know, the one we should watch? And then secondly, you also flagged sub-Q Ocrevus. As I understand the commercial benefit to clinicians, there's a very large amount of money made by buy and bill in their practice. So is the expectation that sub-Q Ocrevus will be physician-administered, and they will keep that financial benefit, or is this something that could be done at home?
Two great questions. The reason that we're flagging the interim is that that is the next cut of the data. As always, we hope that it's positive and that we're able to bring this this treatment to patients as early as possible. This is a highly selective and effective ALK drug, so it's not unreasonable that we could actually see a cross at interim. But that just happens to be the next predefined data point. In terms of sub-Q Ocrevus, I think we should look at this as more of a market expansion opportunity. I think for many physicians and many patients, they will continue to appreciate and want to be on IV therapy.
There are some who either might have capacity constraints in their practices or for whom patients just the ability to actually administer at home would be most helpful. I think we would expect sub-Q to actually expand the opportunity for Ocrevus patients over time. The goal is for it to be home administered. It is possible that the first one might be in office, but the goal is for it to be home administered.
Matthew, you asked about the MARINA, the study about the edema readout?
Yeah, we hit that one on the first one.
Yeah.
Yeah. Okay. The MARINA was originally scheduled for 20 for this year, and then it shifted basically over to next year. Yeah. We can take a question from Richard Vosser. Awesome. Please. Row.
Hi. Thanks for taking my questions. I'll try a TIGIT one. Maybe on the cervical TIGIT, you're highlighting data presentation next year. I mean, that sounds subtly different to a readout. You know, have you seen the data? For that, what's it looking like, if you can give us any sort of color. On Vabysmo, we saw last week high dose Eylea data, which looked reasonably comparable with Vabysmo. Just your thoughts on how that looks and how that can affect the uptake and commercial launch and potential. Thanks very much.
I think we're gonna let Nilesh cover the Eylea high-dose data in his section this afternoon, just so we can kinda get the full context in. In terms of cervical cancer, the study is still ongoing. The final readout will be presented next year.
We hand over to r ight. Sachin, you want to continue?
Thanks. Sachin Jain, Bank of America. I'm gonna try another digital one as well, if I may, even though you've said you wouldn't. So SKY006, just any color you can give on the upsize criteria. Was it RRF, SOS, and did you... This is the one I'm most interested in. Did you require any improvements versus the comparator arm to upsize, given you've made that phase three decision? Like, what level of confidence do you have to move that to phase three? Second question is on Tecentriq adjuvant lung. I think you said in your commentary that adjuvant lung is now the biggest single growth driver. So I wonder if you could just clarify that, and how much growth you see in that adjuvant lung indication with peri-adjuvant. Reason for the question is slide 10, which you cited consensus.
Tecentriq is the biggest single growth driver. How much of that can come from the existing indications versus needing some of the adjuvant reads, next year? I shall leave it at that. Thank you.
Yeah. Do you wanna take a turn at batting down a digit question?
SKY006, which is the non-small cell with chemo combination, with Tiragolumab, Tecentriq, and chemo in the broader non-small cell lung population. We had basically a futility analysis planned in, and we had basically a pre-planned expansion to a full phase III contingent on a passing of the futility analysis. That's all we're saying.
Exactly. We're blinded to that data.
Yeah, we're blinded to the data. Because you can understand if you're taking a phase II and making it a phase III, you can't be like, looking at the results. We're blinded to it. There's an IDMC. They, you know, they said it passed the futility analysis. That triggered the expansion to phase III.
Maybe add on from my side on the sales dynamic. You asked about Sachin. I think you've seen it in the U.S. that we had a nice reversal, Q1, Q2. This is the dynamic which you see here in sales. It's really driven entirely by the adjuvant non-small cell lung cancer segment. We have been guiding before that this is a multi-billion opportunity, this setting. I think definitely additional data here, like the peri-adjuvant study, would be supportive of having even some upside here. You mentioned there's consensus upside until 2025. It was at CHF 2.7 billion or something. Yes. I think this is largely, I would say, adjuvant estimates. You know, it's the adjuvant, but then we have the other studies as well. We have the
mm-hmm.
We have the TNBC to come, which was not on the list actually because it's an external study, and the IMbrave050.
Yeah.
There's upside here from depending how this plays out.
Absolutely.
May we continue here?
Thank you. Peter Welford, Jefferies. Two sort of perhaps slightly bigger picture questions. Just first of all on the manufacturing, can you just talk a little bit about now your utilization at the moment of the sort of biologic facilities? And you talked about investing nearly CHF 600 million in gene therapy. Just to understand, is that in anticipation of the Sarepta data? Is that, you know, I guess to meet that demand? Or how are you thinking about that? It seems like a lot of money when you basically highlighted relatively little projects at the moment that are in the clinic for gene therapy. And then just another quick one on the utilization productivity then. You talk about the headcount going down, particularly in the U.S. Obviously, it's come down sharply.
Should we think in the U.S., though, is that trend largely now done, or is there still room to further reduce headcount, do you think, as business models change? Actually, you know, I guess what I'm asking you, are we kind of at the end of that cycle for productivity of marketing?
Yeah, in terms of the production capacity, we were running at pretty much 100%. Sometimes the calculation says we're at 103% of capacity, but I'm not quite sure how that works. That's like a football team giving it 110. The bottom line is we've been at full capacity for a long time, and I'm actually pleased and relieved that in 2022 we are no longer at 100% of capacity. I don't know if it's 85 or 90, but we're actually taking the opportunity to do some important upgrades and maintenance and things. That's great in terms of our global biologics network. I think we're well positioned for the future.
In the case of a positive Gantenerumab readout, we have the capacity lined up, and we've got capacity for the pipeline. I think that's generally good. You asked about the gene therapy investment. That's not primarily about the DMD readout, but really because we have one of the world's largest investments in gene therapy, both at Spark in Philadelphia, but also a significant investment in pRED in gene therapies for a number of diseases. That investment, I think, marks our commitment to gene therapy for the future.
It's also, I should note, that it's flexible enough that that space, if we end up not needing it all for gene therapy, can also be used for some of the more modular production things like things like mRNA vaccines or small capacity single-use bioreactors. We're trying to invest in space and facilities that can be flexible. If you've been through a biologics plant, you have the giant plants like we have in Vacaville with 25,000-liter stainless steel bioreactors, and they're fixed, 'cause you can't really move around a 25,000-liter reactor very easily and fixed piping. The plants of the future don't look like that.
They're kinda big, empty rooms like this, and then you have these modular reactors with single-use, you know, liners and flexible tubing that kinda hooks them up, so they're sort of modular plants. I think it's a good investment. It anticipates our future needs in gene therapy, but it's also flexible enough that if those don't all come through, we can deploy for other things.
We can take the next question over here. Keyur?
Can you hear me?
Yes.
Great. Keyur Parekh, Goldman Sachs. Bill, one big picture for you and then one kinda specific question. You've spoken very passionately the last three or four years about the need to kind of increase your investments in R&D. If I look at your R&D spend, I think you've put together a very clear slide, 27% of revenues on R&D, and there may be three or four other companies in that bucket. Lilly and AstraZeneca, consensus is forecasting them to grow kind of high single-digit, low double-digit top line. The 11 billion in incremental revenues that you spoke about would be kind of mid-single digits on your $45 billion base. At what time do you expect that increased R&D investments to translate into increased revenue growth kind of for the group? That's question number one.
Great question. I think there's a couple factors at play that drive the math, right? I mean, one is we're starting from a significantly larger base than the other two companies you mentioned, and so a given amount of absolute growth isn't the same relative growth, that that's kind of obvious, but you know, it's a factor. Secondly, you know, R&D, it takes a while to mature. You know, you don't invest more in R&D this year and get a revenue payoff next year. The biggest bump ups we made were in 2019 and 2020, and I'd say probably the median time to pay off for that is probably five to seven years, median. That increased investment funded some phase III things like Giredestrant like inavolisib.
It funded our phase III studies in muscular dystrophy, which we'll read out next year. You know, you'll see the beginnings of that paying off in 2023, 2024, but I think the sweet spot of the payoff is probably more, you know, 2025, 2026, 2027. Yeah, I think that's why we feel really good about our growth prospects in that, you know, basically over the course of the decade with steady growth in the early years, but probably accelerating growth in the later years.
Thank you. Secondly, Gantenerumab, both of you've been very specific, and I think those are the words you used, where we will all learn a lot when that study reads out. How would you characterize your level of optimism kind of around the assets, knowing what we know about the space and knowing we're gonna see probably a couple of other competitive readouts before we see kind of the GRADUATE one and two studies? How much of a read-through should we have from those studies on to GRADUATE one and two? Thank you.
I mean, personally, I think it's probably a coin toss. I think we have every reason to believe that Gantenerumab will biologically do what we know it can do, which is to reduce plaque, and the question is whether or not that has a meaningful impact on cognition. You know, I think that is the million-dollar question and the thing that we will learn the most from when those data read out. I think that's kind of what we're all waiting for, is to definitively know whether or not reducing amyloid plaque actually can improve cognition over time.
Yeah. You'll get more on this from Paulo in the afternoon, but I think what I would say is, I think because we're Roche, we tend to be conservative. We want to deliver something before we proclaim victory. Sometimes people read that as a lack of confidence in our asset. I think we have great confidence in Gantenerumab, in the study designs. These are the largest studies. They're 27-month endpoints. I think we have a great opportunity to show a benefit, and the MOA is, it's not conclusive, let's say, based on the totality of the evidence to date. That's where we are. I think we're
You shouldn't read our caution as a lack of enthusiasm for Gantenerumab, but rather it just reflects, I think, the scientific consensus about the impact of lowering amyloid beta.
Yeah. Science is uncertain.
Maybe we take a final question before we head into lunch. One final question.
Oh, thank you. Ben Yeoh at RBC Asset Management. I was interested in AI. Do you think you're seeing any gains from that machine learning, and particularly the advances that DeepMind has made in protein folding, or where that will go in the long term? Secondly, on the Alzheimer's, were you worried at all, some of the originating research around amyloid beta has been shown to be maybe potentially fraudulent or perhaps not as strong as we thought? Obviously, you talk about the totality of data, but that, did that worry you, or I would be interested in your thoughts there. The last one is, I mean, you spoke a lot about the innovation and things that you're doing. What do you think is most underrated or potentially misunderstood about what you're doing at Roche? Thank you.
Hmm.
I'm gonna let you talk about the underrated, and I'll hit the first two, so you can think about it a minute.
Okay, excellent.
Yeah. The first two, in terms of the use of AI, it's basically, it's happening everywhere. I think it'd be great to hear more from Levi and Paulo and Nilesh in the afternoon, but I can say, I've been around the world twice in the last 8 months to all of our innovation centers, and in each of them, and now I'm just talking about research and early development 'cause that seemed to be kinda where you were aiming. It's happening. I mean, for example, in the polypeptide cyclic molecules space, I mean, AI is allowing us to go much more rapidly in terms of creation of molecules and sort of virtual screening.
I mean, it's probably allowed us to accelerate the number of molecules, the number of experiments we can run by at least an order of magnitude just in the last few years, and that's just one of many examples. Not particularly concerned about this recent news about potential inconsistencies in early experiments with amyloid beta. Frankly, I think that's a bit of a sideshow because in the meantime, there's been clinical results, and we all know clinical results trump these sort of preclinical things every time.
I think that's you know that added fuel to the anti-amyloid beta crowd, but the fact is it's you know at this point in time, we're looking at clinical results and you know we're gonna have data on at least two of the major phase III programs in the next few months. We'll hopefully 2023 will be the year where we're arguing a lot less about whether amyloid beta works, and hopefully that'll be because we've settled that it does. In any case, we can you know maybe stop some of that silliness pretty soon.
Great. In terms of where I think maybe we're undervalued or underappreciated, I mean, I do continue to think that people don't necessarily understand the depth and breadth of our ophthalmology investments, and I think we'll go into a lot more detail in that this afternoon. There are a lot of patients who are impacted with retinal disease, and we have a very large early-stage and late-stage set of development programs that are targeted at helping patients with diseases that we've either actually not really been able to have much effect on. In general, I think our ophthalmology portfolio is one that people should take a closer look at. I would say the same thing about our hematology portfolio.
I think in general, people do undervalue everything that is in that hematology portfolio, and there is quite a bit, in some areas that again have significant unmet need, where patients stay on therapy over long periods of time, where we have the ability to deliver game-changing results.
I would add, I agree with you, I would add just because there's so many things to like, but the SERD, partly because of sort of the negative market news on that.
Yeah.
or the competitive news. Actually, you look forward to what Levi's gonna tell you about that. Inavolisib, which is the PI3K, again, because you know some of the early molecules haven't been that great, and we think we have something that really is great and more from Levi.
Well, I'm gonna give Bruno one right now and toss in one additional thing. You did mention the TNKs and the stroke extension. I think again, if any of you have a family member or know someone who's suffered from a stroke, you know what a debilitating event that is for someone. The ability to expand the treatment window is incredibly important.
Mm.
Right now, many patients don't actually get treated because you can't pinpoint the moment when you have a stroke, and so people who might actually have healthy tissue that can't be saved aren't. The TIMELESS trial has the opportunity to be game-changing for patients all around the world.
Okay. Thanks, Bill and Teresa. We're heading to the lunch, and enjoy your lunch, and we will meet back at 12:50 P.M. for the second session.
I can't control that. Now I'm on. Okay. Good afternoon, everyone. I'm Levi Garraway. I'm the Chief Medical Officer and Head of Global Product Development at Roche, and it's always a pleasure to have the chance to discuss our pipeline. Before I get into some of the specifics, I'll just take a couple of moments to give you. There are several strategic pillars in oncology that have guided our investment in recent years, and I'll just kind of at a high level walk you through some of them. Maybe the best known of these pillars are precision medicine, you know, using genetic and molecular data to guide deployment of therapies. Then immunotherapy.
Here we've been, of course, increasingly interested in moving beyond the PD-L1 PD-1 axis into new ways of engaging cytotoxic T- cells against tumor cells.
Now both of those pillars have been empowered by increasingly pursuing rational combinations. As you know, most oncology therapies don't end up as monotherapy. There are regimens that are anchored by busting disease therapeutics, and so that's a big drive for us. Teresa briefly mentioned moving more and more into early disease where you have the chance to achieve more cures, durable control. That's a growing area for us. All of this is anchored by an expanding suite of modalities so that as the science progresses, we have new increasingly creative ways to interdict the targets and the disease biology.
On that last point, you've already seen a slide from Bill showing the breadth of modalities and this is always to me, the modalities are a symptom of innovation and for our R&D organization, the broader they are, that means that there's innovation going on. Bill mentioned a couple of these, you know, the cyclopeptides. This is an area where our scientist colleagues at Chugai, basically, the key innovation here was to be able to generate orally bioavailable cell membrane permeable cyclopeptides. Those are each of those are huge feats, and then the ability to scale the technology to screen these things. Because now what you're doing is you're screening for the ability, for example, to block protein-protein interaction.
That is a feat in and of itself. Having that available and now being able to see actual candidates coming through and the first one to actually be in the clinic, and of course, it's a pan KRAS inhibitor, which could be very interesting. And there's a lot behind this. This is the kind of thing. It's not just a cool modality. You can easily see how there's a lot of unmet need that could be addressed with this kind of approach. Then there's the allogeneic CAR-T therapies. We passed on making an investment in the autologous setting when we've discussed that.
Actually, in its stead, you could say, well, we've made a fair bit of investment in bispecific antibody therapy, and we feel like that was a no regret decision at the time. But we also appreciated that if there could be some advances that could get beyond some of the encumbrances of the autologous approach, that might now be worth a different look. Our strategic collaboration with Poseida Therapeutics gives us now an opportunity to potentially do exactly that. We have rights to several of the products that they generate from that platform, and I'll say a little bit more about those in a second.
Let me now turn to sort of, I guess the meat of the presentation, starting in the heme malignancies, and just maybe a deeper dive into the modality, one of the modalities that we are now first in class in a couple of these indications, the CD20, CD3 bispecific antibodies. You already know about Lunsumio. This is approved in the E.U.. This is of course, based on the, like complete response data of 60%, very favorable compared to historical controls, long duration of response and in these heavily pretreated follicular lymphoma patients, and a fixed duration treatment with a very favorable toxicity profile. This all is compatible with the community outpatient setting. Approval in the E.U., it was achieved.
Filing in the U.S. has been granted priority review. Now, as has already been mentioned, we have a clinical development program that we have a couple of phase III readouts upcoming in second line follicular lymphoma in combination with lenalidomide, in second line diffuse large cell lymphoma in combination with Polivy, and then a broader set of what we think are intriguing combinations that are in earlier stage. Certainly, Lunsumio has the potential to become an important new option for patients in heme malignancies. Sort of the companion to Lunsumio in some ways is glofitamab. Just to remind you that the design hypothesis for glofitamab was that it's bivalent against CD20 on the tumor cell and monovalent against CD3.
The concept there was that that would generate avidity for the tumor cells that could lead to robust efficacy, even in highly aggressive lymphomas, you know, heavily pretreated lymphomas. That hypothesis has sort of borne out in the form of a complete response rate of almost 40%, in a highly refractory population, including a substantial percentage that had progressed even through CAR-T therapy. These complete responses are durable. At ASCO earlier this year, we reported that the median response was exceeding 34 months. And again, this is a fixed duration of treatment, manageable side effect profile. This has the potential to play an important role in the management of aggressive lymphomas.
Here too, we have a development program that is extensive and growing, including a phase III trial, the STARGLO study, that will read out in a second-line DLBCL next year. It's a combination with GemOx and several other exploratory studies as well. We think that both of these bispecifics have the potential to play an important role in a range of hematologic malignancies. Now, you could say in some ways that the initial success with bispecifics in part has helped to open the possibility of bringing similar advances into different areas, including areas of hematology, where, as a company, we haven't necessarily had a major presence. One area in particular that's of interest to us is multiple meloma.
Multiple myeloma, of course, like every other area of oncology, this is a competitive space, but there's still actually quite a high unmet need in multiple myeloma. The backbone therapies come with real side effects. Some of the emerging regimens, they're cumbersome, affordability is an issue. There are quadruplet regimens. In general, we think that in our portfolio, there are actually several modalities that have the potential to benefit patients. Two of them are bispecifics. There's the small molecule, Venclexta, and then our allogeneic program that we through our recent strategic partnership with Poseida. In the bispecific space, one of the candidates that we're bullish about is called cevostamab. This is a. So you have CD3 on one arm and then a target called FcRH5 on the other arm.
This is a membrane protein that has near ubiquitous expression on myeloma cells. This would be a first-in-class opportunity for us. You can see on the right side of this slide that the initial monotherapy data is looking quite encouraging. We have an overall response rate of over 56%, very good partial response rate of 33%. The safety profile, the CRS in particular, generally confined to early cycles. This is an opportunity where we're moving this forward in combination with not only internal partners, but also external candidates that are obvious choices in myeloma as well. That's one bispecific opportunity. The second one is, it's now analogous to Glofitamab and that is a two-to-one format, so bivalent against the target.
In this case, the target is called GPRC5D. This is a G protein-coupled receptor that is one of the most specific targets yet identified in myeloma. And now you have CD3, so kind of similar mechanistic concept. Here again, we've got over 40 patients treated where the overall response rate looks quite encouraging, over 71%. Very good partial response rate of 52%. This too is an area sort of orthogonal bispecific opportunity that we are exploring again in various combination studies are in the planning stages. Now, as a company, it's likely that our first actual foray therapeutically into myeloma will occur with Venclexta, and this is through the subset of patients, the 20% subset of patients that have the t(11;14) translocation.
Incidentally, the reason why this was a biologically plausible opportunity is because that subset has particularly high expression of BCL-2, which of course is the target of Venclexta. In general, BCL-2 is a key survival factor in myeloma. Now, you can see the subgroup analysis of the BELLINI study that led to sort of the clinical plausibility of this hypothesis. We'll see very, very soon through the CANOVA study whether this hypothesis proves correct. If so, we think actually, although the initial indication would be a subset that the translocation subset, but there are other subsets of myeloma that also have very high BCL-2 expression, so there could be opportunities for expansion there.
While we're on the general topic of Venclexta, I should also just emphasize the data that supported the Verona phase II trial in high-risk myelodysplastic syndrome shown here on the right is quite encouraging. The combination with Azacitidine and Venclexta, you had an 84% overall response rate and a robust duration of response, which was over a year. Obviously, we are very much looking forward to the readout of the phase II trial, which is expected next year. Now, the last point I'll make on the myeloma front, but it's of course relevant to several to a broader spectrum of hematologies, just diving again more deeply into the allogeneic CAR-Ts. We've already mentioned sort of the encumbrances of autologous.
Basically, the concept here, obviously, is that if you now have an allogeneic pool, you have converted cell therapy into something that is a little bit more traditional in the sense of it's scalable, it's off the shelf, you have lower cogs, you basically don't have delays to treatment. Basically now you've opened up access to outside of a very restricted sort of healthcare context. The reason, the basis scientifically for our collaboration with Poseida was the fact that the specific expansion of allogeneic stem cell precursors is in this subset of T- cells, which are basically the T-cell stem cell memory T- cells or TSCMs.
These this subset of T- cells if you can expand them, the data suggests, including clinical data that you can have a higher proportion of T- cells that can be administered. You have you also have a favorable safety profile. You have the opportunity for greater persistence, and also the efficacy potentially could get a boost. Poseida has an autologous program, which has already basically shown proof of concept for the method. They've dosed over 100 patients with in an autologous CAR-T, but basically the same subset of T- cells.
Our initial sort of collaboration involves a BCMA cell therapy target, obviously well-validated myeloma target. This particular modality is already in the clinic for the allogeneic sort of subset, and then the one that follows after will be a CD19, CD20. We're bullish from a scientific rationale about this platform, because not only do you have a subset of T-cells that potentially could overcome some of the encumbrances, but there's also additional hypotheses about how you might mediate or mitigate the host versus graft challenges that may undermine persistence by sort of CRISPRing out some of the mechanisms there.
We think there's a lot of reason to be enthusiastic about this technological approach. Now let me move from heme malignancies into the solid tumors, and I'll speak about a couple of targeted agents, and I'll start by speaking about Giredestrant. It's been an active year for Giredestrant, including some disappointing readouts for several of the players, including ours. However, we still feel quite bullish about our program, and there are several reasons for that. Ultimately, this boils down to, obviously, it's a well-validated target, but we believe we have a molecule that has several best-in-class characteristics, and I'll just remind you of a couple of them. One is the potency.
This is the most potent member of the class of SERDs that's been in development, 7- to 15-fold greater potency, depending on who your comparator is. You have a mechanism that is not just about ligand-dependent inhibition and degradation, but it's also this was published in Cell several years ago. The binding by Giredestrant immobilizes prior to degradation. It immobilizes the SERD and prevents engagement of chromatin. So what that means is you get a profound suppression of the oncogenic transcriptional output. You have a ligand-independent effect as well as sort of the traditional kind of inhibition effect. The third is the combinability, so the lack of issues of drug-drug interactions.
We know that in hindsight, in particular, that potentially a fatal flaw of some competitor molecules was the fact that you couldn't dose the SERD adequately. You couldn't dose to the same degree as you could in a monotherapy setting, and you couldn't maintain bioavailability of the partner. For example, the CDK inhibitor when you combine. That is not a liability of our SERD. We can dose fully and maintain there are no drug-drug interactions that we've seen thus far with the obvious kind of combiners that we would like to include. Then there's also the safety. We've seen quite a very reasonable safety profile. Bradycardia has basically not been a factor clinically. These are all obviously very important best-in-class differentiators.
Actually, the most important reason why we are bullish from a best-in-class standpoint is the aggregate clinical data that we've seen. On the left of this slide is a phase II trial called the coopERA study, which is basically a neoadjuvant window of opportunity, which was a head-to-head study comparing Giredestrant with anastrozole. Then after that, both of those arms were continued, but in combination with palbociclib. What you can see in the bar graphs on the right is the fact that Giredestrant, when compared head-to-head, was. This was a positive study, statistically significant increase in relative reduction of Ki-67. There was a higher proportion of patients who underwent complete cell cycle arrest as measured by Ki-67 levels.
This is the first example of a randomized study in which an oral SERD has proved superior to an aromatase inhibitor. This is in the neoadjuvant setting and Ki-67 and ER-positive breast cancer in neoadjuvant studies has often been predictive of what you would see ultimately with hormone therapy in the adjuvant setting. It's relevant to our adjuvant study that's ongoing. That's the coopERA study. Now, the acelERA study was more disappointing sort of at first blush because it failed to meet its primary endpoint in an all-comers population, which of course consisted of metastatic, you know, later line metastatic, ER-positive breast cancer. Many of these patients had already progressed on earlier lines of endocrine therapy.
In that sense, what this sort of taught us, the sort of hypothesis was, "Oh, well, maybe there's still some residual dependence on the estrogen receptor in this population." It turned out, in general, that was not true, except in the subset of patients that happened to acquire ESR1 mutations in their tumors over the course of their treatment. Of course, as you know, in ER-positive breast cancer, if you acquire an ESR1 mutation, ESR1 is the gene for the estrogen receptor. Those tend to be activating mutations. What they signify that those tumors are still dependent on the estrogen receptor. In this Kaplan-Meier curve that we're looking at, that's the subset of breast cancer patients that had ESR1 mutations, and you can see in that subset, clear evidence of activity for Giredestrant.
In fact, a hazard ratio of 0.6. That tells us that even in that metastatic study, if you have dependence on the estrogen receptor, you have activity with Giredestrant. When you take this data together with the endocrine, the earlier stage of the neoadjuvant data that's shown here on the left, you have an aggregate rationale for enthusiasm about the potential for Giredestrant to be an effective medicine, including in settings, including the potential to unseat an aromatase inhibitor in earlier stage settings. There's clearly equipoise for the robust development program that we have with this SERD. That's the Giredestrant sort of story. Happy to discuss that more in the Q&A if helpful. Then the other one I'll mention is inavolisib.
Bill sort of teed this up. This is our PI 3-kinase alpha inhibitor. Obviously, there's a marketed PI 3-kinase alpha inhibitor, but we think that inavolisib has the chance to be a best-in-disease PI 3-kinase alpha inhibitor. Part of the rationale for that is the preclinical data that's shown on the left of this slide. What you have, first of all, is the potency. 58-fold greater potency for inavolisib than alpelisib. There is greater selectivity, several-fold greater selectivity for the various beta and the other isoforms, which of course in the aggregate are a big sort of issue in terms of off-target toxicity. What that adds up to is greater combinability. The ability to combine full dose inavolisib with full dose CDK inhibitor, full dose endocrine therapy.
What that translates to, obviously in our dose expansion cohort, you can see the favorable sort of clinical activity with this kind of combination. The other thing that's not shown on here is that there are some patients who have been on this regimen for upwards of two years. The ability to remain on therapy for extended periods of time, this has been an issue with the competitor molecule. We think that there's a very good chance that we could overcome that. Not only do we obviously have our phase III trial that will read out in 2024, which Teresa alluded to, but we also earlier this year announced a head-to-head study in which we are comparing inavolisib to alpelisib head to head in the post-CDK inhibitor setting.
This is all to underscore our confidence that inavolisib could be a best in class PI3K inhibitor that creates many opportunities for patient benefits, not just in breast cancer, but ultimately in other PI3K mutant contexts as well. Then we have our KRAS G12C inhibitor. Here again, we're behind the competition, but we are persisting because we think there is a very good rationale to believe that we have a best in class KRAS G12C inhibitor. Part of that is the preclinical data that you can see in the middle of the slide, which shows that the potency of GDC-6036 is greater than the competitor molecules.
That sort of already was part of the rationale for our clinical development program, which is shown on the right side of this slide, which includes a phase III trial in the second-line setting and a variety of combinations with, for example, immunotherapy, anti-angiogenesis molecules, other targeted therapies. Here's the clinical data that has us quite intrigued. On the left, you can see the waterfall plots from the second-line non-small cell lung cancer context. Unconfirmed, admittedly still ORR, but you can see shaping up 53% response rate in non-small cell lung cancer. Colorectal cancer on the right, 35% overall response rate. You can look up the analogous numbers. Obviously, there's usual caveats of cross-trial comparisons, but these compare quite favorably to the competitor molecules.
We think this provides a reason, not just preclinical, but clinical rationale, for the possibility that this could be a best in class, G12C inhibitor and certainly justifies our clinical development plan. The final point that I'll make before I move on in the targeted therapy space is our recent entry into the DNA damage repair space. Obviously, PARP inhibitors exemplify the importance of DNA damage repair as a relevant sort of cancer mechanism and a cancer therapeutic mechanism. There's a set of next generation DDR targets that are being explored, one of which is a kinase called ATR. ATR is a key mediator. It basically is activated in response to the DNA replication stress, and it is an important mechanism for repair of homologous recombination disruption.
ATR inhibitors have the ability to disrupt that and just to cut to the chase, it's still early days, but we already know clinically that there's single agent activity with the Repare compound, which is called camonsertib. Now a key question is can we dose to adequate levels in combination with PARP inhibitors? In collaboration with the team at Repare, that's being explored now, so more to come in this space. Certainly this is now a foray for Roche into sort of the next generation of DDR. Okay. With that sort of I guess Blitzkrieg view of targeted therapy, I'll move to immunotherapy starting with Tecentriq in adjuvant lung cancer.
What we're showing here is an updated cut of overall survival, and you can see on the left, this is the overall PD-L1 positive population, and on the right is the PD-L1 high population. In both cases, the curves are separating in favor of Tecentriq, and already you can see for the PD-L1 high group, it's looking quite clinically meaningful. Our follow-up continues here, but this is additional data underscoring the benefit and sort of the rationale for the uptake of this indication that Teresa alluded to in her presentation. We have our Tiragolumab slide. I guess basically, Teresa sort of teed up that I probably could have taken this slide out.
I'll just emphasize the point that the aggregate data sort of justifies that this continues to be an important program to us, particularly although we missed the primary PFS endpoint for SKYSCRAPER-01, the numerical differences that we saw in favor of the Tiragolumab plus Tecentriq arm and the fact that we have two more shots on goal for OS. Basically, as you can see, we have a number of readouts. We've already discussed them.
We've already discussed some updates, but just to underscore that we remain enthusiastic about the potential for this to be a new important checkpoint blockade approach in certainly in lung cancer, and then, you know, we'll see what these other indications hold as well. Now another immunotherapy asset in our earlier stage pipeline that we haven't talked as much about is another bispecific antibody, but here we're co-targeting PD-1 and LAG-3. Now you know that LAG-3 is now a validated checkpoint therapeutically, based on BMS's data in melanoma. But in the preclinical data that's shown on this slide, and I'm sorry it's a little bit small, so you. Let's see if I can make this.
Basically what was seen is that the bispecific antibody seems to have a more profound effect on sort of tumor volume control than the two individual monoclonal. If you have a monoclonal against PD-1 and a monoclonal against LAG-3, they don't work as well as the bispecific antibody. We don't yet know why this is, but one possibility is that by having them both on the same molecule, you sort of increase the avidity in the tumor reactive T-cell context, and you mitigate potentially binding systemically of Tregs, which could bring sort of an immunosuppressive effect. We don't know for sure whether that's the reason, but certainly it's biologically plausible.
Our phase I dose escalation data is shown here on the right, and it's still early days, but what's intriguing to us is that we are seeing responses in both checkpoint experienced as well as checkpoint naive patients. Early days, but already this data to us justified an expansion. We've added several cohorts. We have a cohort in checkpoint experienced melanoma, checkpoint experienced non-small cell lung cancer. We have a study in esophageal cancer. We have exploratory studies with Tiragolumab. Stay tuned on this one. We think this could be an interesting one to keep an eye on.
Okay, the last point I'll make in this section, and I'm almost done, is just when we look ahead to immunotherapy still remaining anchored in the science, but exploring additional approaches to how we can specifically be personalized in immunotherapy. The ability to identify and then engineer therapeutics against the specific neoantigen makeup of individual tumors. Some of these are cancer vaccine efforts, including a collaboration with BioNTech, where, at ASCO, we reported still early days, but some intriguing data from one of these products in resected pancreatic cancer. Then we've also have partnerships where we're exploring the ability to engineer T-cells against those neoantigens and then put them into either autologous or allogeneic settings as a new cell therapy approach.
So there's obviously a lot of hurdles to overcome here, but these are examples of ways that we continue to follow the science, and in areas that seem potentially primed in the coming years to lead to new breakthroughs. Now, I mentioned at the beginning, the migration into early disease. This is obviously the importance of the ability to achieve cure and durable control is not lost on us. What we're showing here is that already on this slide, there are. We have 10 ongoing phase III trials across five earlier cancer indications. There are additional, at least a couple of dozen additional earlier stage studies in various early cancer indications that are happening in our portfolio.
As these mature, obviously, we think this gives us opportunity to bring outsized patient benefit in several, very important oncology indications. I'm gonna conclude with just a couple of, vignettes from our non-malignant hematology, one of which, has already been alluded to, crovalimab. This is our anti-complement C5 monoclonal antibody, which was designed using a recycling antibody technology from Chugai. The important thing here is that, this allows, monthly subcutaneous dosing, which will be a difference, from the other, C5 antibodies that are, that are available, which have either, IV dosing or more frequent sort of patch pump, type dosing. The initial data, which, Bill mentioned earlier, positive study in China from the COMMODORE 3 study, so we already have that in-house. Next year we'll see the global data.
One is looking at patients who might switch to this modality and or to this therapy and others looking at naive patients. That's paroxysmal nocturnal hemoglobinuria. It's a mouthful after lunch. There are several other mouthfuls like atypical hemolytic uremic syndrome, Guillain-Barré syndrome, even sickle cell disease, where there's a biological rationale for targeting complement, and so we have studies ongoing in each of those. Then finally, our Spark hemophilia A gene therapy product. In here, the data that we have, we see several favorable features. One is the sort of predictable expression, sustainable expression. You can see that sort of on the right graph.
In 16 out of 18 patients that maintain expression, the median follow-up here now is approaching three years. Then sort of the middle graph is the reduction in annualized bleed rates, a 91.2% reduction. There's been a lot of work by our Spark colleagues to optimize the dose. We wanna maximize efficacy at the lowest possible dose. Then also to tune the immunomodulatory regimen. We all know very well how important it is to get that right. With that in hand, we expect to start our phase III trial with this asset in the first quarter of 2023.
I'll conclude just by reminding you that what hopefully you already know, that we feel in oncology, we continue to have one of the most, intriguing, certainly one of the largest, if not the most, interesting portfolios in the industry. Today, I've mentioned to you a few things. One is that we have several ongoing programs that we feel can extend our leadership in the hematologic malignancies space, including into new areas. We have several precision oncology opportunities that we think offer best-in-disease potential. We have immunotherapy opportunities ongoing that can break new ground, in many ways, whether it's new checkpoints, new modalities, etc. And generally in our.
Where we have a large thrust in early cancer, and then we with our modalities as a whole, sort of as a symptom of innovation, we think we're exploiting opportunities to take to attack many new targets in many different ways. Altogether, we think this positions us in oncology to remain leaders for years to come. With that, I'll stop, and I'll invite Paulo up to talk about the neuroscience portfolio.
Thanks, Levi. Good afternoon, everyone. It's a real pleasure to be here. My name is Paulo Fontoura, and essentially, whatever Levi did not cover, I'm gonna cover to a large extent, and Neil Ashton is gonna follow me with the ophthalmology update. Just to start on neuroscience. As you can see here, and I've been saying this for a few years, I think at Roche, we have one of the best, if not the best, portfolios. Certainly one of the largest efforts in neuroscience globally. And as you can see here, this includes several molecules, some of which have been launched and developed, some of which are in phase III, but a really steady, robust pipeline, very diversified. Several types of treatment modalities, not just small molecules, but also large molecules, gene therapies, you know, antisense.
also really addressing both very large medical needs, such as Alzheimer's or Parkinson's, but also more rare you know, diseases in which we think there's a faster path towards development. really a very exciting pipeline. I'll be trying to provide a few highlights on the key programs here. starting with Ocrevus, obviously the flagship program. As Teresa mentioned, Ocrevus has really been a game changer in terms of multiple sclerosis therapeutics, the only drug approved for both relapsing and progressive forms. the data just keeps getting better year after year. what are we still doing with it?
Well, first of all, as was mentioned, obviously patient convenience at home is a very key topic, and we think it's a growth, you know, opportunity and the ability to get more patients have access at home. Therefore, our sub-Q program, which allows patients to be dosed every six months, would be a big game changer for them. Additionally, we showed this data before, we know from the analysis of our phase three program that deeper levels of B-cell depletion leads to higher levels of progression control. Therefore, this is something we're trying to really look at now with our high-dose program. This looks at essentially maximizing the effects on progression and disability for both relapsing and primary progressive patients.
The third arm of this is that as we believe that progression is mostly driven by resident B-cells in the CNS, increasing the penetration of, you know, Ocrevus into the CNS using our Brain Shuttle platform, we think could be another arm that allows us to really control progression in these patients. Now, of course, the next target that everyone's really talking about is BTK. As you know, we have a BTK inhibitor in phase III development. Now, we think that ours is possibly the best-in-class molecule here for a variety of different reasons. First of all, it's the most selective one. Secondly, it's a very highly potent one. Thirdly, it's non-covalent binding, so it's reversible, which is important for, you know, safety purposes.
You know, fourthly, we already have a very large safety database, including over 13 phase II trials, over 1,700 patients dosed already, and we know the safety profile of our drug really, really well. Now, what we've tried to do with our BTK is actually to do a development program that addresses the real medical needs. As you can see here, we are going head-to-head against standard of care therapies, both in relapsing and in primary progressive disease. That's against teriflunomide in relapsing disease and Ocrevus in primary progressive. The reason for doing this is that we're not just interested in developing another MS therapy, but really in developing the best MS therapy.
BTK might actually be particularly relevant here because it addresses not just B-cell function, but also microglial and macrophage function, which we think are key drivers in the pathophysiology of progression. Turning a little bit over to risdiplam in spinal muscular atrophy. Now, of course, the data that has been coming out is super exciting. I wanted to point out just a few things. First of all, the largest prevalent population in, you know, SMA are actually patients with type two and type three. These are the older children that have had progression and visibility for a long time. For these patients, the thing that matters the most is not just gain in motor function, but it's actually stability of clinical outcome. Not losing any more function.
The data that we keep putting out from our SUNFISH trial that you can see here on the left-hand side essentially shows that year on year, there's not just an increase in motor function, but actually stability. There's no decline in these patients, especially when compared to natural history, which you can see here in the middle box. Increasingly important as well is that the safety profile of these drugs needs to be compatible with long-term dosing. On the right-hand side, you see here the adverse event rates for, you know, SUNFISH patients, both the ones that were originally on drug and the ones that came to drug after the first year.
You see year-over-year actually a reduction in the adverse event profile that's possibly due as well to the improvement in overall, you know, health motor function. These patients are just getting less sick and therefore the overall outcome is much better. Of course, we're always very, you know, excited when we look at data from our RAINBOWFISH trial, and Teresa mentioned this. This is a trial done in babies with SMA who are identified by neonatal genetic screening. This is possibly the biggest paradigm change in terms of how you treat, you know, patients with SMA as early as possible. We know that leads to a better clinical outcome. RAINBOWFISH was decided was essentially trying to address that.
Could pre-symptomatic or as early as possible treatment result in an almost normal clinical development? You know, the data is here. Essentially, it shows that both on CHOP as well as on motor milestones, these babies are developing essentially normally and achieving maximal scores, and again, with the same safety profile. Now, of course, this is a big game changer and the fact that for risdiplam, you do not need to do any sort of testing for, you know, antibodies or things like that, or you need a special IT. This is much easier for physicians essentially to diagnose and start treatment as soon as possible. For these babies and moms, every day counts, literally. This is super relevant. Where next? I mean, we've had three disease-modifying therapies for, you know, SMA developed in the past decade.
For the most prevalent population of type two and type three patients, these patients need to regain motor function. One of the best avenues to do that is just to rebuild muscle. Muscle growth became a very important topic, and one of the best validated mechanisms to do that is blocking myostatin. Myostatin is a key negative regulator of muscle growth, and therefore targeting myostatin has become really topical. Now, GYM329 is a molecule that came from our Chugai colleagues. We think it's the best-in-class molecule to target the latent myostatin. It does so extremely potently because it has this sweeping recycling, you know, technology. It's once a month dosing. It's a very, very good drug. We have clinical data. Sorry.
Preclinical data that you can see here in the middle panel that shows that in animal models, it leads to muscle buildup and return of function in these animals. What we did based on this is actually started a trial now called, you know, MANATEE, that looks at the combination of risdiplam and GYM329. Why does risdiplam make the most sense here in my mind? Because you need a drug, you need a disease-modifying drug that is administered and has systemic effects, not just CNS, you know, targeting. If risdiplam being oral and systemically, you know, available to all the body, essentially corrects the genetic defect in muscle cells in the whole body, and then you can combine that with an anti-myostatin that would lead to muscle growth.
Moving on to Enspryng. Enspryng is, we think, the best-in-class anti-IL-6 receptor, you know, antibody. Again, the molecule coming from our Chugai colleagues, sweeping and recycling, you know, a technology that leads to very high levels of suppression of IL-6. Now, we know that IL-6 is central to several diseases of the nervous system, myasthenia gravis being one of them. You know, therefore, after our approval in NMOSD, we decided to go to myasthenia gravis as our next big disease. Of course, this is not an uncommon autoimmune condition for which there are several therapies. There's still a tremendous amount of medical need for these patients, especially for patients with generalized myasthenia gravis, and therefore we started a trial to look at that.
At the same time, we have other trials looking at other diseases of the nervous system which are mediated, we think, by IL-6, such as MOG, you know, AD and autoimmune encephalitis. You've heard already this morning a lot about our excitement around gene therapy. For Duchenne muscular dystrophy, gene therapy could be the biggest game changer in the history of this disease. Up until now, this is an invariably fatal, you know, condition with very high levels of disability. The treatments that are approved right now really provide very, very small benefits. Gene therapy is and will be the big game changer if it works. Now, we're very excited about this one. It's called delandistrogene. Talk about mouthfuls. This is a...
It's a gene therapy that we are developing in partnership with our colleagues at Sarepta. It has, we think, the best mini dystrophin construct with a promoter MHCK7 that essentially drives expression in muscle and, you know, cardiac cells. At the same time, it has an AAV vector, which is specialized, AAVrh74, for which there's much lower levels of pre-existing, you know, antibodies, and therefore it's much more likely to be administered to a bigger range of patients. Now, we're very excited about this one as well because of the emerging clinical data. Now, in the middle panel here, we're showing you the data from study 103. This is the commercial product, essentially the product that is developed in phase three.
We see here in this trial that has 20 patients, an increase in over four points in the NSAA, which is a motor score, the primary endpoint. That's over one year. When you compare that with natural history, which is the bar chart in the middle, you see essentially a delta of about 3.5 points. Now, that's not only remarkable, but clinically very, very meaningful. On the right-hand side, you see data from the first study ever done, study 101. For these patients, we see already four years data. In those patients, you see essentially a seven points increase in the NSAA. Now, durability in gene therapy is a very important topic, especially as we know these boys grow, muscle cells divide, and therefore, there's this worry, will this stay.
Will this benefit stay, you know, in place? Apparently, it does so. Now, equally importantly here is that the safety profile that we've observed so far for delandistrogene is very encouraging. As we know, we have seen this, gene therapies are still very young technologies, and there are still safety concerns about them. Delandistrogene appears to be a safe therapy that can be administered very, very broadly and provides clinical benefit. Based on that, we're actually in the middle now of a very large phase three program.
On the left-hand side, you see our core pivotal trial, which looks at boys between four and eight years old, looking at one year duration of follow-up and the NSAA as the primary motor endpoint. This is still for us, the core package of data that will lead to approval for delandistrogene moxeparvovec. On the right-hand side, you see the additional pivotal trial. We're going to look at both older ambulatory and non-ambulatory boys, but also younger below three years of age children. To really try and get it as a broad label as possible and you know, demonstrate the clinical benefits of this therapy in the widest possible range of these patients. Now switching over, which I guess is one of the reasons why you're all here.
Gantenerumab has been mentioned already several times today, and as Bill mentioned, our conservative view here does not represent a lack of commitment or, you know, enthusiasm, but it is a very difficult area. I thought it'd be important just perhaps to level set where we are now by starting to describe what is the background as we come into this big data readout in the end of this year. Well, first of all, you know, Gantenerumab is an anti-amyloid beta targeting, you know, antibody, targets fibrillary aggregated forms and plaque very, very potently and very safely. We know from our long-term extension data from SCarlet RoAD and Marguerite RoAD that after two and three years, over 50% and over 80% of patients become amyloid negative by PET. It clearly does what it's supposed to do, gets in the brain, removes amyloid.
Based on those data, we designed a GRADUATE program. A GRADUATE program, we believe is going to provide essentially kind of a conclusive answer to the question that we all care about. Does treatment with Gantenerumab over a sufficient duration of time, so we have 27 months, at a high enough level, so everyone's titrated up to 1,020 milligrams regardless of APOE genotype, in the right patients, so prodromal and mild patients identified by CSF testing and PET imaging. Essentially, does that right experiment demonstrate clinical benefit or does it not? We're very, very excited about the outcome here. Obviously, we don't have a crystal ball, but I think we're very confident in the job that has been done. This is a very well-designed program which will provide clear answers.
Now just preempting one of the questions which I know that we'll get is, does the change in, you know, amyloid or Alzheimer's diagnostic criteria, you know, over time make a difference, the inclusion of tau versus not at baseline? We really don't think it matters much. We're showing you here the baseline data for the patients of GRADUATE. Essentially, these are very typical prodromal to mild patients which are, you know, identified with state-of-the-art clinical and biomarker, you know, criteria. So again, we think we've done as much as we can here. Now, this doesn't end here. Of course, we know that Alzheimer's is a disease that develops over years and decades, and therefore, actually the biggest population out there is the presymptomatic one.
If a drug works in prodromal and mild, I think it's a fair question to say, does it work in presymptomatic patients as well? Based on that, we've decided to start this phase III trial called Skyline. This is looking at presymptomatic Alzheimer's patients that we can identify now based on biomarkers such as CSF testing or PET imaging, and look at them over four years to see if we can prevent the onset of dementia. Now, of course, it's a very different clinical problem to try and treat presymptomatic patients. These people, by definition, have no symptoms. How do you know, identify them not only for clinical trials, but then for future practice?
That's why we are developing as well these blood-based biomarker screening tests to allow people to have an easy way to essentially have a high probability of making it into the screening funnel. These blood-based biomarker tests essentially allow you to double the screening efficiency, you know, if you want. Many fewer patients will get in to do CSF testing or PET imaging if they have a positive blood-based biomarker test. For this is running on our, you know, Elecsys platform, and we've got breakthrough device designation for that as well. Now, you know, Gantenerumab is obviously the flagship here, but it's not our only program. I'd like to mention very briefly two other avenues that we're continuing to develop, one of which is the Brain Shuttle version of, you know, Gantenerumab.
It was mentioned already that one of the biggest problems we have with large molecules is that only about 0.1%-0.2% get into the brain. Obviously, a technology that would allow up to 50-fold higher CSF and brain parenchyma concentrations would be very, very relevant. Brain Shuttle Gantenerumab is based on that. It's essentially Gantenerumab with a module that targets the transferrin receptor on endothelial cells in the brain and allows the transfer of this antibody. You see the CSF data here from our first phase I trial, which shows up to 8-fold higher CSF levels of brain shuttle Gant versus the non-brain shuttle version. We're really excited to see these data.
Tau remains, I think, inevitably one of the big targets of interest for us. It is undoubtedly a key in the pathophysiology of Alzheimer's. We're targeting it now with two monoclonal, you know, antibodies, the semorinemab and the bepranemab. The data are still coming in. It's not been easy, and it's not going to be easy, but, you know, this is one of the long-term bets that we're, you know, excited about. Tau is gonna be part of a solution for Alzheimer's and for many other neurodegenerative conditions, inevitably. We wanna keep doing that. Now, switching gears here to the earlier pipeline. For Parkinson's, which is one of the most common neurodegenerative conditions out there really has not been a breakthrough in two or three decades.
We're still treating patients with Parkinson's essentially with dopa agonists, and that's really it. New therapies, disease-modifying therapies could be really a game changer for these patients. Alpha-synuclein is one of the most validated genetic targets in Parkinson's, if not the most. Therefore, we are excited to develop prasinezumab, which is a monoclonal antibody that targets aggregated forms of alpha-synuclein. Now, the data I'm showing you here is really the first glimmer of hope for this target and for this molecule. Other companies have tried this and failed. Our data shows, at least in the PASADENA trial, that in patients with very early Parkinson's off dopaminergic therapy, you do see a separation in the motor score of the UPDRS.
This separation prolongs itself not just after one year, but after two years. We saw it as well in our digital endpoint, which you see here on the right-hand side. This is a new technology based on the Floodlight platform. That kinda gives us a little bit more assurance that this is a real signal, but obviously, this is by no means a definite signal. We're trying to confirm these data in the PADOVA trial. The PADOVA trial looks at early Parkinson's patients treated with dopaminergic agents, and we're trying to see if we can replicate this signal before, you know, moving forward. Just a brief note on Angelman syndrome. This follows on our quest really to look at rare neurological, you know, diseases with highly validated targets. In this case, Angelman's is a rare form of neurodevelopmental disorder.
It's a form of autism, you know. These children essentially, after two years of age, don't develop any more cognitive function. They have mental retardation, they have seizures, they have sleep problems. Really high burden, not just for them, but for their parents, for their caregivers, and there's no therapies here. Now, we know that Angelman is caused essentially by a loss-of-function mutation in a gene called UBE3A on chromosome 15q . What we found out is that we can actually de-repress the parental copy of this gene in the brains of obviously, you know, animal models, but of these patients as well, by using an antisense, it essentially blocks a blocking signal that all of us already have, you know.
Therefore, we're kind of rescuing this function by using a gene that's already there. Now, it's a very exciting, you know, a new approach, and we're in the middle of our first trial. This is called TANGELO. You see it here on the right-hand side. We have a first portion, which is essentially a dose-ranging, multiple-ascending dose portion in children up to 12- years of age. We're really going very carefully here because we know, and so one of our competitors had this, there are concerns around safety. So far, we really have not seen anything, and we were able to dose escalate to the maximum dose level. Now we've moved from this first multiple-ascending dose stage to the long-term, you know, extension phase on the extreme right-hand side here.
This part two of this trial really will look at the long-term benefits, potentially, that patients can get by de-repression of the UBE3A gene, and we're very excited to see that. Hopefully, we'll get data as early as the end of next year or beginning of 2024. The final word on stroke is to pick up on where Teresa left. I mean, stroke is one of the real medical needs in neuroscience. It's the fifth global cause of death from any cause. In neurology, it's the leading cause of disability for all patients, especially for older patients. Unfortunately, really, no advances have occurred in this field in the past 30 years. You know, alteplase, which is still the only approved drug with an FDA label, is a drug from the 1990s. It's a great drug.
It has this limitation that it can only be given up until three hours. Now, that precludes the large majority of patients from getting thrombolytics. Only 50% of the overall stroke patients get alteplase. Of the eligible patients, only 50% of them get it because the thrombolytic. It has a higher affinity for thrombin. It has a higher specificity for fibrin. It's a faster onset of thrombolysis. So essentially it allows this drug to be more potent, if you want, and to have a faster start, and therefore to be administered as a single bolus instead of an infusion. So on that side, an advancement was made.
What has happened in recent years is that more and more trials have been made with this drug, which has not led to an approval, but have generated a lot of evidence that it's equally as good as, you know, alteplase, potentially better for large vessel stroke. Really the question here is what happens if you don't get to the hospital within that time window? That's what the TIMELESS study is trying to look at. For patients that have salvageable brain tissue, and now we have advanced imaging that allows us to say, for any stroke patient, there's still brain tissue that can be rescued. Can we, up until 24 hours, still give tenecteplase safely and have clinical benefit? That's really what the outcome here is.
We're looking at patients that will be treated both with tenecteplase as well as mechanical thrombectomy, meaning that against a broad range. We're very excited to look at these data as they come out early next year because if positive, this could really be the first real breakthrough in this field for decades. Now switching quickly to our you know you know immunology efforts. Of course, we're very excited about the medicines we have on the market now, but they are coming to the end of their life cycle, and you saw that there's still a huge medical need here. This you're seeing here is really the renewal of our efforts in this field. Right now, the most advanced programs are in nephrology and respiratory. We have earlier programs as well.
I briefly mentioned we also obviously have our dedication to flu, to you know hepatitis B. Today, I really would want to focus on our emerging pipeline of late-stage molecules for nephrology and for you know respiratory. The first one is Gazyva in lupus. Lupus and nephritis is a disease that affects about 5 million people worldwide, so it's a big medical need. About 25% of them really don't get any stabilization with current therapy. They go on to end-stage kidney you know disease, and therefore we need just better therapies here. Now, Gazyva is an anti-CD20 you know antibody that has been engineered to provide much deeper levels of depletion of B-cells, both in the blood and in tissues.
This is relevant because we've realized that a lot of autoimmune, you know, conditions are really driven by locally resident B-cells and not by systemically circulating B-cells, and therefore depletion in tissues has become a real target for us. Now, we're very encouraged by the phase II data that we've generated. In the NOBILITY trial, essentially in lupus nephritis patients treated over 54 weeks, we saw essentially a 20% absolute increase in the percentage of patients that achieved complete renal response, so were essentially stable. This percentage seemed to increase over time. Now for REGENCY, which is our phase III trial, we're extending the duration of treatment up to 74 weeks.
Based on these data and others, we're also extending to look at other diseases of, you know, such as nephrotic syndrome and membranous nephropathy, which are again major medical needs in the nephrology field. Our most advanced program in respiratory disease now is the zinpentraxin alfa program. This builds on our commitment to idiopathic pulmonary fibrosis. Pentraxin is an immune regulatory protein that essentially shifts the differentiation profile of macrophages from pro-fibrotic to pro-resolutive, and therefore we think reduces fibrosis. What we're very excited about is here in the middle panel is the data from our phase two trial that was run and that got breakthrough designation.
These data showed for the first time that on top of standard of care therapy such as Ofev or, you know, Esbriet, we still saw a significant improvement, or preservation in functional vital, you know, capacity over 2.5 percentage points over about 50%, 50 mL of FVC. At the same time, a stabilization in motor function over six months. This is unheard of, and therefore, based on that, we went on to phase III. Our phase three trial is a very large trial, around 660 patients over one year treatment, again, on top of either Ofev or, you know, Esbriet. We're really looking forward to seeing these results in 2024.
Really the final one that I wanted to talk about is our recent addition to the pipeline, which is our antisense ASO Factor B, a program for IgA nephropathy. Now, IgA nephropathy is actually the most common immune-mediated glomerular disease in adults. It is a severe condition. A high percentage of these patients go on to end-stage kidney disease, need a transplant. We do know this is a disease caused by immune deposition of both antibodies and a complement. Therefore, targeting Factor B makes tremendous sense. It essentially blocks that complement cascade. Now, we have phase II data, which is not published yet, but I can share just top line.
We've seen a very robust and significant reduction in the decline in glomerular function. Therefore, based on those data, we were very, you know, very eager to bring this molecule in and start phase III trials, which should get started as early as the beginning of next year. With that, I think I'll turn it over to Nilesh to tell us about the ophthalmology pipeline. Nilesh.
Thank you. Thank you, Paulo. Let's just get this right. It's a real pleasure to be here with everybody. It's my role over the next 15 minutes or so to give you an overview of what we're doing in ophthalmology. I'm Nilesh Mehta. I'm based in Basel. I'm the global lead for ophthalmology. Let's just start off actually with the unmet need here. In the advent of anti-VEGF therapies, we still know that there's a huge unmet need for patients here, both in terms of in clinical trials, where patients are followed up really robustly and treated rigorously. Even then, only about half of patients get to really good outcomes for visual function.
In the real world, of course, we know that healthcare systems and patients can't keep up with those treatments, and therefore they get much worse outcomes than the clinical trials. Both ways, what we're looking to do is even when you're treated robustly with anti-VEGF therapies. We know that that's however much anti-VEGF we give isn't the full answer for these multifactorial diseases, and therefore adjacent pathways become really important. Then in terms of real world, you know, as we get to greater durability, we'll be able to treat patients for longer and sustain their visual outcomes that way. Here I wanna just walk us through two slides here for the Vabysmo trials. Vabysmo in DME. Here, the study design is quite important. In DME, there were three arms to the study.
The control arm was a loading phase of aflibercept, give it and then followed by every eight weeks. Then two other arms, faricimab with the loading phase and every eight weeks. Also faricimab, a loading phase, and then what we're calling personalized treatment intervals. This is really aligned with treat and extend principles that many doctors use in the clinic today. What's important to note over these two years, we've now shared these data, the one-year data in 2021, and this year, the second-year data, is the consistency of the BCVA curves over time. Every time point slightly favoring faricimab and the two-year data, in terms of anatomy, for both of those arms, slightly favoring faricimab. That's been consistent over these two years. With AMD, the design was slightly different.
In the first year, again, the control arm was aflibercept with a loading dose and then every eight weeks. The arm of the study would start off with Q16 dosing, Q16-week dosing. At weeks 20 and 24, patients could drop down to 12 or 8, and then they maintained that dosing regimen right up to week 60 when patients rolled over into a personalized treatment interval into the second year. You can see here the really consistent results, both in terms of function as well as anatomy on the right-hand side of this graph. I think, you know, we'll see longer term extensions from that data as we move forward.
We're really excited to be able to share, you know, with Vabysmo now the Q16-week dosing increasing from year one, sort of 50%, to year two, 60%. You know, this is now multiple cycles of Q12 and Q16 dosing. This is consistent across all four studies. I think this is really interesting and consistent data for the community to take away. You see the disease control in terms of CST. You're also seeing the safety profile of the product in the phase III studies look very much akin to IVTs as doctors know them. As Teresa mentioned, we now have about 130,000 vials out, and we're not seeing any concerning safety or new signals of safety emerging.
Further, the clinical development program continues. Retinal vein occlusion, which is really the third biggest area of retinal diseases, we expect data at the end of this year. Then AVONELLE-X and RHONE-X are gonna be really important because these are long-term extension studies that will go on for four years. We'll also be able to see the impact from the comparator arms switched over to faricimab over a long period of time. You know, if we talk about real-world, and I'd like to talk about this study, which is the TRUCKEE study. This is not a study that's actually supported by Genentech or Roche. This is a ground up investigator-led set of studies of about 14 sites currently operating. This data is being shared at a number of conferences this year.
It's really early, real world evidence for Vabysmo in clinical practice. What you're seeing is really even in patients that are quite recalcitrant to anti-VEGF therapies, the early doses of Vabysmo are really showing a really potent impact on the anatomy here. On the right-hand side here, you're seeing previously monthly treated aflibercept patients treated one injection or with Vabysmo and quite a lot of normalization of the retina, which is really encouraging to see. Now you're seeing about 1,000 injections in this study, and again, no concerning safety effects. Susvimo. You know, if we move to Susvimo, this is the first drug device combination in retina. It's truly a s...
It's miraculous to see over so many years, the development of this program. Obviously, as you know, after the surgical procedure, you only need a refill every six months. On the left-hand side here, what you're seeing is that this is maintaining vision over two years compared to the gold standard, which is monthly Lucentis injections. That's never been bettered in retina, and you can see that the durable response doesn't seem to be going down. You're really still seeing 94% of patients going six months or longer with their refill exchanges. This program continues. We're gonna see data from the Pagoda and Pavilion studies, which will be in DME and DR, towards the end of the year.
The Velodrome study, which will look at nine-month dosing as well. The other thing to note here, I think, is that really there's no competition in the near term for this product at all or in the midterm even. The Port study, which will be real-world evidence, by the time anything we think will emerge in this space, which will be a port or a long-acting device, this will have such long-term data, I think it will be really challenging for people to catch up with that long-term efficacy and safety data. It's gonna be very important to see how that data continues to roll out. Here with the ophthalmology pipeline, we're really excited that we have Vabysmo, Susvimo, being...
have launched in the U.S. and Vabysmo in a number of other markets this year. There's a huge pipeline following in ophthalmology. I think this speaks a lot to what Bill was saying about the earlier investments in R&D, allowing us to accelerate some of these programs into clinic. What I'd like to really talk a little bit about is some of the programs that we've disclosed, and I'll touch on some of these in the coming slides. Before I go into that, what I'd really like to do is just frame for you how we're thinking about approaching ophthalmology. Today, where we are in this middle column, today's therapy, we see this functional loss, and then we treat patients, and they get some of that loss back.
We're trying to optimize there with new modes of action, new modes of biology to the eye, adjacent pathways to anti-VEGF to optimize outcomes. But also in the future, we'd like to go into earlier stages of disease, and that's becoming possible because of the amount of imaging as well as clinical biomarkers that we have. We can really apply now AI and deep learning to those images to find those tipping points. In the future, we hope to be able to prevent vision loss, especially in conditions like intermediate AMD or diabetic retinopathy.
Further, the science is evolving so that with cell-based therapies or optogenetics, we'll be able to restore vision in parts of the retina, in tissues of the retina, to give people who are blind now the ability to see again, and I'll talk about a couple of those programs as well. Let's start with one of the programs here, which is the IL-6. The unmet need here is really inflammation in ophthalmology and in retinal conditions. This has been an area of unmet need over many years. I might even say decades, if you go back to the earlier work from Professor Coscas and Massin. There's been decades in coming.
The important piece here is that the only approach to inflammation right now in ophthalmology is steroids, and they come with a plethora of adverse events. Here we see IL-6. We know that it's involved in inflammation. You can see on the right-hand side here, how in pathologic eyes, how upregulated that is as a cytokine. We have an anti-IL-6 monoclonal antibody with a modified Fc portion that will allow us long acting in the eye, but quite fast systemic clearance. We have a phase two study ongoing in diabetic macular edema. That's in combination with anti-VEGF therapies. This year we've seen phase one data in uveitic macular edema, UME. This is a disease which is predominantly driven by inflammation.
We think it could be a really interesting area. We're gonna accelerate this from phase I into phase III, with a study startup towards the end of the year or early next year. DutaFabs. I think this is something you've all heard of before, in some of these meetings, but worth just touching on. We really think of these as the next generation of antibodies. They are able to be concentrated, they're Fab fragments, to highly concentrated and with high affinity to their binding site. What this allows us to do is have a stable molecule that could also go into the Port Delivery System for sustained release. The first of these that's going into clinic is going to be the VEGFxAng2 DutaFab.
That's in a phase I study, and it will go from the IVT into the Port Delivery later this year. Let's move to geographic atrophy. One of the last frontiers of unmet need in retina. It's a multifactorial disease and highly correlated to age, as you can see from this chart. In fact, I joined Roche partly for the lampalizumab program in GA, and I'm really proud that the team continued to analyze that data and provide data to the community because this will allow us to expand our knowledge to address this devastating disease. Here's approach in phase II. It's in collaboration with Ionis. ASO Factor B, we're seeing emerging evidence that complement is a pathway that is involved in geographic atrophy, and ASO Factor B targets the alternative complement pathway.
Both the preclinical and phase I studies looked very encouraging and this study is ongoing and we expect some data in 2024. Moving on to cell-based approaches. The OpRegen program is a deal with Lineage Cell Therapeutics. What this does is allow us to introduce retinal pigment epithelium into the retina. As you can see on the left-hand side, after the introduction of a single delivery, subretinal delivery of this, the retina's you know really becomes quite more normal than before. You see a huge amount of both anatomical convergence to norm as well as functional gain here, 7.6 letters, which we thought even with 12 patients was very encouraging.
These cell-based therapies will now really provide the opportunity to restore vision or anatomy even in quite advanced diseases. I'd be remiss if I didn't also mention the tremendous efforts being made across the organization on personalized health care. They're both in terms of remote vision monitoring, which will allow patients with their chronic conditions to have a much better experience of their diseases and their clinical practice. Also, with the amount of data that, as Roche, we're gathering internally in our studies and the ability to apply AI and automated segmentation for OCT, for example, we'll be able to probably have better target selection, enrich patients into clinical studies, as well.
Both of these areas are areas that internally and externally, we have lots of collaborations ongoing. We think that in the future we'll be able to address patients' disease over time with far more specific management tools. Really, you know, with that, I'd like to say we're in the cusp of really new standards in retinal care. I'd be remiss if being in London and using the analogy about buses that, you know, you wait for three hours and then two turn up together. We're at the time where really we've waited for 15 years in retina for new innovation. Now we've got two Vabysmo and Susvimo that both came together, which I think is quite amazing.
Using that as a backdrop with our pipeline, we'll be able to hopefully expand outcomes for patients as we move forward. Thank you.
I think with that, I would ask all our speakers back on stage for the final second round Q&A session. I think now we have all the experts on the stage to ask all your high-level earlier questions because I think there are probably some around. Don't be shy. Emmanuel, you're the first one.
Thank you. Emmanuel Papadakis, Deutsche Bank. Perhaps I'll take the privilege of the high-dose flu aspect question perspectives on that eight-week data. Any nuances you think we should consider in terms of the competitive risk it may or may not represent? Question on SERD, Giredestrant, your degree of confidence in showing an outcome of benefits in persevERA and lidERA based on the clear skewed benefit in the ESR1 mutants and the acelERA data you just presented. And then perhaps a final question on the bispecifics on my left. Pretty late on GPRC5D. Sovostamab, we saw great data two years ago, doesn't seem to have got very far since then. Thoughts on phase III, how are you gonna catch up and differentiate in that landscape? Thank you.
Do you want me to go with the high dose first then?
Yes.
Okay. Thanks. Thanks for the question. Yeah, we're obviously we've seen the data. I think the headlines are one thing we'd really be interested now to see, the fuller dataset, hopefully at AAO, especially with the BCVA curves over time and the CST curves over time. To put that in context, as I sort of mentioned in the studies for faricimab, we had quite strict control criteria where you would look at both, anatomy, function, and clinical examination, and any one of those could trigger a shorter dosing interval. We'd like to be able to understand this data a little bit further. Once we see the BCVA curves and CST over time, I think that will put more context on that data.
Yeah. Maybe I ?
Yeah.
Just to maybe reinforce that a bit. I think in our studies, we had a high bar for putting patients onto a less frequent dosing.
Mm-hmm.
In other words, a very much of focus on delivering the maximum benefit, clinical benefit, maximum duration for every patient and a high bar for going on a less frequent. I think what you'll wanna ask and probe on the data from competition is, do they have a high bar for achieving or for taking patients onto a less frequent or a low bar for putting patients on less frequent, sort of a high bar to maximize the percent of patients on less frequent dosing. I think that's, to me, that's what really stands out on our data is that, you know, the patients in the 16 In the 12-week arm, they are getting very similar, almost identical outcomes to the patients in the other arms.
If you see sort of a tailing off of efficacy in the less frequent dosing arms of another study, you know, that might be because of a compromise on that.
Yes. Maybe I'll take the question on Giredestrant. I think the key point is actually the fact that it happened to be ESR1 mutations in the later line. The key point is the context where there is dependence on the estrogen receptor for signaling in that cancer. The earlier you go in breast cancer, the greater proportion of patients that have dependence on the estrogen receptor. Basically, in the frontline, untreated metastatic setting, and certainly in the early stage adjuvant setting, there's a near uniform dependence on the estrogen receptor. Basically that's why. And the potency that we have, it's irrelevant whether it's mutant or wild type. It's the same phenomenon. As long as you have dependence on the estrogen receptor, Giredestrant has a shot at bringing a benefit.
In the setting of the myeloma, a general rule in cancer is that it's not about whether you're first to the later line therapy. It's about whether or not you can achieve the right dose and the right combinations and move forward in therapy. We think that within our portfolio, we now have several opportunities to ultimately generate differentiated combinations that are anchored by very interesting molecules that can lead to a lot of patient benefit. There's clearly plenty of unmet need remaining in myeloma that has not been addressed.
Thank you. Just wanted to mention, we also have one more person here standing by from the team, which is Sascha Fauser, who is our ophthalmology head in pRED.
Ophthalmology.
Ophthalmology head in pRED. If you have any questions on the early ophthalmology pipeline, he will be the person to take. Wimal, can you please first?
Oh, great. Thank you very much. Wimal Kapadia from Bernstein. First, just on zinpentraxin alfa. Now, this is quite a tough to treat population, and I would argue some of the phase II outcomes were not only comparing like a 2.3% difference I can see on FVC, the lung volume was the same. I guess this could be a very, very big asset. There's a level of conviction into that early 2024 readout. I would be curious to hear that. Then maybe just a high-level question on the pipeline. If I take a step back and I look at your portfolio of assets that read out over the next two or three years. How does Roche actually think about the risk profile of these assets?
If I'm thinking here, prasinezumab in Parkinson's phase II mixed, IPF, heterogeneous population, DMD gene therapy, quite difficult. Fenebrutinib, you've never tested the drug in MS before. There's quite a few high-risk assets within the portfolio. Are you happy with the risk profile, or do you think you need a few, you know, maybe more conservative surefire bets within the portfolio? Thank you.
Thank you. I guess I'll take the zinpentraxin alfa first. I think when you look at those phase II data, and obviously there's lots of caveats. It's a small study. It's 180 patients, only six months. It's a breakthrough in the sense that no one has ever seen that type of reduction in decline in terms of forced vital capacity. So 2%-3% over six months possibly translates into something much bigger at one year, which is what we're looking at now. Again, this is on top of standard of care for these patients, right? These are not highly declining patients, at least in this study. I mean, there are other phase II trials out there which look at much higher deltas. Again, these patients are really, like, declining super fast.
These are normal patients on optimal therapy, and we can still demonstrate the benefit on top of that. Additionally, it's not just on forced vital capacity. You look at the six-minute walking test, which is one of the key secondary endpoints, and that essentially measures, you know, how patients function, their endurance to physical stress. You have stability over six months. Again, something that doesn't happen in these patients. IPF is a very severe progressive condition. I think these data are very encouraging in that sense. Now, are they definitive? Of course not. That's why we're doing a phase III trial, and we're extending the duration to one year to really see what the benefit is. We're powering that study to really detect a robust difference. It's from 180 patients to 650.
We're still putting it on top of standard of care for these patients, 'cause again, at the end of the day, we want something that's clinically meaningful, right? Level of confidence, I'd say it's a very exciting new, you know, hypothesis that we're testing right now. I don't know if you want to take the risk questions. This kind of relates to the risk question.
Yeah. I can start, and then if others wanna chime in. It's a great question, certainly something we talk about a lot. You know, of course, a cynical approach to reduce risk would be to make nothing but me-toos. Of course, that's not who we wanna be. That's not who we are. Inasmuch as your portfolio is innovative, you will carry some risk in the portfolio. It's sort of just baked into the business that we are. Now, having said that, I would argue that there are several programs that we presented today that we actually feel like the risk is quite reasonable. I mean, it's not zero, but we think the risk of ESR1, that's ESR1 is a very well-validated target in breast cancer. The risk of PI3K inhibitors, that's a very well-validated target.
Important oncogene, not just in breast cancer, in many other contexts. KRAS. You know, there are several programs that we actually think they are reasonable value that they could bring, but also they are reasonable risk. Now, there are others that are higher risk, but in all of those cases, what we are trying to do is say, well.
What is the scientific rationale? Is the scientific rationale robust from the standpoint of this therapeutic hypothesis? If the answer is yes, well, that's usually a bet that we wanna consider. We don't wanna skew our portfolio only to those kinds of high-risk bets, but we wanna have enough of those because that's where the breakthrough advances. Over time, some percentage of those will pay off for patients, and that's who we wanna be as a company.
Maybe I could just add, so I've been, you know, part of this portfolio for 16 years, and I'd say the risk looking ahead is about like the risk looking back. You know? That's the nature of the game. If you look, I think in our last 22 molecules that we've had approved, three of them had in-class, you know, competitors. 19 were all by themselves, which can be lonely and risky, but, you know, it's also been our success. I'm not sure I would do it any other way, you know, given our commitment to breakthroughs. And as Levi said, I think, you know, there's a lot of. You mentioned DMD and the risk, but, you know, now we have data up to four years in those first patients, and they're rock solid.
I mean, they improved, and then they've stayed rock solid. That's not the natural history of muscular dystrophy. I mean, this is a rapidly declining disease and as an example. The combination of biomarker data and that clinical data, I think gives us. Again, it's not like, oh, this is in the bank or, you know, this is a done deal, but it gives us pretty.
May I ask you to just stick to one question, please? Luisa.
Thank you. Luisa Hector from Berenberg. Maybe to move to fenebrutinib. I noted your comments on number of patients treated and the profile, but how confident are you in the liver enzyme situation that competitors are experiencing? When might we expect to see the data from the two different studies? Thank you.
Yeah. Thank you for the question. Yeah, I mean, I think these are all physicochemical properties and profile we have is based on the selectivity of this molecule. It's the most selective BTK inhibitor out there. The non-covalent binding properties, right? Of course, a big safety database. We're not, to your earlier question, just jumping into phase three with an unknown molecule. We know this molecule very, very well. So far, we have seen some liver enzyme elevations that are transient, asymptomatic, no Hy's Law cases. We, of course, have a very stringent safety monitoring program, which means if anything ever happens, we're there. So far, we haven't seen anything. I do believe this has to do with the properties of different molecules, not the target itself, right?
It's not like BTK inhibition causes the damage. It's how do you go about it, right? We think that Fenebrutinib is clearly, or so far at least, seems like they have the best profile out there. The studies are recruiting well. It's still not done. Of course, there's been disruptions recently because of the war and international situation, you know, but we're making all progress to overcome those. I think we're still on track for a readout, I think, in 2024. I think it's the earliest date.
Well, okay. We start there. Matthew Weston, please. Go for it, bro.
Thank you. It's Matthew Weston from Credit Suisse. Bill, it's one for you. I promise I'm not asking for 2023 guidance. At the very beginning of your presentation, you laid out a question you've got a lot was the next wave of biosimilars and how robust you thought the in-portfolio growth was to mitigate that. Next year, depending on COVID, you could lose probably $2 billion of revenue from Ronapreve and the COVID Actemra treatment. I'm just very interested psychologically how the organization is thinking of that. Is it like power through, keep R&D spending, and the P&L will sort itself out over the midterm? Or is it we've got productivity tucked away to partially mitigate that? Or we're gonna think about margins over time? I'd just love to think about how the organization's thinking about it, particularly as we go into 2023.
Yeah. In those particular instances you mentioned, Matthew, I think the situation is probably a little better than maybe is assumed. We think we will have Ronapreve sales in 2023. It's not a hard stop. Who knows? We might have Ronapreve sales beyond that. I mean, I know that I don't wanna be the most unpopular person in the room. The pandemic conditions are over. Unfortunately, COVID is not quite in the rearview mirror yet, and let's see. In any case, we think we'll have some Ronapreve sales based on basically existing commitments that'll be delivered in 2023. Likewise, Actemra, the COVID sales have really fallen off.
I mean, in Q3, it'll probably be the biggest impact on Actemra because last year we had the Delta variant. Remember that was only a year ago? Remember Delta? And so that was actually the biggest sales quarter for Actemra ever was last year, Q3, and this year it's very quiet. It's not such a one-year phenomenon. Meanwhile, you know, the growth engine is strong. I mean, we're gonna have Polivy in first line launching around the world, including the US next year. We've got Vabysmo launching around the world this year. Next year will be the big impact on sales because obviously, you know, this year is kinda like the ramp up, but next year the sales starts to hit in a bigger way.
I think that's why we feel good about our growth prospects despite some tail or some headwinds.
Maybe Stefan.
Stefan Schneider, Vontobel. Just if Gantenerumab works, could you remind me how the testing would work afterwards to identify your patients? There is biomarker blood testing and there is imaging, which is very expensive. Who's gonna be tested and what's the sequence?
Shall I give it a try?
Yeah.
Clinically. I'll address it from the clinical standpoint, right? Right now, patients are diagnosed, as you said, using either PET imaging or CSF testing. PET imaging is expensive, CSF testing is not, just to be clear, and it's available on the Elecsys platform, so it's a very standardized procedure for neurologists. I would imagine that it will be hard to have mass testing because it is an invasive procedure, so there'll have to be a fairly good degree of suspicion if patients have symptoms compatible with Alzheimer's, right? Given that the test is there, it's not a complicated thing. Actually, that's why we developed the CSF testing in the first place. Now what we're working on now is blood-based biomarker screening, right? Blood-based testing, essentially. We're pretty close to having it.
We have breakthrough device designation, we have the validation of the data. Once that is on the market, I think what that provides is that opening of the funnel for screening. So at an earlier time, if there's a suspicion, it's much easier just to do a blood test and say, "Well, based on this, I think you should have a CSF test, or you should have a PET amyloid imaging," right? So that opens up that screening cascade, basically. It would be hopefully incorporated then into normal clinical practice. Teresa, I don't know.
Yeah, spot on.
Yeah.
Okay.
Hi. I had a question on crovalimab. Next year, in terms of the readouts which are coming next year, like, where would you rank the importance of the phase III data for crovalimab? Given that generalized myasthenia gravis is such an important indication for the currently marketed C5 inhibitors, why is this indication not being more of a priority?
Can you repeat the first part of the question?
Just, you know, the relative how you would rank the importance of the phase III data for crovalimab next year in terms of the readouts that are coming.
Okay, next.
Yes.
Yeah. Well, when you say relative importance, I mean, we already have positive phase III trial data in hand from our COMMODORE 3 study in China. Speaking of risk, we think that one will be on the lower risk end of the spectrum, we think. In terms of importance, value, maybe Teresa, I don't know if you wanna take that one.
Sure. I mean, I think with PNH in particular, while there are PNH therapies that are approved and on the market, there remains a fairly significant level of unmet need because in many instances, while approved, those drugs have never sought reimbursement and launched. I think as we were thinking about crovalimab and how to bring it to market fast, we started with PNH, knowing that we could take a very responsible PNH indication as we then continued parallel development in other indications, which are potentially more unique. I think, Paulo, we'll bounce to you.
Yeah. No. Speaking about the generalized MG, I think our approach was that, you know, both Soliris and the next generation C5is are already very well entrenched in last line treatment for generalized myasthenia patients. For us to go into their rare disease, it wouldn't make a lot of sense, and it wouldn't be the most value that we could see out of this. On the contrary, we're thinking about Enspryng because we're trying to address the large majority of patients who don't wanna go to a last line therapy, essentially, and have the risk associated with that. That's why it's just a different way to look at that clinical problem. We think that the biggest medical need, actually, is after you are in first-line steroids or IVIG, you wanna go to the next level.
You want a therapy that's safe, that's convenient, that controls that disease before you have to go to last line. It's kinda like we think it's the best way to use our existing pipeline to have the most you know impact, basically. Yeah.
Sachin.
Sachin Jain, Bank of America. Just one back on Gantenerumab and GRADUATE. So you've said a couple of times today you expect a very clear answer, which is obviously both studies hit or both fail. There are a lot of gray scenarios, so I just wanna be clear, is there any reason you don't think gray happens? Or is there... and if you could remind us, what your intention is within the headline press release to comment on regulatory interactions or filing intention, if you do end up in that gray scenario. Thank you.
Shall I give it a-
Sure.
Well, of course, everything is gray, right? I agree with you. In science, most things are gray. They're not black and white. The way we're thinking about it is that at the end of the day, we're gonna have to make a decision whether we think the data is robust enough and convincing enough to take to health authorities and file and try to get approval or not. That is kind of a black and white scenario, right? You don't half file. Either you file or you don't. The data at the end has to be that. What I mean, it has to meet that bar. It has to be statistically significant. It has to be clinically meaningful, so the effect on two trials have to replicate themselves, you know, to be consistent.
It has to have a good safety profile, obviously. I think there's lots of gray, right? There are scenarios in which we can think about, "Well, it didn't quite make it, but maybe in the earlier patients, it might." We can look at all of those, but the likeliest is that we're gonna try and look for a black and white answer. Do we wanna file or not, right? I guess based on that, we'll be putting out a press release, you know, or at least it says that.
I think you said it right. I mean, we've seen lots of mixed outcomes over the years. I can think of very few where the mixed outcome left us uncertain as to whether this is an important medicine or not.
Yeah.
You know, I think you know, knowing how we're wired, if we think. Well, we're just not the kinda company that would look at a mixed result that's kinda poor.
that we don't think is really offering a compelling benefit for patients, but we're gonna file it anyway because we think there's some way to make money or so. That, that's not gonna happen. I mean, we're either gonna have a compelling benefit for patients or we're not gonna have a medicine.
Richard?
Thanks. Hi, Richard Vosser from JP Morgan. Maybe on the PI3 kinase alpha, how's the tolerability looking on a blinded basis in terms of the combination? I hear you that it's more selective and so for better tolerability. What are you seeing in terms of discontinuations and recurrent diarrhea? I think that would be the major concern.
For the phase III study, we can't comment sort of in an ongoing way on what the tolerability profile looks like, except that obviously, like with all phase threes, we have IDMC, we have regular safety reviews, and there's been no red flags during any of those. We can't comment on the phase III. All we can comment on is the earlier phase data, and certainly in the earlier phase data. There are some side effects like hyperglycemia that are just baked into this. This is just on target, on mechanism toxicity.
In terms of some of the other challenges and the frequency of challenges that cause early discontinuation, I mean, in the early dataset, it's obviously limited by small numbers, but we're encouraged by the ability of patients to stay on the regimen. It's not tox-free, but it's manageable in a way that we think could be differentiated.
Maybe the final question. Simon?
Yeah. Simon Baker from Redburn. Probably another one for Levi. On the slide about allogeneic cell therapies, two of the reasons you cited as advantages, of course, are scalability and no delay to first treatment. You're also involved in individualized cancer vaccines. Last week, Moderna was saying that they're targeting a biopsy to therapy time of about six weeks. It's actually slower than cell therapy. I was just wondering what you're targeting and how much you see that as a problem, and also the general scalability of individualized mRNA cancer vaccines.
First of all, I'll point out that those are, at some level, kind of apples to oranges because in the cell therapy, for example, the Poseida deal, these would be key malignancies, and oftentimes you're dealing with aggressive malignancies, and you really struggle to sit on your hands at all once you have a patient with active disease. The time to treatment matters very much in that setting. That's, as you know, in the real world with autologous CAR-T therapy, that can be a fundamental constraint to use. Now, in the setting of a cancer vaccine, which of course, as you mentioned, we have several programs ongoing, the context can be very different.
In fact, if you think about it, that sort of scenario is exactly when you don't use a vaccine. It's like you don't use a vaccine we have for COVID. You use it to prevent. Actually, a lot of the thinking for the cancer vaccines is, you have a patient who is basically had definitive treatment, but they're high risk for recurrence. In that setting, you actually have a bit of time. You've done the resection, you can do exome sequencing, you can find the new antigens. You have time to kind of, you know, engineer a more personalized approach, while the disease is still not detectable. That would be the sort of concept behind the cancer vaccine.
Okay. With that, I think we will close the session, and our speakers will still be around, so you will still have the opportunity to grab them and ask additional questions. I would also like very much to use the occasion to thank all the speakers for their dedication and the time they put in the preparation, and also Sascha, who is online. Then also, of course, to the IR team. I think the IR team has been busily working on preparing all this here. It's like Sabina, it's Lilith, it's Andreana, Jan, it's Lauren and Anita and Jared, who all contributed over several weeks. Of course, all the pharma teams who contributed and also our colleagues from finance. With that, I would like to. Bill, do you have any final comments?
Well, again, we started out this morning talking about how glad we were to have a chance to just interact with you all in person. It's been great. Enjoyed catching up with a number of you at lunch as well. We're super excited about the trajectory of the medicines we have in the countries around the world today, the readouts we have in the next 12 to 18 months, and the long-term future with our amazing early R&D centers and the practice-changing medicines that I know they're gonna deliver. Anyway, thanks for your confidence in Roche over the years. I know many of you are long-term holders and or long-term followers, and we aim to deliver. Great. Again, great to see you all, and wish you a great week.