Ladies and gentlemen, welcome to Roche Virtual Farmer Day 2021. My name is Henrik, and I'm the technical operator for today's call. Kindly note that the webinar is being recorded. I would like to inform you that all participants are in listen only mode during the call. After the presentation, there will be a question and answer session.
You are invited to send in questions for this throughout the entire session using the Q and A functionality of Loom. In addition to that, you may also raise your voice for hand to address your questions verbally. At this time, it's my pleasure to introduce you to Karl Mahler, Head of Investor Relations and Group Planning. Karl, the stage is yours.
Okay.
Then let's get started. Welcome to our traditional Pharma Day, warm welcome from my side. I'm just checking the attendance list. So it's still piling up, but we do expect today More than 700 people, so that is really a considerable high interest in the day. So thanks for your interest in Roche.
We will have possibility to ask questions via the phone, via the Zoom chat, also with the e mail. So you can also Drop me an email on the call. Malaeroche.com. And I trust that you had an opportunity to download the presentation by now. Please note that there are also some API slides in the same link, respectively, on the website.
I know that many of you use these FS slides not only during for this event, but throughout the year. And so this is in high demand. And last but not least, we also do have a So we want to be also a learning organization here. So in the second part of the day, there will be A pop up of 10 questions. And if you don't like to answer the questions, then just move it to the side, which is perfectly fine.
If not, then we would be extremely pleased If you could kindly help us improving ourselves and the event for next time. So this is the program for today. So we're basically 2 parts. First part, Bill will open with a strategy. He will give us reasons While we aim to invest more in R and D, while we believe this is the right thing to do at the moment and while we believe it's the right thing to We shifted the amount of resources into R and D.
Then we have Theresa. So basically, she's talking about Where the current funding of the strategy is coming from, she talks about launch excellence, product differentiation, with the focus clearly here on main trucks ongoing. And we will have a short break of 5 minutes, just a kind of a mental break. Then it goes into the 2nd part. Levi and Paolo will give us an answer on the questions where do we see our pipeline products Making a difference to patients, where do we see the standard of care moving, why we invest at the moment In which trial, in which asset and how we can contribute to the changing standard of care.
And then we have 2 call outs. One will be on ophthalmology by Nilesh and one from Berry on infectious disease. And interestingly, infectious diseases, many companies have said goodbye. We are not invested in. We have still a commitment here as we had for CNS many, many years ago, and you know that we have a leading pipeline at the moment in CNS by just focusing on science and on the long term and on the right things.
In terms of Today, we try to be now ready fifty-fifty this time, so 50% presentation time, 50% this all have Q and A. And before we go into the event, maybe 2 slides from my side. This is the first one on this shows a bit history of Roche 2011 to 2021, the past 10 years, you can see basically three things on that side. First of all, pharma was growing by €5,000,000,000 which is a lot. Second is, you can see that we had really a focus on oncology, 55% to 60% was We're about 55% to 60% maybe 2011, it's now down to 20%, for the group, it's maybe 10%, 15, so you can see the huge reshift and what we really what the Pharma division could achieve during this time by reducing the risk.
2nd is That there is a clear product portfolio rejuvenation and diversification Ongoing and you can see it here in the colors by having less orange and much more for immunology and neuroscience and other therapeutic areas. And why this was the case and why we could achieve this one, You can see in the left side, it was a continuous focus on science. We are the company with 38 breakthrough designations, We which we received since 2013, 8 in immunology, 3 in neuroscience, oncology 25 and ophthalmology 2. So there's also a good rejuvenation and diversification in the innovation part testimony. And on the right side, it's a kind of an external, Yes, a call out here, a testimony from Evoloid Pharma, which was published last week, which shows Also here the refreshed outlook for the Roche Group for Pharmaceutical Roche.
And with this one, I would like to hand over to Bill. Bill, over to you.
Thanks, Karl, and thanks all of you for joining us. I think we've been really excited to have an opportunity to talk about the progress that we're making and To explain a little bit about what we're doing and why we're doing it. And so let me just start, You see the title of my presentation, Sustainable Growth by Delivering More Patient Benefits at Less Cost to Society. And many of you know that About two and a half years ago, in early 2019, we committed to really a fundamentally new strategy for Roche Pharma, wherein we said, we started by looking at what the society need. And it was really clear that there's still a lot of diseases with high unmet needs And patients need better medicines.
They need targeted medicines. They need medicines that are curative. They need medicines that Really solve their problems rather than giving them 6 weeks or 2 months of additional life that cancer patients would have a cure, That babies born with spinal muscular atrophy would have new options and ability to live a normal life and that people with hemophilia I would have also really a new day to move beyond the tired old medicines
that they've
had to rely on for so many years. And we said, so how do we do this? And we said we fundamentally have to do 2 things. We have to invest a lot more in R and D. And in order to do that in a reasonable way, we have to spend a lot less kind of on everything else.
We also Need to be much better, more efficient, more effective in R and D and that has to do with personal productivity, it has to do with technologies, it has to do with Really moving beyond the 20th century means of developing medicines into things that take full use of the evolution of technology. And then the other thing we need to do is we really need to create a workplace where each person at Roche Pharma has the opportunity to make an impact every day. And in large organizations, too often, People are kind of bogged down in the bureaucracy, in the approvals and going through management levels and that and we said, We're not going to play at changing that anymore. We're going to make radical changes and we began that journey and it's already begun to pay off, and I hope you'll see that as we present today. But let me move on and show you some of that progress.
So first off, let's talk about what's changed in the last year since our last Pharma Day presentation. First off, at the High level on the late stage pipeline, really pleased at the evolution here. We now are up to 18 medicines In Phase 3 and registration, which is a new all time high, you can see the recent past. This is almost an 80% increase over what we've been doing in the last decade. And I think you'll also agree that a lot of these medicines, They're not average medicines.
They have tremendous potential. And in the earnings results that we gave in July for the first half, We announced that we had begun 12 new trials. We've got an additional 10 new Phase 3 studies in the second half of the year. And so basically we're talking more than 20 new Phase 3 studies in a single year. So not only do we have more medicines in
Phase 3 and registration, but we're beginning more pivotal studies
than ever before. And But we're beginning more pivotal studies than ever before. And again, if you look at the list, it's quite impressive, the things that we're taking on. And we've also talked for a number of years about filling the gap, the gap created by the loss of IP on Avastin, Herceptin and Rituxan. And so the last couple of years, we've given this update.
And basically, this is looking at the analyst consensus and what's the difference between our projected launches and our projected losses. And you can see in 2018, we had about $7,000,000,000 more to gain than we had to lose. Last year, That number had grown to €8,000,000,000 and now it's basically €12,000,000,000 So we're really pleased at how we've made progress despite the decline in sales Of Ah and R, really tremendous growth of the pipeline of marketed products and we really, I think are moving past the point where biosimilars is a major factor for us as we look forward. Now transformation, I mentioned, how do we help All of our people have a chance to do something important for patients every day. And this is really a major commitment For all the people of Roche, and the leaders of Roche are really strong behind us.
It's been an ongoing effort. I mean, this slide highlights the areas where we're focused, which is basically everywhere across pharma. It comprises several parts. There's a new way of leading instead of command and control that we call VACC, it's Vision, Architecture, Catalyst and Coach. It's a very different way of operating.
It's required all of us and me included to basically relearn what leadership looks like. People come to work at Roche to do something great for patients. They don't come to work to be managed. And there is a need for vision and for clarity and for structure that helps people get things done, But people don't come here to be babysat. And this leadership approach we find is really A whole new day in terms of empowering teams in a truly dynamic way that allows them to get on and make the best choices.
Examples of things that that's achieved, for example, in regulatory, it used to take us 26 weeks to file. I mean, we have the most filings of any company In life sciences, regulatory filings used to take us 26 weeks on average. Now we're down to 13 weeks. And we tried that for 10 years to improve, and we couldn't until we really turn people loose and gave the teams the power to make decisions. Other parts, operating principles, New ways of allocating resources, moving beyond the tired old budget formulas, and then outcomes based planning, which is a powerful way for People, teams to align their objectives and to drive things forward faster than ever before.
And the whole goal of this is to deliver our vision of many more patient benefits at a lower cost to society, but also to make for better jobs. Better jobs is happier people. It also means that we have we maintain our industry low retention. And I think it's basically a win for the mission, it's a win for patients and it's a win for our company. Now if that all sounds inspiring, but like where's the proof?
Let me share. And by the way, this chart is basically lined up in the order of when different groups began their transformation work. So starting on the left with Pharma Technical, that's our manufacturing and quality organizations and process development and Pharma US, These were groups that started transforming in 2016 already, so it's been 5 years. And what you can see is, for example, 68% volume growth With 18% lower headcount today than we had when that began, and now fortunately, we've been able to do a lot of that through just sort of normal attrition, But the net result is basically a doubling of product output per person. So that means something.
I think that's a pretty clear sign that the transformation is yielding results. In pharma in the U. S, 23% sales growth, headcount is 19% lower. If you do the math on that, that's a it's more than a 50% increase in sales Per commercial employee in Pharma International 18% sales growth, 15% lower headcount and again This is close to 40% increase in per person productivity. And now you see in China and pharma development, A little newer on the curve, but again, impressive figures.
In pharma development, we have 44% increase in new molecular entities at pivotal stage. And we're doing that with 27% more headcount. And I think you'll hear from Levi about our efforts to improve on that. And what do we do with the benefits Of empowering people, of allowing people to accomplish more every day, we can basically invest that in more projects And more R and D efforts from beginning from research all the way through. So here you can see our P and L for the first half.
And what you see here is a reduction in cost of sales of 3%, reduction of marketing and distribution of 6%, G and A down 2%, R and D up 19%. By the way, this isn't this pattern won't endure through the year quite That's starkly. We had a large increase in R and D, partly driven by the COVID therapeutics effort, where we have 3 therapies that we've been For COVID in Phase 3 and Phase 2 and Phase 3 studies. But on the right, you see the net effect. We're talking about fundamentally changing The nature of the company to be much more lean and efficient and customer centric rather than product centric on the commercial side, but to deliver a lot more investment in R and D.
So let's talk about what that's buying us and what do we get for that investment. And so first in terms of the strategy, And we look at the healthcare field and we still see many, many diseases with high unmet need. Patients need better therapies. They need less Toxic therapies, more convenient therapies and mostly they need cures. And if you look, areas like oncology, CNS, Cardiovascular, anti infectives, I mean, still very large unmet needs, but also many, many other therapy areas with big needs.
We're approaching this with many modalities. So on the left, you can see the industry pipeline by therapeutic modality. And what you'll notice At the industry level, the modalities have been shifting. Back in 2000, it was 60% small molecules And now industry wide, it's only 50% small molecules. If you look at Roche and our pipeline, Our pipeline and our modalities have actually evolved much faster than the industry.
And you can see there, it's quite a balanced picture with a lot of different modalities. And basically our approach is we're in every modality when we believe it's the best modality for a serious disease. And so sometimes we get asked questions like, oh, what about this modality? Why aren't you there? And the answer usually is, well, because we have something else that we think is better in for that disease.
But when we see the opportunity, we tend to move. Here's again, for your reference, a listing of some of our key modalities And then these as we're targeting with them, I won't belabor it, but I think again, it reinforces the point that Roche is in every modality. And if we're not in a modality today, if it proves important, you will see us in it tomorrow. We're also, I would say, very agile with respect to deals. We do a lot of early stage deals.
We don't believe in kind of waiting to Phase 3, and then rolling the dice with big transactions. We don't think that's worked very well for large companies in the past. It's definitely a seller's market at that point. And we believe in establishing early partnerships where we're really able to bring the full resources of Roche, Scientific development, manufacturing to bear on the program and to get in early enough to do that. I think you'll also see that we're very disciplined.
So for example, in the 12 months ending last year, we had done 5 late stage deals, Okay. Since that time, we've done 0 late stage deals. And why is that? Because we found 5 late stage deals that were Both strategically important, great science that we liked, but also they made sense financially. In this year, in this calendar year so far in 2021, we haven't seen one that met all those criteria and we don't feel pressure to push the button on deals that frankly don't make financial sense, even if they look good strategically and scientifically.
So let's talk a little bit about the late stage portfolio and the evolution. You're going to hear a lot more during the day today. But high level perspective, in 2018, we had 10 blockbusters as a company. The consensus estimate for 2021 is that we'll have 16 blockbusters this year. And now we have an additional 24 molecules that are either already approved Or that are waiting in the wings in Phase 3 will be approved in the next few years that have large sales potential.
So I think this is one of the reasons we're so excited about what we can bring to patients around the world at Roche in the years ahead. A few examples, ophthalmology, an area that we've been really pioneers of bringing biologics into ophthalmic indications, Beginning with Lucentis back in 2006, now we've got basically 2 late stage Programs, they're in filing mode right now. Faricimab and the port delivery system with ranibizumab, Both of these are going to be approved before this meeting next year, and they have real opportunity to provide a big Benefit for patients and to be important medicines for Roche. And I think it's also important to add that right now, Roche's footprint in ophthalmology It's limited to the United States, whereas with these programs, we will have these medicines around the world. So it's a great day for us to move forward.
But beyond that, we also are working on new molecules for the port delivery system, the so called DudaFAD program that you'll hear more about today. And we're also working on a number of collaborations early on geographic atrophy, which is a really high unmet need area Still in ophthalmology. Central nervous system diseases, again, very high toll on society, And we're really coming at this, I think, with a multidisciplinary approach. It's not only about the science or the medicine, but also for example digital tools, imaging, patient enabled tools, cell phone based Tools. And so you can see this chart gives you an example in MS, in SMA, in muscular dystrophy, A number of areas where we're advancing not only the science, not only molecules, but also tools that can help physicians diagnose patients better, Help indicate which therapy is suitable or when a change in therapy is necessary, but also help patients to really monitor their disease And to know what benefit they're getting from their current medicine or a new medicine.
We're also going early. I mentioned that our goal was to deliver 3 to 5 times or our internal goal is to deliver 3 to 5 times more patient benefit at half the cost Part of how we achieve such an ambitious thing is we have to deliver more cures. It's not good enough To extend life by 2 months, we need people to go to that last appointment with the oncologist, Not the last appointment because they face death, but the last appointment because they face life without cancer, life beyond cancer. And so we're investing very heavily in this. You can see these examples.
So for example, in lung and rare tumor types, These are all studies either in adjuvant, neoadjuvant, Stage 3 opportunities for cure for A sizable portion of the population, and we're really pleased to have already demonstrated that TECENTRIQ works in early stage Lung cancer and that we can achieve a long time of progression free survival there, our disease free survival. Breast cancer, we have a number of molecules, including TECENTRIQ in TNBC and triple negative breast cancer, but also girdestrant That we're looking at a broad range of settings, but this is in estrogen receptor positive cancer and an area that's 70% of breast cancer. But also again in GI and gastrouritatory Cancers and in Hematology with Polarex with the readout recently announced. So the last thing I want to mention is what we're doing to make a sustainable impact. I hope you'll agree that the very nature of our vision speaks to sustainability, delivering more benefit to patients At less cost to society.
And frankly, that's the biggest thing we can do to be a sustainable healthcare company is to deliver What people look to us uniquely to deliver, but we're not content with only that. And so we're looking at a number of other metrics. We're very pleased to be the most to be ranked as the most sustainable healthcare company by the Dow Jones Index For the 11th time, we work hard at that. We've worked hard at that for over a decade and we will continue to earn our place. For example, on CO2 emissions per employee, you can see the chart on the left there where we've brought them down by about half over the last 8 years.
And that came through concerted investments, Clear strategies and really a will to change. And I want to make clear, this is not by buying credits, okay? Buying credits is, I think that's debatable, what good you bring to the planet. I think reducing emissions, there's no debate. And this is pure reduction of emissions.
Also in terms of access to our products, and we have international differential pricing around the world so that patients in countries With lower incomes are able to receive our medicines at a much lower price. In the U. S, we've been very careful about price increases. We've basically had our net price increases in line or below medical inflation in the U. S.
For a decade. You can see the most recent years here. And then in terms of things like diversity and inclusion, we think that's really important, Not only as a contribution to society, but it's just a fundamental right for all of our employees to feel like this is their company. It's a place That belongs to them and they belong here. And so you can see as an example, our progress in women, in the workforce and women in leadership.
We've increased the number of women in senior leadership by over 50% in the last 6 years. I think that's good progress. And we think there's tremendous gains ahead on that, both in the name Of gender parity, but even more than that in the name of performance. So I hope You're convinced that Roche that we mean business when it comes to sustainability. Now what can you expect for us going forward?
A couple of things. We were going to continue to enter new franchises, new areas of medicine, new areas of unmet need. I think our plan that we set out 10 years ago when we faced the looming introduction of biosimilars, We came up with a plan, how we were going to handle that. You can sort of see that in the blue bars in the middle. But then if you look Sort of the next bar over to the right, the peach color, these are sort of additional areas that we've entered Beyond the areas affected by biosimilars, and there's just more ahead.
And if you look at the readouts That we have in 2021 still to come, 4 more significant readouts and then many, many readouts In 2022, I think we've listed 13 that we think are particularly notable. That's basically every 4 weeks on average in 2022. Three pivotal readouts for tiragolumab, givridesterin, our first pivotal readout for our Estrogen receptor degrader program and then the port delivery system in DME, gantenerumab in Alzheimer's And then a number of important readouts in early cancer for TECENTRIQ and ALECENSA. So Again, a big year ahead. We're really excited to have that opportunity to bring the pipeline forward.
And then lastly, I just want to say We've reiterated our positive outlook. We said a few years ago, we believe we can grow through the biosimilar impact Time and we still believe that. All indications are go. The pipeline continues. The progress of our launch products remains strong.
And we look forward to continuing to deliver great news for patients, but also for investors in the years ahead. So with that, I want to hand it over to our Head of Global Product And our Chief Marketing Officer, Theresa Graham.
Great. Thank you, Bill. Good afternoon, everyone. Normally in my presentation, we would take a pretty comprehensive look Through the full late stage portfolio, but given the sheer amount of activity that's happening over the next 12 to 18 months, we're really going to focus in on the near term growth drivers, the things that as Bill mentioned are going to help us fill GAAP. Before we jump in though, I did want to take a moment and just reflect on what COVID-nineteen impact has meant to healthcare systems around the world.
We've seen variable continued impact across geographies and across different therapeutic areas over time. In oncology, for example, patient visits have by and large Return to pre pandemic levels, we are still seeing a slight depression in the hematology patient visits And contrast that with multiple sclerosis in the U. S, where those switch numbers are still 10% to 15% below what they were in pre pandemic times. With the emergence of the Delta variant in certain parts of the world, we are seeing sort of a renewed impact, particularly in our ability to see physicians. But we are Still really being able to focus on all of our launches and delivering our great medicines to patients.
As Bill mentioned, we've had some really significant news Hello, just over the last year, the adjuvant non small cell data for Tecentriq, Polerix for Polivi, The AMD data for furosemab and then a series of trials that have reinforced the benefit of Ranaprive in COVID-nineteen patients. And coming up shortly, we'll have the 1st pivotal data for our 2 bispecifics, MOSIN and GLOFIT. Bill touched on many of the exciting data That we have reading out in 2022, including all of the adjuvant and neoadjuvant data for TECENTRIQ, we also have an adjuvant Non small cell lung trial cancer ALENA reading out for ALECENZA, the first pivotal data for terugolumab and gergesterone and then the very hotly Anticipate gantenerumab data in Alzheimer's. So now let's take a more deep dive into some of the individual opportunities and let's Start with Tecentriq. Tecentriq already has annualized sales of more than $3,000,000,000 with some significant near term catalysts.
Near term growth in 2021 2022 will be largely centered around driving the launch of adjuvant non small cell, particularly in the U. S. As we continue to expand in ex U. S. And geographies that have not yet launched for small cell and TNBC.
Next year, we have the 3 readouts for 4 trials in early disease, including head and neck RCC, HCC and then the neoadjuvant study in non small cell. Additionally, there still remains high unmet need across tumors where PD-one and PD L1 have been approved. And first line non small cell, for example, We still see that overall survival is less than 2 years. And that provides a great opportunity for next generation CIT combos like Tecentriq and tiragolumab to really reset the standard of care in markets where Tecentriq may not already be the market leader. So let's talk a little bit about adjuvant non small cell.
So we presented very exciting EMPOWUR-one hundred and ten data for Tecentriq in adjuvant, which was Followed under the real time oncology review with the FDA as well as Project Orbis. The granting of OTO Really speaks to the unmet need in this patient population as well as very compelling data. I think many of you already know that adjuvant So an evolving treatment landscape and currently only about 30% of non small cell patients are diagnosed with respectable disease and treatment rates continue to be modest, primarily because of the limited benefit and toxicity of chemotherapy for these patients. We do expect as more treatments come online like TECENTRIQ, Like potentially EGFR for EGFR positive patients and for ALK positive patients that we will see screening increase, we'll see testing increase and ultimately we'll see systemic therapy increased for this patient population. Moving on to tiragolumab, I think Bill mentioned this as well.
We have 9 Phase 2 or Phase III trials initiated. We have the broadest and most advanced clinical program in Tiara With 4 readouts planned for next year, these readouts allow us to not only build on places where Tecentriq is also strong, But to compete in new indications with head to head trials against standards of care, including derva in Stage 3 non small cell and pembro plus chemo in first line non small The market opportunity for tiragolumab is significant, particularly when we look at the lung cancer market where PDL and PD L1 and PD-one to date accounts for $10,000,000,000 in annualized sales, and we believe that this is where a combination such as Centric Intyra has the opportunity to reset the standard of care. Switching over to breast cancer, we continue to innovate For patients with HER2 positive breasts, we continue to see solid growth for Kadcyla in the adjuvant setting where we've established an extremely high bar, Both in terms of efficacy and safety, we're also seeing really encouraging uptake for fesco, both in the U. S, particularly in academic settings, but also in Parts of the world that are typically more receptive to subcu formulations.
For example, in the U. K. Right now, we see 1 out of every 2 patients actually receiving Fezco, Which is really encouraging. We are also continuing to build on the standard of care. So the graph that you see here is the PD L1 subset of the K2 2 study where we saw very encouraging signs for both PFS and OS, which has encouraged us to actually launch Some combinations with Tecentriq both in combination with Kadcyla and Perjeta both in metastatic and early breast settings.
Moving on to girdestrant. As you know, and I think Bill mentioned this as well, hormone receptor positive breast cancer is an extremely large opportunity, comprising about 5% of all breast cancer patients, that's 3 times the population of the HER2 market. In hormone receptor positive breast cancer endocrine therapy, including fulvestrant aromatase inhibitors continues to be the standard of care Across both early and late line settings. And it is our hope that girdeserit will replace endocrine therapy across all lines in the future. There remains significant unmet need in this patient population up to 50% of early breast cancer patients will actually stop their treatment early due to toxicity And about 30% of patients will ultimately develop metastatic disease.
We do believe that iridesterant has the potential To be best in class, both because of its differentiated MOA, because of the high potency, we believe that we're 7 to 15 times more potent than other SIRDS in development. There was just recently a paper published in the Journal of Medicinal Chemistry that Levi will talk about in his section. We are well tolerated both in mono and combination therapy, and we are able to have a standardized dose both for mono and combo because we don't See those drug to drug interactions. We have the broadest clinical program out there with CERD, including a head to head trial with standard of care in So lots of really exciting data coming for geridesterant, and we do believe this has the opportunity to be a game changer. Speaking of game changers, POLYVI plus R CHOP, the first positive trial in first line DLBCL in over 20 years Since the introduction of R CHOP.
I think as everyone knows, first line DLBCL can be a curative setting. But unfortunately, about 40 Percent of patients are still not cured with R CHOP in the first line. And that means that patients that either are resistant or relapse unfortunately have a relatively This is precisely where we believe that polity can play. This is a very large multibillion dollar market There has been no new first line therapies approved since R CHOP. And we do believe that We have the opportunity to really change the standard of care.
We're excited to present the POLYVY data later in the year and we are actively discussing with health authorities about how to bring POLYVY to Patients as fast as possible. Also in the hematology space, we've got Mohsin and Glofit, our CD20 and CD3 bispecifics, both of which have the potential to 1st in class and best in class in follicular lymphoma and DLBCL. Mosin continues to demonstrate high and durable And treatment lines, so particularly things like follicular lymphoma or elderly unfit patients. For GLOFIT, It has the opportunity to be the best in class efficacy comparable to what we see with the CAR Ts. We are seeing in our latest data that Checkup dosing can actually help to manage higher target doses, while maintaining a manageable safety profile.
So really excited to see the 1st pivotal data Out of both of these drugs a little bit later this year, the most pivotal cohort and third line plus follicular will file at the end of this year and we expect the GLOFIT pivotal cohort and third line DLBCL to file at the in early 2022. And third line DLBCL to file at the in early 2022. We have also launched randomized Phase III trials And both relapsing and relitting follicular lymphoma Formosan and in second line plus DLBCL with GLOFIT in combinations with standard of care. And we are thinking about how to move into first line DLBCL in combination with Polyvi. So moving on to non malignant heme.
Henlever continues to be transformational For hemophilia A patients regardless of inhibitor status and age, we see the 3 year no bleed treatment rates HEMLIBRA being in the 80% to 90% range compared to 40% to 50% for our Factor VIII. We continue to gain market Sure, both in the U. S. And globally, our non inhibitor approvals are now at 90 more than 90 countries with reimbursement in more than 30 of those countries. And just for a little bit of context, in the inhibitor space, where we already have very strong penetration for patients, we see reimbursement in 90 countries.
So we would expect That will be bringing a lot more countries online in the very near future. We also have a significant amount of data that will be coming out For HEMLIBRA next year, starting with HAVEN6, which is the mild to moderate study that we ran in the EU, we hope that this will not only inform a label Update for mild to moderate patients in the EU, but we'll continue to provide reassuring data for those patients who are being treated around the world. We have the 5 year follow-up data from HAVEN 1 through 4, which are also expected next year. And then very importantly, we have the HAVEN 7 data, In which HEMLIBRA will be the 1st novel therapy to be studied in the prophylaxis setting for infants also expected next year. So just HEMLIBRA continues to be a really important and foundational drug for the treatment of hemophilia.
Now I won't spend too much time on ophthalmology because you have Milash coming up in a little bit. But in any conversation about How we are approaching commercial opportunities for the next 18 months, it would be really remiss not to talk about ophthalmology. We're preparing for our first launch in PDS in 2021 in ferricimab at the beginning of next year. And I think as everyone knows, This is a very significantly large and growing market expected to reach up to $15,000,000,000 in 2025. But we still see a significant amount of unmet need And this is where both ferricimab and port delivery system really come in.
Ferricimab is the first new MOA in AMD and DME in more than 15 years and has shown Strong durability with the majority of patients being able with about half of patients being able to be maintained on Q16 dosing. For those patients who are already responsive to anti VEGF therapy, but for whom can't be maintained On a current extended treatment regimen or just simply can't manage the logistics of going into the office as frequently as they need to, The port delivery system is a wonderful alternative to maintain steady vision well with almost all patients being able to be maintained on dosing every 6 As Bill mentioned, we now have the global rights for both ferricimab and for PDS. And we're really looking forward to these launches. These are physicians that like to switch. They like to try new things in their armamentarium.
We would expect a reasonably fast adoption for ferrousumab. And if any, I think again, as Bill mentioned, with port delivery, we've got to go slow to go fast strategy here to make sure that we're managing The introduction of a new kind of surgery. Moving on to OCREVUS. OCREVUS continues to have a very strong growth Profile in the U. S, we are seeing the anti CD20 class grow to now over 50% of patients, but with significantly more room to expand.
Within the anti CD20 class, OCREFIST continues to have the best in disease efficacy and safety. We remain the only medicine with a consistent disability progression across all endpoints and trials. We're the only therapy approved in PPMS and the higher dose OCREVUS studies look to further improve on that best in disease profile. The twice yearly dosing drives better compliance. We see a greater than 90% persistence Compliance after a year, which is superior to what we see whether they're oral and injectable medicines and shorter infusion is continuing to gain traction in the markets in which Moving on to one of the drugs that we launched last year, EVRISI.
EVRISI is the first and only Oral SMA treatment with meaningful efficacy in the broadest SMA population ever studied in pivotal trials. We see patients in all SMA types in a broad range of agents, Both treatment naive and previously treated coming on to Ebrozsee, and we have had the fastest uptake for DMT with our launch in the U. S. That strong performance in the U. S.
Is being mirrored with what we're seeing in our ex U. S. Launches with about 20% market share in Germany just within 4 months Of launch, we have ongoing dialogues currently happening with regulatory authorities throughout the EU and we expect To be able to bring EBRISI to many, many patients in the future. The global SMA market continues to grow. We expect it to be greater than $5,000,000,000 by 2025.
And in many cases across the globe, there are significant numbers of patients who are significant percentage of SMA patients that are currently untreated. The profile of Efrisde makes it attractive both for patients who are not yet on treatment as well as patients who may like to switch their therapies. And so we see a lot of really good things ahead for Efrisde. And last but not least, gantenerumab. So with gantenerumab, we will bring the most comprehensive data set in Alzheimer's disease with the Graduate studies, which we'll read out next year.
We're very confident that with Graduate, we will be able to deliver a clear and robust data set. We have 2 well powered parallel studies with about 1,000 participants each. We have extended trial duration, the longest duration out there of 27 months. We've optimized titration in the single dose, and we have demonstrated plaque reduction, particularly in our OLE where 80% of patients were below amyloid positivity at 3 years. Also importantly, we will be the 1st and only subcutaneous treatment for Alzheimer's disease.
Subcu allows a treatment flexibility, which is not only just important to patients, but it's important to healthcare systems as well, Reducing the IV burden of infusions for patients and for healthcare systems. As we would do with any of our medicines, we are in conversations with healthcare with regulators around the world to learn how we can bring this drug to patients in a way that makes the most sense. And so with that, I think I am actually turning it over to Karl for a break.
Yes. Thanks a lot To both of you, we will have a short as announced 5 minutes break, a mental break before we go into the detailed Analysis of trial data and so on. So we reconvene here at in 5 minutes, so 50, 250, our time CET. Thank
you.
So, yes, thanks a lot. So we're coming to the second part Of the day. Actually, we have 3 locations today. 1 is in Basel. 1 is at South San Francisco.
So welcome. It's an awful time for you. Levi, I guess you are used to now since you have always these 9 hours difference, but Thanks that you put the burden on you to wake up so early. And then we have Barry sitting in Berlin. And I'm always Wondering how well that works with all these technical interlinks and so on.
Levi, over to you. Thank you.
Yes. Thank you, Karl, and hi, everyone. It's always a pleasure to discuss our pipeline. And actually, Carl, we actually have 4 locations because I'm pleased to recognize our new Head of Global Oncology and Hematology Development, Charlie Fuchs, He's also with us virtually today from still from Boston, Massachusetts area. So you'll have a chance to hear from Charlie during the Q and A session.
Next slide, please. So our Oncology pipeline remains among the strongest in the industry. And since the Pharma Day a year ago, Our portfolio has continued to deliver the kinds of medical advances and patient benefits that Bill talked about. So I'll provide several examples that illustrate Some of those strengths, starting with our heme malignancy portfolio, where we have exciting data for several assets. And then on the solid tumor side, I'll touch on recent developments in our breast cancer program, and then I'll review The progress of our adjuvant programs as well as some of our new efforts and newer efforts, I should say, in immuno oncology.
And then finally, I'll conclude with updates from our benign hematology programs. Next slide. So this is a high level view of time lines for pivotal data readouts from our late stage pipeline. And as you can see, Already this year, we've had 3 of 5 key pivotal readouts, and they've had positive results. 2 of these, The Tecentriq adjuvant long result and polyvi in first line DLBCL represents significant new opportunities for these medicines.
And in 2022, we anticipate at least 8 key pivotal readouts. And 5 of these will be new molecular entities, and those include glofitamab, which is one of our CD20, CD3 bispecific antibodies. By the way, another bispecific, most of the tuzumab will report out later this year. And then we also have tiragolumab, our anti TIGIT immunotherapy asset. We have giridesterant, which is our oral SERD.
We'll have overall survival data for ipadasertib, which is our AKT inhibitor, together with abiraterone, a metastatic And you'll recall that's that it was already positive for PFS in patients who are p10 negative by IHC. And then we will have covalumab in paroxysmal nocturnal hemoglobinuria from one of our Phase III trials readout, the one being run-in China. And then we also have additional indications for Tecentriq and an adjuvant study of ALECENZA reading out. So it will be a really interesting year for our pipeline next year. And then as Bill mentioned earlier, when we look out beyond 2022, we have many more key pivotal readouts on the horizon.
So we think Our oncology portfolio should remain industry leading for years to come. Next slide. And when we say industry leading, We mean both quantity and the diversity of our pipeline innovation. So in oncology, for example, we have Long since moved beyond small molecules. I mean, Bill illustrated this earlier.
But also even monoclonal antibodies And ADCs where our portfolio now includes bispecific antibodies, protein engineering innovation and cutting edge platforms such as neoantigen
vaccines and personalized T cells.
But through it all, the And personalized T cells, but through it all, the mantra is always to follow the science. So we allow disease biology insights To guide development of 1st in class and best in class treatments that improve outcomes. Next slide. And I would say nowhere are these principles more evident than in our hematologic malignancy pipeline. And for example, in both indolent and aggressive B cell malignancies, we brought forth breakthrough medicines on multiple occasions ever since rituximab In the late 1990s and most recently, this has been evidenced by VENCLEXTA in CLL, now Polivi in First line DLBCL and we have reason to believe that our portfolio will continue to change the standard of care In B cell malignancies, in particular, our bispecific antibodies are showing real promise here.
Next slide. And furthermore, we're expanding into other malignancies such as acute myelogenous leukemia, multiple myeloma, myelodysplastic syndrome. Specifically, we're developing VENCLEXTA in additional AML context and a 1st in class bispecific antibody called sevastimab In multiple myeloma. So we'll talk a little bit more about that shortly. But overall, these efforts should allow us to benefit patients in disease areas Well, we've not previously had a presence and thereby extend our hemolynmacy impact.
Next slide. All right. Let's take a closer look at a couple of these opportunities, starting with POLYVI. So in the POLYRIQ study, which has already been mentioned by Bill and Teresa, And of course, this read out positive recently. We tested the hypothesis that giving Polivi together with rituximab and CHP, so in essence, Swapping out vincristine for Polivi in the R CHOP regimen, we tested whether that might prove superior to R CHOP in the frontline DLBCL treatment setting.
And despite the fact that more than 20% of DLBCL patients eventually relapsed their refractory to treatment, ArchUP has actually stood as the standard of care for more than 2 decades, and there were at least 11 prior attempts to improve on R CHOP, all of which were unsuccessful prior to this polaviv base regimen. So R CHOP had already set a high bar And DLBCL treatment and it stood for a long time. But this what we call Polar R ChIP regimen has shown an efficacy and safety profile That could potentially bring a new standard of care treatment for newly diagnosed DLBCL patients. And so we'll be presenting these results in an Upcoming meeting, but we're obviously very pleased with that outcome. And meanwhile, we continue to pursue a robust development program with Polyvi and that We'll include a Phase 3 trial, the SUNMOST study in combination with mocenituzumab in second line or greater DLBCL And then multiple other combinations with agents from our heme portfolio.
So overall, Polyvi seems positioned to bring new patient benefits, not just Now let's turn to glofinumab, which is one of 2 CD20, CD3 bispecific antibodies that we're developing. And in a moment, I'll remind you of the rationale for developing 2 bispecifics, but first, let's take a look at some illustrative data. So you will recall that glafitamab Was engineered to have what we call bivalent CD20 binding. So that's 2 binding sites on one arm of the antibody against CD20. And then monovalent CD3 binding, so one binding site against CD3 on the T cells.
And this feature may allow enhanced efficacy against malignant B cells, but in some sense, it may also increase the need for hospitalization to manage the cytokine release syndrome, which of course is an on target Toxicity of these types of antibodies. But in heavily pretreated non Hodgkin's lymphoma patients, both aggressive and indolent disease, We are indeed seeing robust and durable response rates with the step up dosing approach that we'll be using moving forward. And also, as Teresa mentioned, the safety profile with this step up dosing approach seems manageable. Thus far, most CRS events have been confined to cycle 1. And so this is certainly encouraging.
And therefore, we have a comprehensive development program for glofitamab, starting in aggressive non Hodgkin lymphoma settings, where cures are possible in principle, and therefore, Efficacy receives particular emphasis. And so monotherapy results in the 3rd line or greater diffuse large cell lymphoma setting should read out next year. And we also have a number of combination studies, which include our Phase III trial with GMOS chemotherapy in the second line or greater DLBCL setting. We have the combinations with Gazyva or Archop and polar archip, also in diffuse large cell lymphoma. But the big picture here is that we'll always Following the data, I mean, and toward that end, we're looking at glifidaab monotherapy and various combinations in indolent lymphomas as well.
So we'll see Where those results might take us, but certainly, very promising outlook for glifidumab. Next slide. All right. Now let's look at mostenituzumab, which is our other CD20, CD3 bispecific antibody. So in contrast to the 2:one design of glofitumab, Mosinotuzumab has a traditional one to one antibody design, which means that each arm of the antibody is monovalent.
And this design, as you heard from Teresa, has enabled good efficacy from fixed duration treatment in several settings With a safety profile that enables outpatient administration. So our mosanituzumab development plan starts with follicular lymphoma And the monotherapy data in the 3rd line or greater setting there should report out later this year. And here, our combination Studies include an ongoing Phase 3 trial of mocenotuzumab plus lenalidolide in second line or greater follicular lymphoma. We have various combinations in both follicular lymphoma and diffuse large lymphoma, including mocilmab and polyvi in the 2nd line greater setting. And here too, we're following the data to determine where the efficacy safety profile of mocenituzumab versus glofitumab Might best serve the needs of patients.
And so the big picture here strategically is that this dual strategy with bispecific antibodies Could eventually help enable a personalized health care approach in B cell malignancies as a whole, because together, nocenituzumab and lefidumab May provide optionality across the spectrum of disease severity and the full range of treatment settings in which patients may find themselves. Okay. Next slide. So now we'll shift gears to VENCLEXTA. And as I mentioned earlier, this is our BCL-two inhibitor, which has already brought significant patient benefit in CLL And now a subset of acute myelogenous leukemia.
And it's now showing efficacy in additional AML context and in myelodysplastic syndrome. And so for example, the data here is from a combination of VENCLEXTA and azacitidine in high risk myelodysplastic syndrome patients. You can see The overall response rate is 78%, the median overall survival is more than 27 months. Both of these endpoints appear superior to Historical treatment outcomes. And based on these data, we initiated the Phase III VORONA trial in frontline Myelodysplastic syndrome back in the Q4 of last year.
And in addition, our ongoing development plan It includes the Phase 3 VYALI M study in first line FIT acute myelogenous leukemia, the maintenance setting. This will be done together with the azacitidine molecule that was recently developed by BMS. We also have the HOVON Induction and consolidation study in newly diagnosed AML patients. And meanwhile, we also have the Phase 3 CRYSTALO study in first line FIT CLL, that's ongoing and it has a minimal residual disease primary endpoint and that readout should happen in the 2023 timeframe. And finally, we have our Phase 3 Canova trial in multiple myeloma patients, actually the subset of multiple myeloma patients that have the T1114 That's also ongoing.
We expect results next year for that. You may recall that this translocation is associated With an increase in Bcl-two expression relative to another anti cell death protein, Mcl-one, and the bottom line is That provides a specific biological rationale for the mechanism of action of VENCLEXTA in that setting. Next slide. So speaking of multiple myeloma, which would be a new indication for us, we also have a 1st in class Biosecic antibodies that we're developing for this indication. And in addition to the CD3 on T cells, Savostamab targets a protein called FcRH5, which is expressed on all myeloma cells.
And our dose escalation approach Has identified a step up dosing mechanism, which is producing very good response rates in highly refractory patients and Rates of cytokine release syndrome that appear manageable, most of these have been Grade 1 and 2. We've only seen one patient with Grade 3 thus far. And so we expect to provide updated results on our Phase 1 savastovam program later this year. Next slide. Okay.
Now let's take a look at some of our solid tumor programs, starting with ER positive breast cancer and geridesterin, which is our oral SERD. So we believe that geridesterin has best in class And there are several reasons why we believe this. One reason is its potency. You've already heard in vitro studies suggest that geridesterone is 7 to 15 fold more potent than competitor oral SERP molecules, and this was nicely described in a recent editorial, as Teresa mentioned. Another reason we believe gerodestrant may be best in class is its mechanism of action.
And so obviously, it's an oral SERP, but in addition to that, Our gRED colleagues published a paper in Cell in 2019 that showed that when girdestrant binds to the estrogen receptor, It becomes much more difficult for the estrogen receptor to access chromatin. And so that causes profound suppression of ER target genes prior to degradation of the ER protein. And this is important because aberrant transcriptional activation Of downstream effector genes, that's the primary mechanism through which the estrogen receptor acts as a breast cancer opportunity. So this is a differentiated mechanism of action with Giridesterin. Now a third reason why we think Giridesterin could be best in class is its safety profile.
At the 30 milligram dose, Which we're using for all of our registration studies, monotherapy and combination studies, which are shown here. So we've only occasionally seen, for example, any bradycardia, which has been viewed as an on mechanism effect, It's only been Grade 1 bradycardia. It's not been clinically impactful. We've not had discontinuation. We've not had dose interruption.
And we've seen no adverse pharmacokinetic effects or drug drug interaction issues when gerodestrin has been combined With other molecules, for example, palbociplib. And that's different than other surgeon development. For example, the dose of amikestrin Needs to be cut in half when that surge is combined with Palbo. And by the way, the Palbo exposure is also reduced By nearly a quarter in that context. So those are several reasons why we think dura destin can be best in class.
Next slide. But perhaps the most important reason why we think it's best in class is the clinical efficacy that we've seen thus far in both the metastatic and early disease settings. At ASCO earlier At ASCO earlier this year, we presented some initial neoadjuvant data, as shown here on the left, in which gerodestrant achieved a 78% mean reduction in tumor Ki67 levels and 55% of those tumors showed evidence of complete Cell cycle arrest after 2 weeks of treatment. So we'll present additional neoadjuvant data for geridesterin and ESMO in just a few days. So be sure to take a look at that.
But the totality of the data fueled our decision to initiate an adjuvant study of geridesterin 30 milligrams a day Compared head to head to aromatase inhibitors in high risk early ER positive breast cancer. And that 30 milligram per day dose It's also the dose we're studying in the metastatic setting. We've seen good efficacy across the board in that setting. That includes patients with ESR1 mutations, It includes combination with palbociclib. And of course, as I mentioned, both of those medicines are administered at full doses, no drug drug interaction issues observed thus far.
And so the result Of our Phase II study and the second line and third line ER positive breast cancer setting, we'll read out next year. Recruitment for this study is going very well. And we also have a Phase 3 trial ongoing of geridesterant and palbociclib in first line metastatic ER positive breast cancer. Next slide. Let me also just remind you briefly that we have what we believe Could become a best in class PI3 kinase inhibitor.
So GDC-seventy seven is highly selective for the alpha subunit of PI3 kinase. It can induce degradation of oncogenic PS3 kinase mutant proteins, and it can combine with other targeted therapies at full doses. So an example of that is shown here of the clinical efficacy of our PI3 kinase inhibitor combined with palvaciclib and letrozole In PIK3CA mutant breast cancer, again, full doses. And so we have a Phase 3 trial of this combination ongoing in frontline metastatic breast cancers that harbor PIK3CA mutations. Next slide.
All right. So another important area of emphasis for us involves Deploying our pipeline in earlier cancer treatment settings as the science dictates. And Teresa and Bill both mentioned earlier that this is the setting Where durable control and cures are most often possible. And also, we believe that we can increasingly leverage emerging liquid biopsy platforms to identify Patients who might benefit from earlier treatment intervention. So our adjuvant program spans several solid tumor types.
And in 2022, We should have multiple data readouts, which include studies of TECENTRIQ in neoadjuvant non small cell lung cancer, Adjuvant renal cell carcinoma, adjuvant head and neck squamous cell carcinoma and adjuvant hepatocellular carcinoma, and that's a study of Tecentriq plus Avastin. And in addition, our study of Alectinib, our ALK inhibitor, should read out in the adjuvant ALK positive lung cancer setting next year. Next slide. So of course, you've already heard and you already know that one key study from our adjuvant program has read up positive this year, And the relevant data is shown here. In PD L1 positive patients, we saw a greater than 7 month increase in median disease free survival with TECENTRIQ Compared to best supportive care, the overall survival data is premature, though perhaps it hints at a favorable trend.
We'll have another OS readout next year. So these data have been filed through RTOR and Project Orbis and granted priority review by the FDA. Next slide. So we also continue to explore immuno oncology solid tumor opportunities beyond Tecentriq. So for example, We're combining ciragolumab, which is our TIGIT inhibitor, together with Tecentriq in several solid tumor settings.
Just to remind you, TIGIT is Another immune checkpoint receptor with biological similarities to PD-one. And this program was galvanized by the intriguing randomized Phase 2 data That we saw in our CityScape trial in which tiragolumab together with Tecentriq showed increased response rates and prolonged PFS in PD L1 high and non small cell lung cancer. And in 2022, we will know a lot more about the potential for tiragolumab. We have 4 trial readouts next year, and those include a Phase III trial in PD L1 high non small cell lung cancer. That one will replicate the CityScape result.
We also have readouts in first line extensive stage small cell lung cancer and in frontline esophageal cancer. And then in addition, we'll see Phase 2 results in cervical cancer. Next slide. We've also been leveraging our bispecific antibody platform to develop assets capable of inhibiting 2 immune checkpoint receptors simultaneously on T cells. And one of these bispecifics is a dual inhibitor of PD-one and LAG-three.
This is interesting because combined PD-one and LAG-three inhibition was recently validated clinically in melanoma, And that was presented earlier this year. And the second bispecific is a dual inhibitor of PD-one and ten-three. And the guiding hypothesis behind both of these bispecifics is that they may help overcome T cell exhaustion mechanisms And thereby boost the antitumor activity of CD8 positive T cells relative to PD-one inhibition alone. So we're both of these bispecifics across several tumor types including melanoma, non small cell lung cancer and esophageal cancer. Next slide.
So I'll conclude with a few words on 2 of our benign hematology programs, Starting with our gene therapy asset for hemophilia A from Spark. And to remind you, this is an adeno associated viral vector in which a Codon optimized factor VIII gene is under the control of a liver specific promoter. And in our clinical data, in 15 out of 17 participants in this study and
at a
2.8 year medium follow-up, we've seen sustained factor VIII expression, Durable protein activity. And in terms of clinical endpoints, this corresponds to a 91% reduction in annualized bleeding rate And a 97% reduction in annualized infusion rate compared to the year prior to vector administration. And so the safety profile continues to be acceptable at the dose of studies. But of course, for us, a key goal is to ensure that both the dose And the immunomodulatory regimens are optimized. And with that said, we expect to make a decision on the start of our Phase 3 study Of this gene therapy asset later this year.
Next slide. Okay. So lastly, we have an anti C5 antibody called covalumab. We're studying this in several complement mediated disorders. And covalumab was engineered using recycling technology developed at Chugai, which enables prolonged neutralization of And so Phase III data for covalumab in Chinese patients With paroxysmal nocturnal hemoglobinuria, we'll read out next year, as I mentioned earlier.
But we're also exploring the benefit of covalumab In other disease settings where the pathophysiology is driven at least in part by aberrant complement activation. And so These include atypical hemolytic uremic syndrome. There, we're initiating Phase III trials in both adult and pediatric populations. And also sickle cell disease, there's a role for complement there as well in the damage of the sickle cells. We expect to start Phase 1 and Phase 2 trials in acute and chronic Sickle cell disease later this year.
So hopefully, I've convinced you that our oncology pipeline remains one of the most robust, If not the most robust in the industry. And with that, I'll stop and I'll turn it over to Paolo Fonchura, who is our Global Head of Neuroscience as well as immunology, ophthalmology infectious disease, and he'll discuss our neuroscience portfolio.
Thanks, Levi, and hello, everyone. Very nice to be here again. So I'll take you on a little brief A tour of our late stage pipeline in neuroscience and immunology, talking a little bit about our belief programs in MS, Alzheimer's, SMA, Duchenne and Parkinson's and then touching briefly on our immunology pipeline as well. Now this is a picture of our current late stage and early stage neuroscience pipeline. And I think one of the important things here is that this is still and remains one of the biggest And unfortunately, despite that, the number of large pharmaceutical companies developing medicines Has reduced in the last decade, but fortunately, Roche has committed to this area for a long time now, and you see the result of that commitment here.
This is a very strong pipeline, potentially the best in the industry, with several assets, which are either 1st in class or best in class, Targeting major areas of medical need and with 3 launched medicines already, 2 of which last year, ENSPRYNG and EPRISD. And as was mentioned before, if a certain technology or modality makes sense, we will be sure to pursue it. So as you can see here, And you saw a similar slide from Levi in neuroscience rare diseases, NI2O, we are pursuing several of these technologies and platforms to really Target biology at its most fundamental level because we believe by doing so, we can develop transformative medicines and achieve breakthrough outcomes. Now at the same time, one of the core problems in neuroscience generally has been the ability to measure Behavior to measure endpoints accurately and close to patients. So because of that, for several years now, we've been investing strongly in digital technology and wearables to try and address that.
And there's multiple reasons to do this, not only to essentially increase R and D efforts by allowing us to measure behavior more quantitatively and more frequently. Secondly, because actually by measuring these outcomes close The patients, it would demonstrate much better the value of our medicines and therefore contribute to create the value proposition for across our whole pipeline in neuroscience. So our ability to measure things like cognition, motor function, Speech, ADCETRIA is being deployed consistently across a range of our trials programs, and I'll give you a couple of examples of that later on. So starting with OCREVUS and our flagship program in multiple sclerosis. As Teresa mentioned, this Remains the only medicine that has been approved for relapsing and progressive forms of MS.
It is it has the most robust data set ever in demonstrating effects, both On measures of relapses as well as progression, and this is really the large remaining medical need for patients with MS Is the ability to control long term visibility and therefore to control progression. So it's really with that in mind that we've decided to expand The OCREVUS program to study higher doses of OCREVUS, and we currently have 2 Phase III trials, both in relapsing as well as primary progressive patients looking at And really trying to measure outcomes on the progression of these patients. Now the rationale behind this study is actually a really great example of Following the science, looking at our Phase 3 dataset, which got the approval for OCREVUS, it became clear that at deeper levels of B cell depletion And at higher levels of exposure to OCREVUS, we would see a better benefit for patients in terms of CDP outcomes. And therefore, we're really studying now essentially 1200 milligrams or 1800 milligrams for heavier patients To try to maximize the impact on those progression outcomes. And as I said, these 2 Phase III trials have been started in 2020 and are recruiting very fast.
Now as a part of that, I also wanted to point out the launch of Floodlight, which was our first Send the device to measure progression outcomes in MS. Now this is based on this digital platform and wearables on a Pretty basic cell phone technology that everybody has that sits close to the patient and measures a number of active and passive monitoring tests. And by doing so, create a different value proposition. On one hand, clearly better quality data in terms of viable more frequent, which allow us to derive better data insights for patients and hopefully even derive new endpoints. At the same time, because this is close to patients, It would allow us to measure what's called silent progression, meaning health outcomes that typically are not getting measured because patients see their doctors Maybe every 3 months, maybe every 6 months.
And therefore, this will detect those changes and allow for patients to be better informed in managing their own care. And at the same time for society, as well, if our objective is to prevent long term disability, and we know this is the most determinant of health outcomes for these patients, the earlier intervention coupled with early detection of silent progression will allow us to do that much better. All in all, we're very excited about this and the potential that this has to change how patients are managed. Now switching over to talk about our BTK inhibitor program in MS. This has been a target that has generated a lot of attention in MS.
Of course, it builds on the B cell mode of action story that we pioneered with OCREVUS, but it adds Something to it because of the dual mode of action. We know that our BTK, fenrutinib, targets both B cells as well as myeloid cells. Now when you talk about BTK drugs, there are several in development right now. So it's really about the differentiation. We do believe this is potentially the best in class drug out there.
Based on one hand, on being the only reversible and highly selective BTK inhibitor, and you see data here on the right hand side, it Shows essentially a kindness of selectivity assay, which demonstrates about 130% plus Higher selectivity compared to other BTK inhibitors in MS right now. And at the same time, because it is reversible, It does have a long residence time as bound to BTK, which means that it essentially acts as an irreversible inhibitor From a physiological standpoint, but when you stop dosing, 24 hours later, the enzyme is free again. Now this is a program that we started and have We have 2 trials ongoing, both relapsing as well as primary progressive patients. These are really innovative trials. Again, our outcomes here, we're mainly trying to increase effects on progression in these patients.
And therefore, we are comparing to standard of care to teriflunimide In relapsing disease or to OCREVUS in primary progressive. And our key endpoint is really what's called a composite Confirm disability progression at 12 weeks. So this is a measure not just of EDSS, but also of upper limb function and walking ability for these patients. Now switching over to Alzheimer's, and this is really a narrative has had a lot of interesting news in recent times. I just wanted to remind you all that we are still committed to developing gatenerumab.
This is, we feel a really best in class molecule profile. It's a very selective anti amyloid IgG1 antibody that targets specifically neurotoxic oligomers and plaques. It has been studied over a decade at very different dose levels, including familial Alzheimer's, and we've demonstrated very strong Our engagement for this molecule, as you can see here in the middle, essentially at 3 years, over 80% of patients are amyloid negative. At the same time, in familial Alzheimer's, we've demonstrated that, but also impact on downstream markers of neurodegeneration, So it's hospital tau or CSF near filament, you know, a wide chain. Now when we designed the graduate program, Which started a few years ago, and it's just wrapping up now, and you will have the readout next year.
We really wanted to design the best Trials to test the hypothesis that targeting amyloid at sufficiently high levels would result in good clinical outcomes. So we made a very A few very conscious choices, one of which was to have everyone regardless of APOE genotype, titrated up to the highest dose level. So that's The 10 20 milligrams subcu every month. So everyone is getting up to that very high level. We've extended the duration of clinical Follow-up to 27 months because Alzheimer's is a disease of years decades, not a disease of months.
So we really want to know what the long term safety and benefits Profile is, we have one simple titration regimen that lasts 9 months, and that's really to be able to bring up safely all the patients up to that maximum dose. And again, we've designed these 2 very large over 1,000 patient studies that are essentially going to, we think, Provide the best data set next year to evaluate the efficacy and the safety profile of an anti amyloid targeting therapy in Alzheimer's patients. Now we have a couple of follow on programs I'd like to touch on, one of which is our brain shuttle platform, gantenerumab. This is essentially to get around one of the biggest difficulties in CNS drug development, which is getting enough monoclonal antibodies or biologics Generally across the blood brain barrier and into the target organ. So in this case, we're coupling gantenerumab to our transferrin receptor 1 Brain shuttle module, and this allows, as you can see here in the middle, in our preclinical animal models, both in mice and in monkeys, to essentially go up 30 to 50 fold higher brain targeting for against neuromab.
Now we already have this molecule in humans, and I'm Showing you here on the right hand side, Phase 1 data, PKPD data in healthy volunteers, which shows about an eightfold higher CSF Concentration of the Brinjold version compared to normal against neuromab. And we're running right now a Phase Ib trial in about 120 patients with mild to moderate Alzheimer's to look at impact on biomarkers. The other key target in neurodegeneration is clearly tau. And we have 2 programs in Phase 2 right now, samurinumab and vipranumab. These target different epitopes in the tau molecule.
And the proposed mode of action here is that you would essentially interrupt cell to cell spreading of tau pathology and therefore block The second hallmark pathology in Alzheimer's disease. Now in our first trials, and I'm showing you here some of the biomarker data, We did show pharmacodynamic engagement in these patients. We did have two trials, one of which called Toril Red out negatively in prodromal to mild patients, but just recently we've announced the top line data from our Phase II trial in mild to moderate Alzheimer's patients called LORIT, in which for the first Time for tau antibody, we've demonstrated a pretty robust significant impact on cognitive decline in these patients who were excited about these data It's something that we want to continue
to look at.
Switching over to Efrisde. You heard from Teresa, this is the 1st and only oral splicing modifier that has been developed for Essentially, the broadest patient population of Type 1, 2 and 3 patients, it has really changed the lives of many, many people. It is a very well tolerated, very efficacious drug. And of course, we want to continue to expand on that story. And therefore, we are continuing to study this molecule.
And here I'm showing you data from our rainbow FISH, which is our study in presymptomatic babies With SMA, so these are babies with a mutation in either 2 or 3 copies of the SMN2 gene. Now, of course, earlier intervention Usually leads to better outcomes in these types of diseases. And as you can see here on the right hand side, we essentially are bringing these babies Up to a normal development profile, all of them are sitting up, some of them are standing up, their CHOP INTEND scores that you can see here are essentially maxing out to a normal level. We feel really, really excited about these data. And hopefully, we'll be having conversations with health authorities to be able to expand that label.
The other program we're very excited about is our gene therapy partnership with Sarepta for Duchenne muscular dystrophy. Now of course, Duchenne's is an area of tremendous medical need, and there's really no good disease modifying therapies out there. So a gene therapy could actually be the 1st break The micro dystrophin gene therapy we're developing here has some unique properties. The vector is the AAV REH74 vector, which allows for much better tropism for skeletal and cardiac muscles and also Avoids pre existing immune responses. The expression the cassette is actually has a promoter that maximizes the expression of this micro dystrophin gene And as you can see here, this is data from our 103 study in which we're using the first time the commercial Formulation of this gene therapy in about 20 boys that were dosed with it with 1.33x1014 viral genomes.
So this is This is our target dose. And you can see here a clear demonstration, not just the safety, but also very high levels of expression, Both in terms of numbers of viral genomes per cell, which is almost 4, but also in the numbers of the expression of this protein Measured by Western Bot, by immunofluorescence. So essentially, a really clear demonstration of the Biological efficacy of this gene therapy in restoring dystrophin to these muscle cells, and we're on track to start our first Continuing to talk about neurodegeneration, And you've probably seen this data a few times. We just wanted to mention that we continue to develop prasinezumab for Parkinson's disease. This is the most advanced disease modifying therapy for Parkinson's right now, targeting alpha synuclein, which is one of the Key targets in terms of misfolded proteins for Parkinson's.
And we had a Phase II trial called apasadena that you can see the data here for. Although it missed the primary endpoint, it was the first time that an effect was seen on the MDS UPRS Part 3 scale that measures motor symptoms in these patients, both in terms of the change in this continuous variable as well as the change in time to worsening, so how fast patients are progressing. Now interestingly, at the same time, we had deployed a digital score based on the Floodlight platform, which showed very, very And actually, it was the concurrence of both clinical data and digital data that encourages us to continue to study this medicine. And right now, we have a Phase 2b trial called Padova. It's going to look at slightly more advanced patients we are which are being treated with symptomatic therapies such as enoa L dopa.
Now this digital endpoint, just to build on that story of needing to measure more accurately the things that actually matter. As you can imagine for Parkinson's patients that have a variety of motor symptoms on a daily basis, which fluctuate, there are good days, there are bad days, Having the ability to measure symptoms really closely and very frequently in these patients could actually be much more sensitive. And that is basically what we're seeing here. As you On the left hand side, there's a variety of both daily active tests, such as measuring tremor or rigidity, finger tapping, but also Passive monitoring of walking, balance, etcetera, which altogether derive a motor score, which has a very high degree of
So I think this
is just a great example of how technology can help solve Clinical research questions, and we're currently in dialogue constantly with health authorities globally to see if endpoints such as these might actually become Acceptable for actually using in clinical trials. Now switching over to ENSPRYNG in Mycenae gravis. As you know, we got approved answering last year for neuromyelitis optica. Myasthenia gravis is another chronic autoimmune rare disease. Although there's only there's almost about 1,000,000 patients globally, of which about 80% really don't have stable management of their Disease and in about 10% of them, this can actually result in myasthenic crisis, which can be life threatening.
Right now, standard of care, it's either treated treatment with steroids or IVIG or then very highly potent immune suppressant drugs With not such a great safety profile. So we actually feel that ENSPRYNG might be a really interesting new mode of action for these patients that would allow Essentially safe targeting of 1 of the key pathophysiologies here, but at the same time with a very convenient subcu dosing every 4 weeks. Now finally, switching over to immunology. I wanted to mention our Gazyva program in lupus nephritis, Memorinist nephropathy and systemic lupus. This really builds on our long standing knowledge of B cell depletion as one of the key mechanisms This is using Gazyva, which is a glycoengineered anti CD20 antibody with much degree, much higher potency.
And we do know that resident B cells in tissues such as the kidney for lupus is one of the key drivers of the biology for this So we're basing ourselves as well on Phase 2 data from our NOBILITY trial, which you see here in the middle, Which clearly show compared to a placebo, a much higher degree of complete renal response at week 76, About a 50% response in people who are sustainably depleted of B cells. And therefore, this could really be a breakthrough for these patients. And we're continuing to study this molecule now in Phase III trials in lupus nephritis, which we've started just about now, But also in membranous nephropathy and in systemic lupus. The final molecule I wanted to mention is our program in fibrotic diseases with contraction 2 in IPF. Now this is Still a very much a major medical need.
Most patients with IPF die within 5 years. Standard of care hasn't really changed much. There are 2 drugs which are approved, but don't really change the progression Significantly, and we're excited about this molecule because on one hand, the mode of action is that it changes fibroblast differentiation from a pro fibrotic, pro inflammatory to a proresolative state. And at the same time, we have Phase 2 Results that show that on top of standard of care in these patients, for the first time, we've demonstrated an additional benefit. So a substantial reduction In the progression of loss in FVC at 6 months, but at the same time sustained endurance in terms of the 6 minute walking test.
So this could really be the 1st breakthrough for these patients. And therefore, we're very, very excited to have just started our first trial in IPF this year. So with that, I'll thank you and turn it over to Nilesh.
Thanks, Alain. My name is Velez Veta, and it's my privilege to share an overview of the Okta portfolio at Roche. Over the next few slides, I'll cover the landscape and unmet need in retina. I'll overview data from our late stage assets ferrisimab and port delivery system And then touch on the off the pipeline and our personalized healthcare approaches. So as you can see here, in spite of the tremendous Impact of IVT anti VEGF therapies, there's still a high unmet need in retina.
In clinical trials where patients are dosed frequently, Approximately 3 to 4 out of 10 patients don't achieve 2,040 vision, and that's usually required for driving. But even more so in the real world, patients are not able to adhere to their treatment intervals, either because health care systems cannot provide sufficient capacity for injections All patients can't manage the frequent visits and as a result, lose vision. Doctors will tell us that approximately 50% of patients can eventually be Extended to Q12 week dosing. But with both furosemab and forward delivery system, we believe we can provide physicians with truly innovative options to address this unmet need The durability and thereby improve real world outcomes. The key message here is that durability is directly linked to vision outcomes and the benefits that gives to society.
So firstly, let's touch on faricimab. It's been filed in the U. S. And in EU, and we've got Approvals for this expected in 2022. Faricimab is the 1st bispecific antibody developed specifically for ocular administration.
It simultaneously binds 2 distinct pathways, well known in retinal pathology. So the well known anti VEGF part, But also now to angiopoietin 2, which has been implicated in vessel destabilization. As Teresa mentioned, it's the first new MOA in retina for over 15 years and really distinctly different to monotherapy anti VEGFs. It's engineered with a modified FC portion that allows for longer action in the eye and but faster clearance systemically. So quite unusually, Farisov was studied in both AMD and DME simultaneously.
It's the first time a company has conducted these Studies in parallel, and both indications have been filed with key regulators around the world. Further, we have Phase III Positive data in DME and NuVascular AMD has been presented at conferences through the year. On the left, you'll note The consistent data across all four Phase III studies in both indications showing approximately 75% to 80% of patients Being able to be extended to Q12 and about half to Q16 is the first time this level of durability has been demonstrated In a Phase III setting, all of these arms in the furosemab trials provided BCV8 gain similar to a flibercept dose every 8 weeks. In DME, the anatomic outcomes favored faricimab. So this has been both absence of DME And absence of infraretinal fluid.
The safety profile was in line with current anti VEGF IVTs with small numbers of adverse events And no cases of vasculitis reported. And in our opinion, this sets furosemab up to be a potential Future new standard of care in the IVT setting. Furthermore, we will be delivering on long term data, So RoNex and Avon LX, which are ongoing and will provide 4 years of longitudinal data for furosemab. So shifting to another innovative program, the port delivery system with ranibizumab. So this has been filed in the U.
S. And in the EU in quarter 2 this year. And FDA approval is expected in October of this year, as recently announced. Just as a reminder, the port delivery system is a permanent intraocular implant about the size of a grain of rice, And almost all patients were able to be dosed every 6 months. The implant procedure is 30 minute outpatient procedure and the refills are akin to an IVT injection performed in an office setting.
I'd like to point out here the Pagoda study, which is also now fully enrolled, and it's about 5.40 patients. And the speed of the study enrollment really suggests both the importance and the interest of retinal specialists in the PDS. I should note that there is robust IP protection around the PDS device and the formulation that Ranibizumab that goes into it. Touching on the data. In the Phase III ARCHWAY study, PDS patients dosed every 6 months should equivalent visual acuity gains to monthly anti VEGFs.
And nothing really has come even close This level of duration with almost all patients going every 6 months with no drop in BCVA. 98% of patients did not require a supplemental And further, in a survey conducted as part of the trial, 93% of patients Reported a preference for PDS over IVTs. The PDS implant and refills were well tolerated with a safety with a favorable profile. So as these programs are in regulatory review, we're planning for global launches. I think Theresa mentioned that this is the first time we're going to have a global footprint in ophthalmology.
And for the launches, we're really focused on ensuring And for the launches, we're really focused on ensuring consistency of the implant and safety for patients. To support these objectives, we'll be supporting eye surgeons to practice both the implant and the refill procedure using virtual reality based systems. And in addition, we'll have field based surgical device liaisons in place to help surgeons in the OR. Hiring and training are ongoing. We know how important payer discussions, access and reimbursement are for this community, and these are progressing as we speak.
So further to the late stage assets that I've just shared some data on furosemab and port delivery system. Here you can see the robust pipeline that we have in ophthalmology. There are sort of 8 new molecular entities that are in either Phase 1 or 2. And this really forms one of the leading pipelines in ophthalmology. I think as the science on different pathways involved in pathologic eye conditions And the associated imaging and clinical biomarkers continue to evolve.
It makes for a very exciting time to be in ophthalmology research. One of these platforms I really want to highlight is the Dutafabs. I think Bill mentioned it earlier, which are really next generations bispecifics. They can be concentrated significantly and are being developed to be compatible with port delivery system. The next one to progress into clinic is anti VEGF and 2 bispecific, but other pathways are also being assessed.
Finally, beyond the therapeutics, we believe there are other technologies. I think Paolo has alluded to them in NS as well, but that can patients in clinics to have a better experience of managing their chronic eye conditions and therefore, hopefully, better personalized care for patients and their families. One to call out here would be My Vision Tracker, which is a app based vision test, which can provide patients and their physicians confidence to monitor vision Between extended visits to the office, the teams in ophthalmology continue to work on imaging modalities and have a number of real world data collaborations ongoing, which you can see on the slide here. With that, it's my pleasure to hand over to Barry Flinch.
Thanks, Ines. Next slide please. So, I'm grateful to have the opportunity this afternoon to speak to you a little bit about our infectious disease franchise. I'm going to talk in 3 sections. Basically, first of all, a little bit of time spent on our HBV franchise, and I'll talk about the different molecules we have there.
The bulk of the time I'll spend on our SARS CoV-two franchise and looking molecule by molecule at the 3 key components of that. And finally, to finish up with a little bit of an outlook of how we're thinking about where the pandemic and this virus are going to go over the next months and perhaps even years. So, we can move to the next slide. So, in our hepatitis B portfolio here, I I think it's a good illustration of some of the points that Bill had made right at the outset and others of my colleagues have too. We're interested in a cure So the goal here is a functional cure for these patients and a wide modality base as well.
We're looking at Both siRNA approaches, loctonucleic acids, small molecules. So we're taking technology technological approaches that make sense to us, Given what we know about the disease biology of chronic HBV infection and we believe that we will need Different approaches to deal with this virus, part of it on the left hand side of this slide is directly attacking the virus itself. That's going to be important. But on the other side, We also believe stimulating the immune system to gain control of the virus ultimately is going to be important as well. So we have MOAs that target both sides of this.
And we believe combinations will be necessary. Our thesis is that it will be something that targets the virus plus something that modulates the immune system, either the innate Or the adaptive that's going to deliver the outcomes that we want for patients in terms of a functional cure. And if we can go to the next slide, a key part of this He's going to be rapidly evaluating these different combinations. As you can imagine, with complex biology and a number of opportunities, there are plenty of permutations Combinations that can be tested. So we've got this now running this Phase 2 platform study, which will basically allow us to seamlessly Take in and out different combinations from our pipeline to study them.
And given the ambition that we have for functional cure and the fact that we know what we need to measure, so So we're looking for S antigen loss because we know this is a key driver of the disease state of chronicity for these patients. This allows us to We have relatively small and efficient studies that will provide very robust data outputs that will allow us to select between these different combinations. As well as that, it will also allow us, as you can see on the left hand side, the opportunity to take interim looks at different points. We're going in with certain assumptions about how long we need to treat and what effect size we'll see, but we can actually monitor this relatively real time And make adjustments as we're going along with these interim analysis. And that may allow us to either find surrogate markers of control earlier on Or adjust, in fact, the duration of treatment that's ultimately going to be required to deliver functional cure for these patients.
On the right hand side there, you can see some of the combinations that we have Running at the moment. But this is ongoing at the moment, and we expect to see data readouts in the coming months from this that will start to allow us to home in on that ultimate combination. So So we could jump to the next slide and switching gears to SARS CoV-two and our response to the pandemic. So before going into the Molecules in particular, I just want to take a step back and have a look at the totality of what Roche has done in the pandemic space over the last 12 months or so. This comes from both the diagnostic side and the pharma side.
And on the diagnostic side, our colleagues were very rapidly able to bring forward Not only typical hospital analyzer based gold standard PCR testing, but also near patient antigen testing As well as antibody testing to verify whether patients had already been exposed to the virus. So we are testing from all the necessary angles to help with both the diagnosis The epidemiological management and characterization of this virus is from a very early stage. You can see much of this happened early in last year, so it's Extraordinarily rapid development. On the treatment side, we've looked across and I'll go into these in more detail. We've had 3 key approaches Through Actemra and immunomodulation, ronaPrieve is a direct anti antiviral, but a large molecule and AT-five twenty seven, again, direct anti antiviral, but a small molecule.
And various readouts have been going on throughout this year, but I'll talk about them in a little more detail as we go through each molecule. So we go to next slide.
Searching on our strategy, perhaps before
I get into the molecules themselves, we were obviously faced With the same task that everybody was last year of how do we address the pandemic. And one of the things we wanted to do was have an impact And play to our strengths. And the pyramid or triangle on the left hand side of this was our way of looking at the landscape and thinking about where could we have the biggest impact And where would best play to our strengths? And while I think we all realize that vaccines when it comes to infectious disease are the best, prevention is always better than cure. For us, Getting into the treatment space was definitely going to play to our strengths and allow us to have the biggest impact on the pandemic.
And we sort of stacked these up starting at the bottom with an oral antiviral because of the breadth of impact that could have, the number of patients that would have the opportunity to treat, Followed by neutralizing antibodies and for those patients in hospital, immunomodulation is clearly important. And so we have AT57, we have RonaPrev and we have Actemra. And although I won't go into it in detail, you can see on the right hand side the degree of activity and the degree of success we've had in bringing these molecules to patients. We can jump to the next slide. Looking now molecule by molecule, so this is looking at Actemra specifically It's already been widely approved in a number of indications before now.
And it was clear from relatively early on in the pandemic that IL-six seems to play an important role as a driver of Information, especially in the critically ill patients. And so it looked fairly obvious that Actemra could be useful, but it needed data to back it up. Roche has conducted a number of studies. You can see on the right hand side, EMPACTOR, COVACTA and Randacta, but also some of the big platform studies also So the merits of Actemra brought that into their platforms, namely RECOVERY and REMAP CAP. And importantly, the final analysis of all of this data It clearly shows us that there is a place in the hospitalized patient for treating COVID-nineteen with Actemra.
Well, the recovery study very clearly showed it 14% improvement even on the back of steroids in the risk of death. And then more recently, with a large meta analysis All of the Actemra data, including more than 8,000 patients, underscoring that particular benefit and leading to WHO guidelines for the use of Actemra. I think a great success story for this molecule. Moving to the next slide. Switching directions, so now going from immunomodulation to a direct This is the collaboration with Regeneron and their cocktail of 2 distinct neutralizing antibodies Targeting the spike protein on the surface, but in non overlapping, noncompetitive spaces.
And we thought this was, From the outset, particularly important with our experience with respiratory viruses and knowing their ability to evade treatments, Having dual antibodies targeting different sites, we believe is going to be very important for the durability of a treatment like this. And indeed, that has been shown to be the case With even up until today with variants of concern and variants of interest all well covered by RonaPrix. And here again, multiple studies are being run Together with Regeneron through different patient populations going from outpatients who are at risk through prevention and post exposure setting And to hospitalized patients and as well, again, with the RECOVERY platform all giving positive readouts, meaning that we've got a very impressive data set for RONAPRIV, Ranging from impacts on the risk of hospitalization or death into impacts on the likelihood of having symptomatic illness And the same with the RECOVERY study showing a 20% reduction in the risk of death for patients who don't so seronegative patients who don't announce their own immune response. So this is a very robust set of results, and we're working very hard to roll this out and make it available to patients around the world.
So if we can go to the next slide. And finally, within the COVID space, we have AT-five twenty seven. This one is certainly the earliest in its Progression compared to the previous 2 I've just spoken about. This is a small molecule now, direct to anti antiviral that targets The polymerase right at the heart of the machinery of this virus and its ability to make still more viruses. This is a very nice molecule.
It has the ability to target 2 parts of the polymerase, not only the catalytic site where the Nucleic acid is being synthesized, but another distant site from that, which is also important for the virus' ability to replicate. So we're targeting 2 different parts of the polymerase with this molecule. And although it's early stages yet, although it's only early stages, we have some very encouraging preliminary data on the viral load impact from interim results From ATIA's own Phase 2 study in a very mild to moderate hospitalized patient population. It's early days. These are encouraging results.
We've got our own studies in a Phase II, which is intended to confirm the dose. And in parallel, we've also started a Phase III trial, which is enrolling currently And where we expect results later this year, but so far so good. And finally, we'll turn my attention to what might happen next. This is a very difficult challenge. I think all of you will appreciate predicting the future is probably never a very good idea, and I don't think COVID is any exception to that.
We've tried to think about this nonetheless. And broadly speaking, we've sort of seen this in 3 possible categories. You could have a very optimistic outlook on the left hand I don't think no, hang on a minute. We've got great vaccines. We've got great treatments.
This virus is on the way out. In fact, maybe it can be eradicated completely. And this seems very unlikely. This seems unlikely when we thought of this some time ago, but it seems even less likely now with the emergence of the Delta variant. On the other hand, you could be very, very pessimistic indeed and think this virus is just going to outfox us at every step.
And no matter what we've done and any success we have, it's only temporary. But I would say also a low likelihood that this is true. The more likely scenario sits somewhere in the middle, where we think that everything that we're doing will be durable and it It will contain and it will manage the virus, but eradication will not be an option. It's going to be something we're going to have to learn to live with. It Would be expected to become endemic.
It would be expected to become seasonal and join the panoply of winter viruses like RSV, Like influenza. And with that sense that, yes, while it will become much, much easier to manage over time, it will still need management. And with that in mind, we're going to continue to develop diagnostics. We're going to continue to develop treatments to manage this important pathogen. At that point, I will finish.
Thank you.
Yes. Thanks a lot To all the presenters, and we are now moving into the Q and A. We have 1, 1.5 hours So we are really very much in time. As promised, very proud of our presenters. There is really no slippage.
And Maybe Henrik, you could kindly share with us what should be done, what can be done in order to address the questions. And maybe you also can give us A hint on how this survey works in the end, what the people have to do and what they also have to do in case they don't want to address these questions.
Yes. Thank you, Carl. So we are coming now to the Q and A session. And for that, you can either use the Q and A functionality of Zoom For the survey at The end, there we will, yes, send out a push up window for you. And then there are 9 or 10 single choice questions.
You can just answer them live. And yes, then if you do not want to answer those, you can just click on the red X, and then you can go ahead. And with that, I will hand over again to Karl.
Yes. Thanks a lot. I have to admit, I couldn't hear all what you said, but I hope that it was transmitted via Via the phone and that the people on the line could actually listen and hear what you said. Maybe we just first, for this reason, take a question from the chat. It's from Sarita.
She was asking how important the head to head for our 3rd versus Wolvestrant in the H1 'twenty two, so beginning of next year, To providing credibility to the 3rd class as an earlier line of treatment, so how important is the trial? And her follow-up question was, Would a differentiated safety profile without superiority efficacy be able to support the fighting? Maybe Levi, that's one for you.
Sure. Well, maybe I'll start, and I'll let Charlie add. So a big picture here. So obviously, Hopefully, you all appreciated our enthusiasm for our service in general. When you think about the study that we're running head to head against fulvestrant And later line ER positive breast cancer, one thing that we know as a field is that the later you go in treatment Of ER positive breast cancer, the lower the dependence on the estrogen receptor in those tumors.
So When we think about we often talk about patient heterogeneity as a buzzword. In ER positive breast cancer, that's what we're referring to when we think about ER directed therapy. The later line metastatic patients are less dependent. There's still some dependence, but they're less dependent. So what that means is that we think From the efficacy and the pharmacokinetic data that we've seen for geridesterin, it has a chance to perform very well head to head against fulvestrant.
And so we'll be looking forward to seeing what those results look like. But it also means that it's difficult to extrapolate what that will mean for earlier lines of Treatment where the dependence on the estrogen receptor is much more profound. So we're looking forward to seeing the results in later line, but I think we have to be cautious About over interpreting those results in later lines to what they might mean earlier lines, which is a very different biological question. But I'll let Charlie comment to maybe On the other element of the question?
No, I think, Levi, you addressed it. And as you point out, I think the preclinical data and the emerging clinical data really do suggest, Given its mechanism action, geridesterant is appears superior to the available Drugs that inhibit the estrogen receptor pathway. And I think the readout in the coming year in the second, 3rd line setting against fulvestrant will be important and we're also really looking forward to the data we see at ESMO next week But I think really speak to the clinical applicability of the unique mechanism of action that we're seeing with this drug.
Yes. Thanks a lot.
So I would say
let's go into the question via the phone. Wimal from Sanford, I'll open your line now, please.
Great. Thank you very much for taking my questions. Thanks, Karl. So Maybe just starting with Polarix. Maybe you had a little bit more time to digest the data.
So I mean, I guess, where is your conviction On this becoming the new backbone therapy standard of care, and if it is very high, why is this not a global €5,000,000,000 opportunity. You mentioned €2,000,000,000 at the 2Q call, but if it becomes a standard of care, it shouldn't be much Larger than that. And then just tied to that, could you just provide us an update on filing? Is it fair to assume RTO will be used? And then my second question is maybe just for Paolo on Ganti.
I mean, I appreciate this is a discussion maybe for the future, but wanted to hear your thoughts On duration of usage, so given plaque reduction continues over multiple years, I'm just curious how Roche what Roche believe will be the duration of use Should we see a positive cognitive outcome, could these drugs actually be used for 3, 4 years or longer? And just how much of a role will price I can certainly start, Karl.
I can certainly start, Karl, with the first part on the question on Plerix and then obviously turn to Theresa and Bill on the Commercial opportunity, I think it's been said, the results of POLYRIX are really important and that it's been 2 decades And more than 11 randomized trials since R CHOP set the standard of care in diffuse large cell lymphoma, many attempts To unseat our CHOP with all its benefits, until now, when Polerix shows what we think is clinically meaningful, Statistically significant and important endpoint of progression free survival and we believe that the data which will be presented in upcoming meeting do support This representing a new standard of care. So, we're excited in terms of the filing. We're anticipating global filing. We really can't speak to the details of that now while it's under development, but we're looking forward to making This important breakthrough available to patients globally, but let me turn to Therese and Bill on the commercial opportunity.
Yes. Thanks, Charlie. But I think we talk about this as a multibillion dollar opportunity. So I think we're still in the process of really understanding exactly How big this is going to be and who is going to use it and where? I mean, I share Charlie's conviction that I think this is practice changing data.
It's the first time in 20 years We've seen in advance over R CHOP, which is highly entrenched regimen.
But I think this is going to
be exciting data for the community when they see it.
So, Carlos, should I take the other one?
Yes, please. Yes. I think it is a really important question, Right.
And I go back to the comment I
made, which is Alzheimer's is a disease of years decades and not a disease of months. And therefore, I think long term therapy is going to be required, right? Now, how long can you sustainably Have therapy with a subcu formulation? Well, I think convenience actually matters a lot for these patients. So the ability of not having to go to the hospital for Complicated IV infusion every month or not having to do a lot of monitoring or monitoring based on genetic blood testing, I think all those things count.
The long term safety and efficacy profile counts a lot. And it's again why I mentioned that we designed our trials To go over the typical 18 months more towards the 27 months and of course to generate long term data, I think those data are going to be really, really important to continue
to demonstrate the benefit.
The long term safety of these The long term safety of these medicines is super important. Therefore, I think For as long as patients are getting benefit and the safety profile is acceptable and the drug is convenient, Then of course, other factors play in pricing you mentioned, access, all of that. There's a lot of healthcare readiness work that needs to get done because these are going to be 100 of 1,000, if not millions of patients, and I'm not minimizing the challenge that, that might pose. But Generally, from a medical, biological standpoint, I think long term therapy is going to be the way to go. And not just in patients with Alzheimer's, but also patients Who are at risk of Alzheimer's, pre symptomatic patients, and we already have numerous trials in the community out there addressing this population as well.
We already know that if you just look at the pathology, the pathology starts decades before clinical symptoms start. So In the presymptomatic stage prevention of Alzheimer's is probably going to be a pretty big thing For these types of therapies.
Thank you very much.
Yes. Thank you for the question. We Sachin, you would be the next from Merrill Lynch.
Hi, there. Thanks for taking my questions. A few, please. Firstly, on faricimab And the commercial opportunity, when discussing the launch, Theresa, you mentioned that physicians like to switch. So I wondered if you had some more metrics around that As we think about the 1st 12 months of launch, I.
E. What percentage of this market do you view as poorly controlled or very frequent injectors, however you define that, That is low hanging fruit for that 1st 12 months, Rich. And second questions are on TIGIT, if I may. So thank you for outlining the data next year. I just wanted to check on Sykescraper 6, which is your lung all comers chemo combo for the broader PD L1 strategy.
There's been some debate of some interim data in 2022. Is that still on the cards for next year? And then a bigger picture question, you remain, I think, the only player In Phase 3 outside non small cell, that clearly gives you a time advantage.
But I wonder if you could speak
to a level of confidence In your broader solid tumor strategy, given the lack of Phase III data into those pivotal reads. And then maybe just one clarification Teresa, on PolariX, when answering the prior question, you talked about how broad this may become. Can you just provide some more color there, I. E. How high risk was the Polaris population?
And is extrapolating that more broader The debate as you frame the commercial opportunity. Thank you.
Yeah. Thanks a lot. Maybe Neeraj should take the first one on the ophthalmology.
Sure. Thanks, Sachin, for the question. So for faricimab, we believe really that the profile of the product that we've seen, given that It inhibits both pathologies of disease, providing some vascular stability through the ANG2 and then getting 50% of patients up to Q16 is pretty much a first line setting. So we think that de novo patients will also benefit from the product. From the most recent data we have in terms of where patients are, most physicians will tell you about a third of their patients can't really go beyond either Q8 or Q12, and about half of their patients get to Q12 over time.
So I think there's a significant opportunity there for Furosemel to be used.
Yes. Thank you. Maybe Charlie or and Olivier, on the trial design POLARIX addressable patient population, and maybe you can also kind of take the TIGIT one.
Sure, absolutely. So I think the first question was do we anticipate a readout from Skyscraper 6, which is our 1st line trial in patients with non squamous cell, non small cell lung cancer. And the answer is that Phase 2 readout is for next year, and we believe it will inform a larger Phase 3 study in that effort. With regard to our existing bets of trials, as you heard, we have several readouts next year. We think actually the results of CityScape, the biology of what we know about TIGIT and these diseases, including Small cell carcinoma where the polio virus receptor is present, we think the data do support these calculated bets, And we're looking forward to all these studies reading out next year.
Levi, I don't know if you wanted to add anything.
No, I think, Charlie, you've covered it with the Aggregate data, so the gene biology data, so that's the tigit ligand in non small cell lung cancer, the general importance of immunotherapy in small cell lung cancer that is. And then in general, the aggregate preclinical and early clinical data that we've seen, we think support the best that we're making.
And if you could you also kindly comment on the Polerix situation, patient population? Do you We have always said that we do expect actually a broad label, because the trial set up was also in the broad patient population. I guess Sachin's question was along these lines. So, what do you expect in terms of let's say, yes.
Yes. So we anticipate we're anticipating a broad label for POLYRIX. I mean, that's certainly been the precedent that was really set by Archrock. So given the Clinical benefit of progression free survival in this population in the first line and potentially curative setting Across patients, we're anticipating a broad label in the setting of first line therapy for large cell lymphoma.
Okay. Thanks a lot. Sachin, I hope this addressed all your questions. Next one would be Jo Walton from Credit Suisse.
Thank you. If you could hear me, I've got 3 questions, please. Firstly, you are investing a huge amount in R and D. You've increased your R and D spend. I wonder if you can tell us how you're thinking about About return on investment, do you think that things have changed such as you need to invest more to get the same return?
So are your investments in technology and your confidence in success such that we should be able to see at least the same return on the next $10,000,000,000 of investment that we see on the first $10,000,000,000 My second question goes back right In the beginning, there is some discussion about costs and how productive you use the car in terms of increasing extra sales It was no increase in headcount and lower spend. Can you give us a sense of how far down that journey you are? How do you think that you've got 2 thirds in the way down there? What we're looking in the next 5 years, you could be making the same level change? And my final question is just an update please on biosimilar erosion.
So just if we could have a little bit what your expectations are.
In terms of the R and D productivity, I think that's probably the most important strategic topic for the whole industry. And I would just say, we are not increasing our investment because we think productivity is going down. We actually think First off, there's definitely a battle to secure high R and D productivity based on Disease unmet need, disease biology, smart clinical trials and things. But we actually hope that we can increase R and D productivity, based on the things that I mentioned, both technology opportunities, but also opportunities to be more effective with People's time and people's work. And we have a number of opportunities or a number of activities that are going on with that right now.
Maybe I'll see if Levi wants to comment more on that, but let me just finish. In terms you asked on the commercial side, How far are we down the path in this efficiency journey? I would say we are It's hard to say exactly, but maybe halfway. The good news is that We've probably done most of the reductions that we need to do and now we've got a lot of new products coming and the opportunity we have looking forward Launching new products without necessarily adding lots of people, again, just taking advantage of the great talent we have And the ability of people to do more than what we've asked them to do in the past, again, not more hours of work, not more volume, But just handling more complex tasks rather than dividing those jobs up into little pieces and creating new positions That sort of make more complexity, but really benefiting from the full capacity of our people's talents and abilities. In terms of biosimilar erosion, I think we've guided since the beginning of the year.
We thought biosimilar erosion this year would be about CHF4,600,000. And I think we're still thinking it's about that. So,
yes, Bill, maybe I have another one
here, which goes into the same Directional on John Murphy, Bloomberg. He was asking if you have any sense on the percentage of Roche's current clinical Spend in oncology versus non oncology, do you expect now to spend more relatively oncology or to spend relatively less in oncology? Can you give us any kind of an idea here?
Yes. And I'm going to hand off to Levi, if you have additional comments, Levi, on the productivity question. It's hard to say. I mean, we follow the science. That's one of our key principles as a company.
And if we have more Opportunities in oncology then outside of oncology will increase investment. If we have less, we'll decrease. I would say right now that that ratio is relatively constant. It's not changing a lot because we have a lot of opportunities in oncology as you've heard about today and we have a lot of opportunities outside of oncology. So I think maybe one way to think about it, because sometimes people ask, well, are we really committed to some of these other areas?
And I would say Our investment level, while we are the leader in investment in oncology in the world, we're also the leader in investment in a number of other therapy areas. And I think we aim to continue with our plans to bring many more breakthrough medicines in many diseases, including oncology. Levi, other things you want to say?
Yes, absolutely. So maybe I'll just add that Bill in his presentation talked about at a macro level the shifts That allow the increased R and D investments and what that's meant from a workforce standpoint. Within R and D, we similarly see opportunities For shifts to make sure that the work that we're doing and sort of the infrastructure and workforce infrastructure costs Can be optimized so that the investment is maximally going to the new clinical trial, new molecule opportunities. And that involves Changing ways that we work, Bill mentioned how we leverage technology and platforms and scale. And also the kinds of work, the high what's higher versus lower priority work and making sure that we're removing lower priority work.
And we've already begun to take steps in that direction. We think there's more that we can do. So the increase in R and D productivity is not just a macro shifting From other parts of the company into R and D, it's also within R and D optimizing our work and how we deploy our resources.
Yes. Thanks a lot. Next question would be from Tim Anderson. Thank you, Joe, for the questions. Tim, I open your line.
Okay. Can you hear me okay?
Yes. We can hear you, yes. Thank you. Okay.
Sorry, can you hear me now?
It's Perfectly fine. The line is good. We can hear you clearly.
Okay, great. I have a question on gansenerumab. I'm worried that the risk of failure with the graduate studies might be higher than with monoclonals That rely on IV dosing, it seems like with subcu dosing, you may not get the same pharmacokinetic peaks that you would get with IV. So you get less drug across the blood brain barrier and a slower rate of plaque reduction. And it seems like we've already seen that slower rate play out You're opening up with extension data from Margrave and Scarlet Road.
So you eventually get deep plaque reduction, but it takes longer to get there. I'm wondering if these trials might time out too early where you don't see a cognitive benefit because you didn't reach deep plaque reduction quick enough. So that's one question. And then on your TAO program, mixed results. One trial was a total wash.
The other trial showed one endpoint that was positive, but when you described that program, overall, you still seem reasonably excited. So can we confer that you think that the recent positive data point is strongly supportive of efficacy here And where do you go with this program? This certainly is not a registrational dataset.
Thank you. 2 very, very complex questions. I'll start with the first one on gantenerumab. So there's actually no evidence that you get more drug on target based on IV versus subcu. And even if you do get The peaks and during the peaks, you might get more drug through.
What actually drives target engagement in the brain is how the antibody binds to plaque. So it's build up. It's not so what I mean is that the pharmacodynamic effect is not dependent On the pharmacokinetic profile directly, it's depending on the accumulation of drug at target. So we actually have a lot of data on that. We did have The IV form of gantenerumab, we did all the modeling around that.
And therefore, I actually am not convinced that that's true. Secondly, when you mentioned about the rate of amyloid removal on our open label trials, there's Two points I'd like to make there. The first of which is that, that data that I showed you today and the data from our open label trials are actually from patients that originally for the 1st 2 years We're on very low doses, and they were only moved up to higher doses after the futility of SCARLET ROG. So you're actually not seeing what the real, let's say, the real dynamics of amyloid removal might be on our graduate program. And again, Because this is a very rich data set and we're able to really model these data, and I think we've presented that.
What we're predicting is actually roughly about a 25% to 30 production in amyloid after 2 years, which is very comparable to say other drugs out there. The second point I'd like to make There's actually no and I think I mentioned it, there's no clinical correlation between speed of amyloid reduction on PET And clinical outcomes, right? And that's an important point because what we're actually measuring, we're measuring essentially plaque. We're not measuring what happens To oligomers, we're not measuring what happens to the neurons around them. This is basically a good surrogate for pharmacokinetic effects.
It's a good surrogate endpoint, at least the FDA seems to think so. But it's not a direct predictor of clinical outcomes. So based on that, I mean, I feel very, very confident that, one, we have the right dose, we have the right duration of dosing, That the subcu, on the contrary, will prove to be an advantage because of convenience, because of access. And also because we deliberately wanted, as I mentioned, to take time to titrate everyone up To the highest dose, we actually design trials that are going to last 1.5 years sorry, 2 years and a half, so much longer than we than is So I guess the bottom line is that I actually am not concerned that the trials are going to read out too early. I think this is still the best design trials out there.
Moving over to tau. You're right, there are mixed results, both with our antibodies as well as with antibodies from other companies out there. And in retrospect, I don't think that's remarkable, given that this is very new biology. We're trying to tackle What is clearly one of the key pathologies in your degeneration, and I think that makes a lot of sense. And whether this is the right modality or the best Motality, whether an antisense approach or gene therapy approach might be better, we don't know yet.
What I think is exciting is that for the first time In any trials in Alzheimer's, we were able to show a real benefit, about a 40% reduction in cognitive decline In mild to moderate patients, this is something that is actually quite exciting, because again, it's the first demonstration of that potential. Does it mean that we're going to rush to Phase 3 and this is the conclusive proof? No, it's still early days. We're still looking at those data. We're, I guess, excited enough that we still feel that might be advantages in pursuing this type of anti tau molecule, But there's a lot of road ahead for us, for sure.
Thank you, Tim, for the questions. Simon Baker, Brett Burn would be the next one. I open your line, Simon.
Thank you, Karl, for taking my questions. Just going back firstly to the question of R and D productivity and spend. I noticed that looking at the Paper describing the story of the discovery of duradestrant and comparing that with phenibutinib. On the juridescent paper, about onethree of the authors were from Charles River and WuXi, whereas fenabrutinib, which was only published 3 years earlier, We're 100 percent Genentech employees. So I was wondering if that marks a shift in your approach and utilization of outsourcing And whether that was driven more by capacity or cost.
And then a couple of questions, I suspect, for Teresa. You gave us the chart of oncology visits in the U. S, which showed us back to an almost normal level. That data was for June. I just wondered if you had any newer data there.
And also if there were any meaningful differences by tumor type, Because I think previously, we've seen that lung and breast have been the most affected. And then finally, on Fezco, you mentioned the high Conversion rate in the U. K, I assume that's driven by price as everything is driven by price in the U. K. But I just wondered if there were any other And what that means for the potential of FESCO in a world of biosimilar Herceptin.
Thanks so much.
Yes. Then what's it for the R and D productivity? Dibai, over to you.
Sure. Yes. So I so on the specific example that you gave of the gerodestrant paper and authors versus spinabrutinib, I would say that I wouldn't read too much into that. Those are different molecules and different points in time. And so the nature of the work What was different?
I wouldn't draw too much in a way of conclusion there. As a general picture though, we are always looking at Where is it where does it make the most sense to get the work done that we need to get done? And where does that mean investing Internally in our workforce and the capabilities that we need versus where does it make more sense to leverage external capabilities In a rapidly shifting R and D landscape as we're in, we always have to ask these questions. So we're always looking at this, but I wouldn't read too much into the specific examples that you gave.
Great. Thanks, Levi. And in terms of the other two questions, so related to oncology visits, You're right. In certain parts of the U. S, we are seeing a that are harder hit by the delta variant, we are seeing visits slow down.
For the most part though, we're not seeing Too many differences by tumor type other than that consistent sort of slower comeback in hematology. Interestingly, these results are pretty consistent with what we're seeing in Europe Well, so mostly back to normal, little bit of a softness in hematology. And where the delta Variant is flaring. Unsurprisingly, you're seeing a little bit of challenging patients going in for their care. In terms of the U.
K, I mean, so it's not just about price. I think part of this idea that Bill has been talking about, about cost Society is also what it takes to administer drugs. And part of what may has made the FESGO launch in the UK so Successful is that it is able to actually decrease the amount of resources that hospital staff need to put towards infusions. And so that is a different kind of savings The different kind of efficiency in the system that is going to be more attractive to some systems than others. But When we think about Herceptin biosimilar erosion, I think we have seen things like Fezco and Subcut Herceptin actually do provide Some slowing of biosimilar erosion just because obviously those formulations aren't available with the biosimilar.
And again, for some systems, they see that Reduction in the amount of share time as a really big cost savings for their overall system, and it's not just about the drug.
Okay.
Thanks so much.
Yes. Thanks a lot. Emmanuel Papadakis would be the next one
Thank you, Karl. Manu from Deutsche Bank. Perhaps I could take a couple of big picture ones for Bill, if I may. Margins, You're back up to mid-20s on R and D spend as a percentage of sales. Are you now at about the right level?
Or is that going to continue trending up As you shift the mix from other spend lines to R and D. And overall, thinking about the outlook for pharma margins over the next few years, Back to growth next year. You have been slightly improving over recent years. Is there any reason we should not expect that to continue and even accelerate? You mentioned wanting to keep investors happy.
Could we go through the mid-40s over the next few years? Is there any reason it couldn't get to the high-40s over the mid- to long term? And then we know you're pretty plugged into Washington, put your political hat on. How worried are you about something Informal price negotiation hitting Part B anytime soon. We'd love to hear your latest thoughts.
And maybe if I could squeeze in one on the outlook in for Centric. You obviously have the negative news around the TNBC labeling. Is there any risk we see something similar imminently in bladder given Keytruda was Somewhat surprisingly converted to a full approval despite the miss in KEYNOTE-three sixty one. And does that mean we're actually looking at a few down quarters ahead of The uptake in adjuvant and how fast could that uptake in adjuvant be next year, is that something you'd expect to be relatively rapid? And likewise, with the additional adjuvant studies you
A similar question, Bill, was from Rodent Goldman on the Biden administration proposal, if you could kindly comment
on this one. Let's see. So margins, Let me try to get this right. First off, I would say, we had, as I mentioned, a very large increase in R and D spend in the first half of this year, A rate faster than you should expect to see in future quarters or future years, Based on partly on some one time effects on COVID therapies and also kind of some one time step ups, as you saw, our pipeline Has grown rapidly, very rapidly our late stage pipeline and so that's been a driver as well. But that won't recur at that rate.
We do believe that though the R and D spend, we will continue to increase the relative R and D spend Over the coming years, we think that
is part
of achieving our ambition. We think that's more of what the world needs And frankly, there are many opportunities to spend less on the outside in terms of things like sales and marketing because of Changes in decision makers in the markets where we sell our products. So I think that some of those trends are going to continue. In terms of overall pharma margins, I think what we've been saying for several years is that we expect our margins to be stable. I'm not I'll give you my personal opinion.
I don't think raising margins for an innovative company like ours over time It's really the right call because R and D innovation, it's our lifeblood and today's higher margin is tomorrow's Kind of pipeline gap. And so I think we're going to be conscious of that. As you know, we have Bold ambitions, not only in medicines, but also in diagnostics and in insights. And some of those fields like the insights field is a rapidly emerging field And it's not a profit making field at the moment. And I don't think that's true for Roche, but it's also true for the other companies that are in that area.
So based on that combination of things, I think you should expect from us stable margins, but personally, I don't think I see our margins increasing while we're pursuing this strategy. And in terms of price well, the situation in Washington, Obviously, that's been a hot topic for the last week. Maybe I don't know, Theresa, you've been looking into it more closely and you want to So
the White House drug plan as it came out is sort of largely what we expected. And if you look at what the White House has We proposed it's more sort of a collection of ideas, so sort of a laundry list, if you will, of things that could conceivably be looked at. We and they do seem to be focused more on really tangible demonstration products than projects And truly sort of enacting sort of big, huge change. We've also heard the Biden administration say pretty repeatedly that their goal would be to push something through via legislative change versus just administrative action, and they do want to try and do that through the congressional budget reconciliation package. We are expecting that Congress will be pushing something through in the next few days that will probably largely be based on HR3.
However, there's likely to be changes to that through the reconciliation process as we as it moves through. Our goals in this process haven't really changed. Our goal is to lower out of pocket patient costs and to find more sustainable ways For patients to receive their medicines over time, and we have been and will continue to be in close contact with the administration and on both sides of the aisle To find ways to make that happen. Overall, we believe that the U. S.
Is going to continue to be a great source of innovation and be a great partner in helping to drive innovation and Price is only one part of that, but it's certainly something that we've been watching closely.
Bill, I
don't know if there's more you'd add.
No, I think our long term view is that Patients need relief. The out of pocket costs are too high in the U. S. And we stand at the ready to engage in constructive conversations about how to lower patient out of pocket costs and how to reform many of the areas, whether it's in Part B or Part D that could use reform. And I think we remain optimistic that in the when the senators and representatives Actually get down to drafting legislation, there'll be enough calm minds that appreciate the value of innovation That will end up with something we can live with.
And it may cost us something and in fact, it almost certainly will, but That's okay. We can live with that. And as I said, I think we have a strategy that's built for all seasons. And so we're confident in our plans In any case. And I think, let's say, Charlie, do you want to comment on the question about the bladder indication and Concerns you have about that?
Absolutely. I think the question started with the indication in triple negative breast cancer. And Just to clarify, as you know, we voluntarily withdrew that indication in the U. S. With the FDA.
To be clear, that was a procedural question around the accelerated approval process. It was not a question of the efficacy or safety of the drug And triple negative breast because in fact in PASION 130, we saw a clinically meaningful 7.5 month improvement in overall survival And found that the addition of Tecentriq to nab paclitaxel was safe, but it was around a procedural question. To that end, the drug obviously is approved in roughly 90 countries around the globe outside of the U. S, of which 80 Our full approvals moreover, we're continuing to examine and further confirm the benefit of TECENTRIQ in triple negative breast and Impassion-132, which is an additional study in the metastatic setting, as well as in the early setting with NSABP B-fifty nine, with respect to the bladder indication for first line, as you know, the ODAC voted 10 to 1 in favor Of maintaining the accelerated approval of Tecentriq in first line bladder, the results of the INVIGR-one hundred and thirty, our Phase 3 study met its Co primary endpoint of an improvement in progression free survival, and we anticipate the mature overall survival results Next year in 2022, and we look forward to sharing those results with you.
Thanks.
Thanks a lot.
Can you just ask the
question on adjuvant? Okay, great. So thank you, Charlie, for that. And The question on adjuvant and how quickly do we believe that uptake will be, I mean, I think we do believe that, 10 will become the standard of care For patients with PD L1 positive adjuvant non small cell lung cancer, because the adjuvant treatment setting is still developing, it may Be a little bit slower on the uptake, but we do believe again that this is practice changing information and practice changing data. And that as screening protocols get better, as diagnostic testing gets better, we will continue to see that opportunity grow.
Yes. Thanks a lot. I have to say, so far, we did really well because we had basically 2 questions per person to ask questions. And we try to keep our answers short. And if you can just continue that way, that will be perfect because otherwise, we have A long list of people who have questions so that we can really address everything.
Luisa, you would be the next one. Thank you for your question, Emmanuel. Lisa, open your line.
Thank you, Karl. Thanks for taking my questions. So On girdestrant, I wanted to check a couple of things. For the second, third line study, do you need to show superiority 2,000,000,000 to gain approval. And in the adjuvant study, what duration of therapy have you chosen and why?
And then maybe to come back to Bill on essentially that margin question. So I mean, I think what we can see today, the increased diversity of the pipeline entry into new therapeutic areas is very striking, As is the high number of NMEs. But just now, you're indicating stable margin within pharma And a lower rate of R and D acceleration than we've seen this year. So That really leads the marketing spend. So I'm just trying to, I guess, square the circle.
So should we expect an acceleration in marketing spend With a bit of a lag on that R and D increase, but that you will be very mindful about how you deploy those costs, And this is about entry into those new areas. So just trying to think about that growth in the marketing spend. Thank you.
So thanks, Lisa. Maybe I can answer the last question first and then I'll turn it back to Charlie or Levi For the questions about Giridestrant and yes. So in terms of the margin, so Lisa, yes, let me just clarify. When I was talking about the R and D, so the R and D spend through the first half, I think it was 19% increase. And so I'm saying we're not going to continue To increase R and D spend by 19%.
That was based on some one time factors. But going forward, we do expect to increase R and D Faster than sales and faster than sales and marketing and G and A and operations. So in other words, we're looking to really hold the line On M and D, G and A operations, while we're increasing the investment in R and D, I mean, that's basically our medium term outlook. So I hope that clarifies it. And then Let's see who's
Charlie. Charlie?
Yes. So I can start. With regard to your question about the second, third line trial, I think Levi spoke to it well, namely the mechanism of action, the apparent Superiority preclinically of tiradescine compared to the other available drugs as well as I think the emerging clinical data, We're bullish on the potential in that second, third line study, realizing I think the caveats That Levi mentioned earlier, as you get into later lines of therapy, the dependency on ester receptor has to be looked at. But we We are looking forward to sharing their results and hopefully showing a superiority of geridesterin in both Benefit as well as efficacy and tolerability compared to fulvestrant. With regard to your question of duration of therapy in our adjuvant It's 5 years as is typically the case in the adjuvant setting.
And I think the tolerability of Juridester, which really does Appear to be superior, I think it will allow us to help patients stay on these therapies longer and complete the 5 year duration.
Yes. Thanks a lot. Thanks for your questions. Lisa, Michael Leuchten would be the next one. Michael from UBS.
Thank you very much. Two questions, please. One for Bill. Just going back to the very beginning of your presentation, Bill, where you talked about The aim to increase patient benefit at half the societal cost, just wondering how you measure that. Is that as simple as Bringing down the cost per therapy?
Or is that a separate group that Replicates what maybe ISO does in the U. S. Any color would be helpful. And then a question on covalumab. Just wondering if you could talk about your views on proximal complement inhibition versus downstream inhibition when you think about
Great. Sure. So in terms of The vision and delivering much more patient benefit at half the cost of society. So we definitely Looking at the price of medicines, but also many other factors that determine cost to society. So for example, If you have a therapy that cures someone of cancer versus a therapy that extends their life or extends progression free survival by 6 months And then they go on to another round of therapy and then another round of therapy.
You have an opportunity not only to provide a great benefit for the patient, but also much Lower cost for society. So we're definitely looking at that combination of things. I think we take drug pricing very seriously. We've demonstrated that with The pricing of OCREVUS, which beat the standard of care, yet we priced it lower than the standard of care. We demonstrated it with HEMLIBRA launching an inhibitor, Beat the standard of care, we priced it much lower than the standard of care.
We've done this. We just think that In order to be a sustainable life science company, we have to build trust with the public, with the payers And there needs to be a fair deal, and it needs to be perceived as a fair deal. And so that's our look on it. Let's see. Maybe, Bill, before you before
we hand it over to Levi, there is a question in the chat, which goes a bit in Same direction here about Eurovision, how you want to see the company going forward in the next 5 to 10 years. And this is from Ben YeHo. He was About any metrics or anecdotes on speed, empowerment, decision making in the company, how that evolves And how many what the IMPR turnover is, if you give us could you give us any kind of anecdotes of talent, attraction And so on. So what is your vision on the culture of the company?
Yes. Thanks for the question. No, It's sort of simple. It's not easy to do, but I think it's simple to describe. I mean, really, we have 2 big goals.
I mean, one is we want to deliver On our vision, our ambition for the world, which is that we can deliver many more breakthroughs for patients, much greater patient benefit At half the cost of society, there's many ways to measure that. I mean, we're looking at that. But one of the principles we have in transformation is we're not going to allow Sort of academic discussions about measurement to prevent us from pressing ahead with what we know is the right answer. And so that's the delivering that vision is one of the two goals. And the other goal is that we are the best place For people who want to spend their lives investing in life science, the best place to work and not the best place, not only because of the Trinsic things that people think about, but especially the intrinsic things, the ability to do something great.
And we believe that everybody has That right, if they're going to spend their life at a company that we give them an opportunity to do something great, To do things that they can be proud to tell their friends and family about that Sunday nights that they're excited to come to work on Monday, That they don't have that dread of like, oh no, another week. But they're on Sunday nights, they're like, man, I'm ready to get back. Let's go. So that's the culture we're trying to create. I welcome input from anyone else on the panel.
We see the evidences. I mentioned Some of those in the presentation, we see it from small teams, from large teams, people are excited about it. One thing I'll say is that when I shared some of those figures on productivity, you saw lower headcount, right? But we've not had we've not engaged in a cost cutting exercise that I'm aware of in the last 5 years. I mean, we've been basically going around And saying, how do we make people's jobs better?
How do we take a situation where we have, let's say, 3 people with 3 different roles Serving a customer when actually one person could do that and actually it's better for the customer and it's better for the person. They're not bumping into each other. They're not saying, oh, I'd like to help you with that, but that's actually somebody else's job. They say, yes, no, I can do that. We're creating human sized jobs, which means big jobs that carry a lot of responsibility and weight And people are excited about it.
It doesn't mean that the change is always easy or that every day is a happy day. But I think we're making good progress, and I think we have a long way to go yet. So very excited about it. Yes.
Thank you. Rovalyma, Levi, over.
Sure. Yes, I'll be very brief. It's a great question about PROSIMO versus distal complement inhibition. And So I'll just say, yes, it's an important question. Actually, the specific implications for whether it's covalumab or any other medicine Depend on the indication that we're pursuing.
And there are some indications, which and Apollo could, for example, add in the ophthalmology sort of Immune side, where we have a particular opinion on that. In other cases, we actually we know that it could be important, but we just need to gather data. So we are mindful of the specific elements of complement that may be gating in certain diseases versus others, But it will depend on the indication. I don't know, Paul, if you want to give a specific ophthal example just for illustration.
Yes. Thanks, Levi. And I agree with And just to backtrack a little bit, usually people look at the complement system and it's been a little bit ignored in immunology, but it's actually one of the most complex biological Systems in our bodies ticks over at a constant rate every day. It has over 20 proteins in it, multiple cascades. So To think upstream, downstream maybe a little bit simplistic.
What is clear is that both from genetics as well as from demonstration of clinical benefit Specific molecules to either targeting C5 or C3 or C1Q, certain conditions are Pendant on that particular protein more than others. So in ophthalmology, for example, it's been known for years, one of the biggest genetic risk Factors for geographic atrophies is actually our molecules connected to the complement system. And as you may recall, we have our own program targeting Couple in factor D, which did not work. And now just a couple of days ago, there were top line data showing that actually molecule targeting C3 appears to reduce the size of lesion. So it is a little bit more complex than just thinking upstream or downstream.
I think for each condition, We have to go 1 or 2 layers deep to really find out what is the best molecule.
Thank you. Next one would be thanks for the question, Michael. Andrew Baum from Citi. Andrew, I open your line.
Many thanks, Karl. A couple
of questions. First on business development. Roche has a very healthy balance sheet. You've historically pursued bolt on acquisitions of small size. I'm assuming that's not going to change, but I was hoping you Comments on the outlook from the FTC, which is becoming a lot more muscular and there's some legislative risk ahead.
So from the perspective of the industry, How concerned are you that this could severely impede business development going forward, thinking about your own recent experience with Spark? 2nd for Levi. One modality we're obviously interested in, I don't know if you've disclosed it is mRNA. I'm thinking less from vaccines for you, but for cytokine delivery or its role in immunotherapy. I'm curious whether you believe you have the Technologies in house, or whether this is something that you're interested in building out?
And then finally, a question on gene therapy. There's obviously been a number of deaths associated with competing products. The FDA had a recent panel meeting To discuss and so on, could you talk to how you see the regulatory hurdles for gene therapy in light of some of the recent news flow?
Over to you, Phil.
Great. Thanks, Andrew. Yes, so the question about business development, I think, As I mentioned when I was talking about some of the partnerships that we signed, our preference is to go early. That's why the vast majority, I mean, numerically, it must be 97% or something of the deals we do, partnerships and acquisitions Our early stage, and I think, so we're your point about the FTC, It's probably not going to have a big effect on us because so far they haven't seen or seem to intervene in really early stage things that are high risk. It tends to be more where there's a known product perhaps with data or obviously something bigger than that.
So I'm not sure that's really going to affect us very much. It may more affect the strategy of other companies. I'll turn it over to Levi on the questions about mRNA and gene therapy.
Great. So thanks, Andrew, for the question. Several of us, of course, mentioned the breadth of modalities that we have. Actually, That was primarily focused on molecules assets that have reached clinical stage development. What we didn't talk about at all is The breadth of modalities that we're using that we're looking at in our preclinical setting.
And so there, we're looking at Even a broader range of potential platforms, including actually one possibility is mRNA based Ways of generating assets and of course, the converse is ways of inhibiting mRNA as opposed to protein. So there's a lot that we're looking at. I think the guiding principle here is that, as Bill mentioned, it really starts with the science, the disease biology. What do we understand about the disease? What does it need therapeutically?
And whatever it needs, we're committed to figuring out how to do it. And if it's something that we already have In our wheelhouse, that's great. But if it's something that we need, as we showed even recently with our deal, for example, with Adaptimmune, Then we'll partner to bring it into our wheelhouse. But we'll certainly but we start with the disease biology understanding of the science and then we figure out what the modality solution needs to be. And maybe I'll let Paolo comment on the gene therapy question.
Yes. Thanks, Levi. This is actually a particularly sad day. There was a 4th patient that died on the Audentes trial just today, it was just announced. I think it just illustrates how young of a technology Distill is.
In lots of ways, we're learning how to manage gene therapies, almost like on a disease by disease basis. And there's lots of factors that I think play into that. And we're, again, learning together with the FDA on how to manage those. Part of this has to do with the acute QT in response to a viral vector and different viral vectors seem to have different safety profiles. And obviously, again, we probably need new and better viral vectors.
Some of this has to do with clearly with dose, how frequently and how high we're dosing, the route as well, direct administration to the CNS appears That's so far not to be a very good way to do things. Vectors that target particular organs like the liver or the kidney or the heart, Again, I think we're learning how to manage this. If you recall, like 20, 30 years ago, this is actually what brought down the 1st generation of gene therapies. Now, of course, we're in a different Right now, we're much more sophisticated. And fortunately, a few of these gene therapies have made it all the way to the market and are having impact, but it's still Cutting edge technology and therefore the need for being really, really keen on monitoring safety and making sure we're doing the right things by these patients It's going to be required in the short term and probably in the medium to long term as well.
Yes. Thanks a lot. So we have 20 more minutes. We have so far 6 more people on the telephone line. I hope Andrew we could address your questions.
Richard Forster would be the next one from JPMorgan. Richard, open your line.
Thanks, Karl. A couple of questions on the ganserinumab data. So on the open label extension, There were 38 patients that sort of didn't make it out to the 36 month data point. And I think since the open label Started, there was sufficient time for them to reach this target. So sort of what happened to them?
Was there any reason for discontinuation? Or was it that they just didn't get there? Secondly, on cognition for those patients. So those patients that achieved AB negativity over 36 months, how did that cognition benefit change relative to those who were AB negative at the start of the trial in the open label Thanks, Jen, if I'm reading that data right. And then second question, just very quickly, just on a GloFit in DLBCL.
You mentioned going upfront with Mohsen on top of GolgiVi.
What's the I understand you could use
Clofit for more severe patients, but what's the And you could use Clofit for more severe patients, but what's really the point of using it later on if MOSUN is going to be better early? So why continue with Clofit? Thanks.
Yes. Really, really great questions. And perhaps just Take a step back because most might not know the history behind this open label trial. So basically, back in 2015, when we declared futility for Scarlet Road, This was a very conscious decision to allow patients who wanted to continue to be dosed with gafinirumab and wanted to contribute science to be on this trial, right? And over the years, we've opened it up for other trials as well with MARGARET PROD, etcetera, and we upped the dose, as I mentioned.
But it's really on a voluntary basis because these patients essentially know that this trial is generating biomarker data and safety data. But as you expect for trial or for trials that now have been running for some of them 7 years, you will see some people dropping out. That's just the nature of these things. And it's kind of random, the reasons why. Some are for personal reasons, some are because they want to get into other trials.
But because it was an open label trial, we didn't put any specific measures in place to ensure that people had to stay on the study. Of course, we collected as much data as possible, including safety data to make sure that, yes, the things were going well with them. So that leads to the answer to your second question, which is regarding the efficacy data. Because of the way the trials were designed, This is not a controlled experiment. And because of the dropouts, etcetera, all the readouts we can put into these open label trials are exploratory by nature and very tentative, right?
We've presented and published that when you look at the efficacy data, cognitive outcomes In the open label trials, there are trends that favor gantenerumab, right? But again, this is a very uncontrolled Heterogeneous populations and people have been on drug for 7 years and people have been on drug for 4 years. I wouldn't read much Intuit, frankly, and we didn't look particularly at the patients that were amyloid negative, again, because we're talking about a very, very uncontrolled small data set. So I hope that answers your
question. Charlie, you want to take the future strategy questions on LBCL first line combination?
No, it's a great question about the bispecifics. And let me be clear, we're committed to utility of both Mohsen and Glofit. I mean, obviously, as you're aware, they have similar modes of action, but as Levi would describe well, they have Very different structures and as a result, different profiles. And what I think that as we'll elaborate, I think they allow us To tailor therapy to the disease, the patient, the nature of where the care is delivered And the unique patient needs, obviously, MOSON is showing high endurable response rates Unfortunately, it can be delivered safely in an outpatient setting and we're anticipating filing MOSON in Initially in relapsedrefractory follicular lymphoma and working on it in combination with Bolivian 2nd line, florectal lymphoma. GLOFIT in contrast really has we think has the Potential to offer best in class efficacy, which at least the day to day suggests that it may be comparable to CAR T, but with obviously Easier applicability as compared to CAR T and so we think it's going to be an important therapy for diffuse large cell lymphoma.
We're planning on a filing in 2022 in relapsed refractory, but we are also looking at combinations of GloFIT, including our building on Polerix in first line. So really we think these two molecules will each add to The arsenal of therapies we now have for large cell lymphoma, both important and both I think have unique opportunities to And the outcome for patients improve the outcome for patients.
Thanks, Richard.
Yes. Thank you. Richard Parks, Sam would be the next one. Richard, open your line.
Hi. Hopefully, you can hear me okay. Thanks A couple on Alzheimer's and then one on business development. So I wondered if you could update us on the Feedback from the FDA of the potential to bring forward a gantenerumab filing timeline. I believe you were planning a meeting with the FDA to gather feedback on a specific strategy.
So wondered if that meeting had occurred. And If you could give any insight on feedback from the FDA there, that would be helpful. Secondly, just a follow-up on the tau programs in semirimab. It feels like you're encouraged by what you've seen in that Phase 2 program, but maybe Need to see an improvement in order to progress to Phase 3. So I'm wondering if we should think more about the second Tau program you have targeting the mid domain and maybe you could outline for us why that might be differentiated based on that binding?
Finally, just on business development. I think you kind of flagged that you've been skewing some larger bolt on deals in favor of Smaller licensing type transactions. But when you look at the field of what the opportunity is out there at the moment, do you think you can maintain The very high level of activity you saw in 2020 or should we be thinking about alternative ways for you To return excess capital to investors. Thanks.
Maybe I'll answer the last question first and then we'll turn to Paula for the Questions on Alzheimer's. Yes. So in 2020, yes, we did a number of late stage deals. And that was I would say with respect to timing, it was opportunistic. With respect to strategy, they were all on strategy.
And in 2021, we just haven't seen that same picture emerge. But again, I would say 2020 has been more the or was more the exception and 2021 not so different. In 2019, We had many fewer deals. So I think that was more serendipity in 2020. And with respect to the return returning capital, I think I've already commented on that.
We're looking to maintain our margins stable, increase investment in R and D and be more efficient, more effective everywhere, including R and D. Paula, do you want
to Yes.
Thanks, Bill. So to your first question around gantenerumab, I appreciate the question and the curiosity, but I have to be pretty clear. I mean, we're not going to comment. I'm not going to comment on any ongoing negotiations with health For any reason, obviously, these are private conversations for both their purposes and ours. Let me just say this.
I think it's encouraging and good that the FDA is showing openness to looking at drugs in Alzheimer's disease and trying to find ways to get them to patients faster. I think it's patients do need more options than they have now even with the recent approval. They need more drugs as part of amyloid With different administration routes, etcetera. So, yes, I think that it would be great if that was But obviously, at the end of the day, we want to deliver medicines to patients that have a comprehensive data set with a robust safety and efficacy profile that people can make Informed decisions about their treatment. That is really what our commitment is, and that's why we're waiting for the readout of the gantenerumab trials late next year.
Anything else is a matter right now for speculation, I'd say. So regarding TAO, I mean, I am let me say, I am excited because when we think about the scale of this challenge, which To get a monoclonal antibody into the CNS to target a misfolded protein traveling in between neurons, it's pretty remarkable that you see benefits And that's why it's exciting because that in of itself, the scientific challenge is huge. Secondly, the need For more drugs in Alzheimer's hasn't gone down. I think it will continue to be there. And tau is a hallmark pathology.
So I think that's exciting as well. Of course, there's a number of question marks, right? Why didn't this work in earlier lines of treatment, so in earlier patients? Why have we seen really a functional benefit to go along with the robust cognitive benefit we're seeing in moderate patients? Those are all really great questions.
Those are the ones that we're going to tackle in the months ahead to try and find out Whether the signal is real and what does it actually mean for these patients. Your final point was about the 2 tau programs. Yeah. So we do believe in the same way that For amyloid, it took a while for us to find out which epitopes and which particular antibodies would be the most potent and most efficacious. I think for tau, it's a little bit the same story, right?
So I think it's great that we have 2 differentiated assets in our pipeline, one targets the N domain, one the midterm domain. The both target all phosphorylated species of tau. Whether that makes it different or it doesn't, the data will tell. But our commitment is that this is Such an important target that's so relevant for Alzheimer's and for other neurodegenerative conditions that we want to make sure that we don't miss out On really testing this hypothesis for the field.
Yes. Thank you. Stephen Skalla would be the next. Stephen, open your line, please.
Can you hear me, Carl?
Yes, clearly. Thank you.
Two questions. The slide deck says that ferricimab and Lucentis PDS approvals and rollouts would occur in 2022. Bill, you stated that faricimab and Lucentis PDS I believe in the Q2 slide deck, a chart said approval Was expected in 2021. So it seems that there has been some sort of delay and perhaps a lengthy one. So I'm wondering if you could elaborate on this dynamic.
And then secondly, on giardestrant, Did Roche learn anything from the pyrosophal trial showing fulvestrant was no better than letrozole when combined with
Yes. Steve, thanks for the question. Yes, I think we were just Summarizing things on the ophthalmology program, there's no delay on PDS. PDS will be almost certainly approved in 2021. And, yes, so I think we were just saying that both of them will be approved by this time next year, but We and I don't know, Nilesh, do you want to just reiterate what we've provided in terms of timing?
Because I know it hasn't changed.
No, it hasn't. So for furosemab, we've provided quarter 1 guidance to 2022 for the first approvals. And obviously, through Europe, We'll be getting staggered approvals. For port delivery system, we have said Q4. And actually, I think we've communicated October, End of October as a producer date for FDA and then later into 2022 for Europe.
Yes. Thank you. On the 3rd,
Charlie?
Maybe I'll comment on it. Yes. Yes. So thanks for the question. So there the strategy is, of course, yes, we learn From every study, but specifically, there have been a couple of informative studies in this space.
One is the one that was mentioned, Suggesting maybe a little difference in combination with the CDK inhibitor. There's also been, for example, the FALCON study, which has Suggested differences in various modes of ER inhibition. And I do think that we coming back to One of the reasons why we're interested in geridesterin is there's an opportunity to ask the question in a different way Because of the mechanism of action, so not only are we causing degradation of the SIRD, but because of a distinct In fact, biologically, we're suppressing the transcriptional activity of the estrogen receptor. And this is an important it's subtle, but it's an important distinction because We know that in particularly in the early disease settings, but maybe in metastatic diseases as well, It's not just the ligand dependent actions of the estrogen receptor that are important for the oncogenesis, it's also ligand independent actions of the estrogen receptor. So a medicine like gerodestrin can go after both of those mechanisms and to suppress them both.
So we've learned From we've learned and we have cautionary tales from the existing data, but we also think that the biology that we're able to go after with duradestrant is Separable from some of those earlier studies and hence provide a rationale for the program that we're pursuing.
Yes. Thank you. We have 3 more questions on the line, and I have also one on the anti infective part. So next one would be Keyur, Keyur Parekh. I opened your line, Keyur.
Keyur? Hey,
Yohr. Thanks, Karl. Hopefully, you can hear me okay.
Yes, perfect. Thank you.
Great. Couple of questions, please. The first one for Bill. Bill, I think in response to Joe Wharton's question about R and D, you seem to suggest Confidence in R and D productivity improving over the course of the next few years. You are factually stating that your R and D spend is going to go up.
Should we therefore feel confident that your revenue growth Over the next few years will be higher than what you've delivered over the last decade, just multiplying the keep putting the two things together. Then second one kind of for kind of on the Ophthalmology franchise. There seems to be a degree of confidence on both faritumab and kind of Lisendi's port delivery system from a commercial perspective That is not being reflected in kind of consensus numbers. So I'm wondering what gives you the confidence and what it That we may be missing kind of as other group of analysts there. And then just lastly, on the SORD kind of adjuvant program, A couple of your peers have gone into the adjuvant setting with a much broader kind of program than the one you are kind of specifically alluding to today.
Given your confidence on the safety, tolerability and the potential for greater efficacy there, I'm just wondering why the adjuvant program isn't a lot deeper and broader. Thank you.
Yes. Thank you. Maybe this time first start with the 3rd because actually, I think it's the other way around. But Please correct me, Levi and Charles.
Well, that's exactly right. So the trial that Sanofi As launched, it is actually limited to patients who are essentially intolerant of aromatase inhibitors. In contrast, Because of our conviction and belief in the efficacy and safety of geridesterin, our trial actually is in the broader population of patients We need upfront adjuvant therapy. So really it's the opposite. The other trial is limited and obviously one can only Speculate on the rationale for that invitation.
Yes. Thank you. Nilesh, we would like to take the furosemab and that you definitely will do better than what the market expects from you.
Yes. Well, that's certainly our hope. But no, thank you, Keir, for the question. I think we're very confident that these are True innovations compared to current standards of care. So on the port delivery system, you're seeing a twice Yearly injection provides the same type of outcomes as monthly injections of LUCENTIS 0.5, which has never been seen before.
And I think that's going to be Something important for patients, for their caregivers and also for society, so people won't have to come back. And on faricimab, we're seeing the first time a Distinct pathway, not a different target within the same pathway, but 2 different pathways are really delivering what we've seen from preclinical science All the way through now to clinical science, that vascular stability is driving some of this durability. So we're very confident These can become new standards of care. I do believe that obviously a lot of people are concerned about biosimilar impact in this area. But I think as Karl said, in this area, we've had a certainly in the U.
S, 50% of the volume of the market has been in an Avastin setting anyway. So maybe there's some different ways to look at this marketplace.
Yes. It may be the Combination of a recent launch that didn't go so well in Opta and just the biosimilar question and people are being cautious. But you all are the analysts and we just make medicines. So you'll have to tell us what the difference is. Your question about If we're going to invest much more in R and D and we're going to have higher R and D productivity, then doesn't that mean we're going to have higher revenue?
I think, let's say, our hope the reason we get up in the morning is we want to rewrite the medical textbooks. We want to have the biggest payoff for patients ever and we're really proud of our history. Roche is celebrating 125 years this month. The proud history of Roche, the proud history of Genentech delivering breakthroughs in biologics And clones cloning cells and converting that into something that helps people. And I think for us, I speak for all of us.
Yes, we want to get some new medicines in the history books. And when we do that, I'm sure that will be good for shareholders too. But we're not counting our revenues right now. We're focused on delivering those molecules, and we'll let the revenues follow.
Yes. Thank you. Thanks for your question, Keogh. Peter Wolford, open your line, Peter. From Jefferies.
Hi. Thanks very much for taking my questions. Just to cover, so Firstly, just on immunology. Curious that Roche obviously works in a lot of areas, including in some areas of immunology, but there was Little, I guess, relevant or discussion around either ettralizumab in Crohn's and also besides any other efforts you have Ongoing in any other sort of unmet medical needs still thinking in terms of atopic dermatitis, etcetera. I guess, curious on Roche's view in that area and whether that is an area where you think Roche is currently underweight Or an area of deliberate focus or rather not to be focused in.
Secondly, just coming back to gerodestrant and the pivotal Phase Two readouts coming soon. You presented at ASCO the VERONICA study, where I think you saw it was a failed trial, but I think you saw with fulvestrant And then plus or minus VENCLEXTA, roughly a sort of 2 or 3 month PFS. Do you think that's sort of representative of what we should be thinking about In the pivotal Phase 3 for duridesterant for fulvestrant, and I guess curious what you think perhaps then duridesterant could do There's the active arm to demonstrate the superiority you're looking for in that profile to potentially take it to market based on those Phase 2 data. Thank
you. So thank you. Thanks, Peter, for the question. Maybe I'll take the immunology one first. So I totally agree with you.
Immunology is a fundamental area of biology, and there have been many, many medical breakthroughs in the past for numerous conditions. So if anything, now the bar is that much higher to differentiate and create more medical value for patients, right? It is something we're very committed to. We've had a long trial history here. And you're right, we have a few programs, which Sure ongoing right now in Phase III pivotal trials.
Obviously, we're waiting for the readouts of atrelizumab in Crohn's later this year. I think I mentioned we have our gaziva program with lupus nephritis and in SLE. At the same time, we have our program with 2 in IPF. So I guess the common thread there, if you want, is that We're looking to really break that efficacy ceiling right now. So we're going to have to be a little bit, if you want, more selective about which mechanisms in which molecules we're going to take forward, because right now, there are a lot of great medicines out there.
So for us, it's really differentiate and do What Bill said, which is really right, new pages in the medical textbooks, we're going to have to try different things. Fortunately, we have an amazing research pipeline, Many new mechanisms, and we are committed to doing this. It may take a couple of years until you see new molecules coming in, but we're not lowering the bar, Right. We're not just trying to develop the 5th anti integrin or whatever else anti TNF. We want to do things that are different And fundamentally bring more value to patients.
Yes. Thank you. So, Charlie?
Sure. And with regard to the question about And namely our pivotal trial that we'll read out next year of the head to head comparison with fulvestrant in second, third line. I think, as you've heard, the evidence that our molecule is 7 to 15 times more potent preclinically compared By virtue of its mechanism action works on both ligand dependent and ligand independent mechanisms of Activity and the latter front I think is important, particularly in later lines where we're more likely to see ESR1 mutations. So I think the data really suggests a good opportunity for gerodestrin to prove superior to fulvestrant. We'll find out next year, but I think the data, the safety, and I would draw your attention to our presentation at ESMO this coming week, which I think will provide some additional clinical data of interest with regard to the efficacy of our molecule.
Yes, Henrik, a very important question because it hasn't been explicitly mentioned on fulvestrant, but several questions. Fulvestrant has historically been limited Bioavailability, you just can't get enough fulvestrant in to maximize the effects against the estrogen receptor. And we think one of the features of gerodestrin is the activity and bioavailability they were able to get with once daily dosing. So again, we have to wait for the data, but That's another reason why we are looking forward to the results.
Yes. Thank you. Sam, you It's a privilege to have the last question in the queue, and then I have one more, which is over the chat. Sam Frasselli from Bloomberg, over to you. Thank you, Peter, for the
questions. Right. Am I unmuted? Can you hear me?
We can hear you, yes. Excellent.
Thank you. I'll just thank you very much Carl for taking the questions. I'm going to start with a very simple one. Actemra, Are you supply constrained at the moment still? And if so, is there any way that you can change that in terms of getting more product out in the market?
Then on AT-five twenty seven, you have Moonsong that's got a time 22nd September for completion and whereas the Phase 3 trial Morning Sky, 3rd August, which seems like kind of in reverse in terms of the dose ranging study being Coming later than the Phase 3 study. So if you could just explain a bit where we are with that and when you might actually expect? I know you said by the end of the year. And then lastly, on the brain shuttle gantenerumab, lots of related questions here. Any risk of ADA antibody Antidrug antibodies.
The high concentrations in the brain, have you seen any risk of Increased inflammation more than gantenerumab in the few studies that you've done in a few patients that you've done in Phase twothree? And what is the target product profile here? If gantenerumab works, are you aiming to reduce the dose? Or are you hoping that the brain shuffle will actually help you increase the efficacy? I know there are obviously, it could be a bit of both.
That's it. Thank you, Con.
Yes. Thank you. Actually, you took 2 of the last remaining questions out of the chat. So we can actually close with your questions. Yes.
Look, supply constraints Yes.
So, we are supply constrained on Actemra. We've basically since the early days of the pandemic, Literally, even in March of last year, we had begun supplying Actemra for pandemic use on a sort of experimental basis To countries requesting it, we've I'm very proud to say that we've been able to supply Well over a 1000000 doses and hopefully we've saved many people's lives with that. But the simple fact of the matter is it's a monoclonal antibody. There's only so much And we've also been producing the monoclonal antibody cocktail. And so Basically, yes, we've had all our plants running at 100% capacity since the beginning of 2020.
That continues to be so. As we saw the potential for demand to really outpace supply, we signed contract manufacturing agreements, both with a major contract manufacturer, the largest in the world, as well as with Novartis, our friends down the river in Basel to make more Actemra and actually that Actemra is coming online beginning in October. So we have Probably significant additional supply coming in October, which will help. We were doing fine on supply Up until the Delta variant hit and just the magnitude of supply, we've supplied, I think, through July, we had supplied 60% of our pandemic Supplies went to low and middle income countries, including India. So we've really done our best to meet the need of the world, but Just coming up a little short, but we're hopeful that most patients that were ongoing Actemra patients We're able to kind of make it through or maybe miss minimal number of doses and we'll be able to get resupplied many places in October.
And let's see, the other questions were around faricimab and PDF sorry, AT,527. Barry, go ahead.
Thanks. I'll take that question. So, I think the question was around the relative timing of the Phase 2 moonsault versus the Phase 3 morning sky. They do partially overlap each other. That message on the slide where we said that we would expect the outcome from Morningstar towards the end of this year, that is correct.
That's where that will happen. We intentionally started them with a partial overlap based on preliminary data that we had from in vitro models and from the prior HCV program, Knowing that if that proved to be correct, that would optimize our time to mark and our time to patients, but the Moonsong is there to make sure that we are taking the right dose because it is Critical for us that we bring forward the correct dose so that the medicine has the best possible impact for patients. So at the moment, that's where we And they do partially overlap, and we're still aiming for data at MorningSky at the end of this year.
Yes. So we are coming to an end of Sorry,
there was a question on the branch shuttle. Oh, correct. Yes, sorry. Yes. So that's a really interesting question, right?
This is a technology that is still very much being experimented on and being developed. And this is our First human trial with this platform, right? So as with any new thing, the questions you asked about antidrug antibodies, etcetera, Those we'll have to find out as we move along. Of course, we monitor safety of patients very, very carefully, and that's one of the things we're going to be monitoring. The other question I think you mentioned was around the potential for increased inflammation in the brain.
Now, really nobody knows what causes ARIA to this There is some relationship with dose. There's some relationship with stage of the disease, etcetera. Is there a potential? Yes. It's something we're going to monitor again.
And right now, just to remind everybody, we're just starting this Phase Ib trial with 120 patients For dermaltomat Alzheimer. So the data from those trials from that trial is going to be really informative. Your final question is a harder one. What What do we expect from this molecule, basically? So what's the TPP?
And I think it might be a variety of things, and we will really let the data tell us Which one of them is more likely? It could have to do very simply with dose, with the amount of drug, with the duration of dosing, with the frequency of dosing. It might be that we can achieve faster amyloid reduction, and that does translate into clinical benefit. Again, there's no evidence now, That is a possibility. One interesting twist to the story is that actually when we look at the brain distribution patterns Of the normal gantenerumab and the brain shuttle version, the brain shuttle version goes to different places.
It essentially floods the whole parenchyma almost You know, evenly with drug, whereas the normal version goes mainly through the cord plexuses. So it has more of a Cortical to then deep brain gradient. So it might be that that causes differences in efficacy. But again, it's very early days. We're very excited about the Because again, I think there is concurring evidence that amyloid is an important target in Alzheimer's.
And therefore, we just Since you're going to let us the science tells us what
to do next from this molecule. Many, many thanks. Just from my side, thanks to Bruno Eshley, who took the lead on this event. Thank you, Bruno. I know that There have been some night shifts involved in making that.
The same is true for Lauren in the United States. I wanted to thank you for your time today because you also worked on all the setups. I wanted to thank the back office to make the whole thing running. I wanted to thank you for your interest in Roche, participating in the polyps. I've seen that many people really Actively participated at Polyv, so that is really good news.
Bill, maybe 1 or 2 words from your side. Thanks for your interest in Roche. Wishing you all
the best. And again, my thanks to everyone who's contributed today. Thanks for your questions and for your interest in Roche. As you can tell, we're really excited about what we're going to try to deliver for patients and for the world and we can't do it without our investors And your confidence. And so again, many thanks.
Wish you a great rest of your day and look forward to seeing you all again at another event