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At this time, it's our pleasure to introduce you to Bruno Eschli, Head of Investor Relations. Bruno, the stage is yours.
Thanks a lot, Henrik. And could I have the first slide, please? Welcome to our fifth IR call here in 2023, and this time focusing on the Roche Neuroscience franchise. Especially, we want to focus today on the latest data presented during October at recent conferences, ACTRIMS and CTAD. Let me quickly take you through today's agenda. We have today three speakers with us, two internal ones and one external. The first one is Paulo Fontoura, our Global Head of Neuroscience, Immunology, Ophthalmology, Infectious and Rare Diseases for the clinical development. Paulo will provide us an update on the overall neuroscience franchise strategy, and he also will especially cover the molecules which we will discuss in more detail today. The second part then is by Dr.
Stephen Hauser, Director of the UCSF Weill Institute for Neurosciences and a Professor of Neurology at the University of California, San Francisco. He will lead us through two important trial results in multiple sclerosis, which were recently presented at ACTRIMS, beginning of October. These data comprise the randomized phase III study data of Ocrevus two for Ocrevus six-month subcutaneous formulation. Secondly, the first phase II data for fenebrutinib on efficacy and safety. The third part then will go to Luka Kulic, our Therapeutic Area Leader for Dementias and Medical Director of Neuroscience and Rare Diseases. Luka will provide an update on some early data in Alzheimer's disease, which were presented at CTAD.
So the phase I to dose-finding data, efficacy and safety for trontinemab, our novel brain shuttle antibody, beta antibody. And secondly, phase I data for our highly differentiated and potentially first-in-class, gamma secretase modulator, also in Alzheimer's disease. Overall, the event today will go, scheduled for 75 minutes. We have about 50 minutes planned for the presentations, and then, 25 minutes left for the Q&A session. All speakers will be available to take your questions. Could I have the next slide, please? So before we start with the presentations, I just wanted to use this occasion to quickly provide an overview of how these molecules fit into the broader picture for our portfolio. This was a slide here, which you see here, which we have presented for the first time at Pharma Day.
What you can see here is that we have divided our portfolio in three buckets to outline a bit the future growth opportunities. On the left side, you see here our current portfolio, 11 of the 16 blockbusters, which we currently have on the market. These 11 molecules are molecules which belong still to what we define as young portfolio, which will deliver growth going forward for a long time, and some of them having additional potential due to line extensions. Here highlighted in the middle bucket, you see the midterm opportunities. These are all the NMEs or major line extensions, which could be filed until the end of 2026. Since we first presented this slide, we have added here a significant opportunity with an additional molecule.
We have acquired the leading NCTN 1A antibody, which is to be developed in IBD, but might even have significant potential beyond that in many other autoimmune diseases. And from the profile, you can see that this molecule is a bit similar to the previous molecule, which we acquired, so Beviran. It's a molecule which fulfills, again, the criteria we have been looking for, so highly differentiated on the science and another drug target, excellent, strong, early data, phase III ready, with the potential to redefine the standard of care eventually here in even several diseases. And on the right side, then you basically see the long-term opportunities with filings projected after 2026. Can I have the next slide, please?
So on this slide, I just wanted to show where the molecules are plotted, which we talk about today. And these are four molecules you see here, in the bucket on the left. We have the Ocrevus data, so an important life cycle opportunity coming with the six month subcutaneous formulation. The OCARINA data. In the middle bucket, you see the first phase II data, the fenebrutinib, fenebrutinib, efficacy and safety data for our potentially best-in-class BTK inhibitor. And then we have two molecules to talk about, which are in the on the right side here. The first one is trontinemab, our brain shuttle antibody, where we just showed a couple of days ago, the first data at CTAD.
And then also, I think, very exciting, the first data, phase I data for our gamma secretase modulator. And can we please go to the next slide? And this is just a slide, also a pic, here from Pharma Day, just, to remind people that they can look at how do these molecules work out in current analyst estimates. So you can find a few of these molecules on this slide. The gamma secretase molecule, as it is a phase I, as it is too early, is not yet picked up, but you see here what currently is in the models with regards to the, to the opportunities we discussed today. And with that, I would actually hand over to Paulo for the update on the neuroscience strategy.
...Thank you, Bruno, and hello, everyone. Can I have the next slide, please? So we've been working on the neuroscience pipeline now for over a decade, and what you see here is really the result of that. It's a very strongly differentiated portfolio, both with different targets and different platform technologies, all the way from small molecules and large molecules to gene therapies across all stages of development, with four launched products. Next slide, please. And as you can see here, at growth in terms of the portfolio value that neuroscience represents, this has really been a story of success in the past five years, going from nonexistent on the market now to having a substantial proportion of our sales represented there and being the number one company in terms of sales for this area.
This is really due to the strong growth in products like Ocrevus and Evrysdi, but also the emerging products like Enspryng. You see here on the right-hand side that there are, beyond these assets, a number of other assets as well that have very strong sales potential as well. Let me just point out a couple of them that we're going to be talking about today: fenebrutinib in MS, of course, trontinemab and gamma secretase modulator, but also new molecules like GYM329, or anti-latent myostatin antibody. Next slide, please. Just thinking about the strategy for the neuroscience pipeline, we're focused on three core strategic areas. This is multiple sclerosis, Alzheimer's disease, and neuromuscular diseases. For each one of them, our vision is really to have a transformational impact and bring real value for patients and for society.
As you can see here, in all of these three areas, we have a strong pipeline with assets in all phases of development. For MS, our strategy has been, for the longest time, really to build on the success of Ocrevus, to stop, prevent, and reverse MS. For Alzheimer's, we think this is a momentous time in disease modification for this condition, and our vision is to halt and prevent Alzheimer's disease. And for neuromuscular disorders, these are mainly rare genetic disorders with a high degree of disability. It's really to create a future of strength and independence for the neuromuscular disorder community. And I'll go a little bit deeper into each one of these as we go along. Next slide, please. Starting with MS.
Again, we're building on the Ocrevus leadership story that started around 2017, the launch of Ocrevus in relapsing MS, and then subsequently in PPMS. Ocrevus is really a landmark medicine in the sense it was the first drug approved with this very broad label that includes both the more common relapsing forms as well as progressive forms. Since then, the data that we've kept generating, that you can see here, that includes the shorter infusion data, the subcutaneous data that Dr. Hauser is going to talk about, and the high dose data that we're looking forward to. Our vision is to keep building on that success, and we feel that really the big unmet need right now here is around better control of patients for progression, to preserve the quality of life for these patients.
Of course, Ocrevus is the most studied anti-CD20 therapy, with over 10 years of data that we've recently presented. But at the same time, we're very excited about new molecules such as fenebrutinib, that I'll briefly touch on, as well as employing new platforms, such as our Brain Shuttle technology, that allows to shuttle antibodies into the CNS and hopefully again, improve efficacy in terms of controlling disease for progression. Next slide, please. So briefly touching on the phase III Ocrevus subQ results, and Dr. Hauser will go more deeply into this. Our vision right from the beginning is that we wanted to have a medicine that was very convenient for patients, that would fit the lifestyle of the typical MS patient, who is a young adult that has an active life.
Of course, an IV administration every six months is already very convenient, but the time of administration, we realized very early on, might be a limitation. So initially, we worked actually to reduce the infusion time from the regular IV, 5.5-6 hours, to a shorter IV infusion of only 3.5-4 hours. And now with the Ocrevus data, we are going to reduce that much, much further into something that initially will be done in a doctor's office under supervision, but for which the ultimate goal is to bring to the home care setting, allowing really for very short, very convenient, you know, administration for these patients. The data from these trials, again, Dr. Hauser will speak to those, show the comparable efficacy and safe- you know, safety to the Ocrevus IV formulation.
We feel already, based on the market potential here, that this will really fit into the care settings, whether those are centers that have constrained IV capacity or areas where subQ or even oral are preferred as a therapeutic option, that this really is where the subQ formulation will have strong growth. So we see this very much as expanding further the market and the population that will be capable of taking Ocrevus rather than, you know, switching from Ocrevus, you know, IV. Next slide, please. As I mentioned, we keep providing several data updates and at ECTRIMS just a couple of weeks ago, we provided some more. The subQ data, as I mentioned, showed non-inferiority of subQ versus IV, both on efficacy as well as safety.
The Ocrevus ten-year data, this is really landmark data, because this is following ten years after the phase III OPERA and ORATORIO trials. These data show that in these patients, eight out of 10 relapsing MS patients and three out of 10 PPMS patients were completely progression free. This is, again, our data that I've never seen—been really seen with any MS drug. At the same time, recognizing that MS is mainly still a disease of young women, the data that we're showing of Ocrevus in terms of safety for women with MS that received Ocrevus during pregnancy and postpartum, showing the safety of that, we feel is really relevant. We have ongoing phase III trials that will evaluate immune responses in infants born to and breastfed by women treated with Ocrevus.
Again, further supporting the patient centricity of this program. And of course, we're looking forward to getting the Ocrevus high dose data. This is based on an analysis of our existing phase III data that shows that deeper levels of B-cell depletion, which are obtained by higher exposure to Ocrevus, lead to better control of progression. And so we're hoping to see that result, this high dose, in a further control of what's already a great profile in disease progression. Next slide. Switching now to fenebrutinib. This is our BTK inhibitor that we've just shown data for, which again, Dr. Hauser will go much deeper into. We feel this is the most specific; it's brain penetrant, and at the same time, it's the only non-covalent reversible agent that's currently being developed in phase III trials.
Now, we feel this is very relevant, not just from an efficacy standpoint, obviously, the brain penetration counts there, but at the same time from a safety standpoint. As you can see on the right-hand side, we have a very broad program looking both at relapsing MS patients versus teriflunomide and PPMS patients versus Ocrevus. Then what we hope to show in this program is that this would be really the best-in-class oral BTK inhibitor, given its high potency, high selectivity, reversibility, and the studies that we're doing here against Ocrevus in PPMS. At the same time, we have a very large safety database, over 2,500 patients, that have been dosed with fenebrutinib, not just in MS, but in other conditions as well.
So we really feel that if this medicine is successful, this could really be a new disruptor in the oral segment market, which currently comprises about 40% of the global MS market. Next slide, please. Now, switching over to Alzheimer's disease, this has been a long-standing commitment from Roche. And despite recent, you know, setbacks with gantenerumab, we really feel we still have a very strong pipeline here with medicines that could potentially be best in disease, best in class. And of course, what we're trying to do here is, on one hand, maximizing the therapeutic potential of what's really a more validated pathway, which is targeting, you know, A- beta, and combining that with new platform technologies that allow us to do that much more effectively.
As you can see here on the right-hand side, we also have a growing portfolio that encompasses not only pharmaceuticals such as trontinemab, that Luka Kulic will speak about, or our gamma secretase modulator, but also anti-tau antibodies that are currently in phase II trials, but at the same time, our emerging diagnostics portfolio that support early diagnosis that will enable treatment, prevention and access to therapy. Next slide, please. Now, Luka will go more in detail to these data. I just wanted really to provide here the broader context. The Brain Shuttle platform is a technology we've been working on for over a decade now, and the idea really is to be able to bridge the blood-brain barrier and provide access to biological agents to the CNS.
Of course, if this is successful, it opens up a tremendous therapeutic space for new modalities. And really, our Brain Shuttle technology applied to an Aβ-binding antibody is really the first proof of mechanism for this new technology. Now, trontinemab is specifically designed to have efficient transport across the blood-brain barrier. And on the right-hand side, you see here some of the details of what that looks like. On one hand, one of the things that the Brain Shuttle platform does is that it increases CNS exposure, not just in terms of quantitative, but also qualitatively very differently. So you can see here in this immunofluorescence image, a standard IgG versus a Brain Shuttle IgG molecule.
We see what's really a more, you know, homogeneous brain distribution, which we feel should lead to deeper and faster, amyloid clearance. At the same time, this antibody was really engineered, on one hand, to prevent certain potential, you know, targeted immune responses that might result in a worse safety profile, but at the same time, maintaining full FC factor function to maintain the, you know, efficacy at removing amyloid. And again, Luka will give us a little bit more detail, on that. Next slide, please. At the same time, we've been working for a long time on the gamma secretase modulator.
Now, this is really hard to, you know, to do, to find a very specific molecule on one hand, that cleaves, that modulates the cleavage of the amyloid precursor protein without touching any other gamma secretase substrates, such as Notch, which we know are associated with safety, you know, events. But at the same time, it really shows that modulation of the processing of, you know, APP, meaning you hope to see an increase in on non-aggregating Aβ forms, such as Aβ 37 and 38, but at the same time, a reduction in toxic, more, you know, aggregating Aβ forms, such as 40 and 42.
This sweet spot has been very, very hard to reach, and we're very, very happy to apparently have a molecule now, and Luk a will speak more about this, that really thread that needle, so very excited about the potential that this has. Next slide, please. And this is my last slide. I just wanted to briefly touch on our neuromuscular diseases efforts. You know, of course, we're very happy with the success that Evrydi has, fast becoming a global leader in spinal muscular atrophy. At the same time, we're having combination trials now with our anti-myostatin, you know, antibody. That's in phase II right now. But at the same time, the emerging data for the gene therapy, this is the first approved gene therapy for Duchenne muscular dystrophy. We should have the phase III data, you know, any day now.
At the same time, our emerging efforts with our anti-IL-6 receptor antibody Enspryng in generalized myasthenia gravis. Again, this is an area of tremendous medical need, and we're just happy to be able to keep providing what we feel are really transformational medicines. And with that, I'll turn it over to our next speaker, which I believe is Dr. Hauser.
Thank you, Paolo. Let's. There we go. Thank you. As a clinician, it's difficult for me to overstate the impact that Ocrevus has had on MS. A generation ago, the average person with MS would become non-ambulatory within 15-16 years. And now, for young people whose disease is just beginning today, we can be reasonably confident that they have a superb long-term prognosis for a life free of significant disability. In the phase III Ocrevus trials, the impact of treatment on focal brain inflammation, which is the pathologic substrate of relapses or attacks of multiple sclerosis, was over 99% with Ocrevus. This is an effect size that I think is unequaled in modern clinical trials. It's really quite remarkable.
That, those data from those trials, as you've heard from Paulo, has been amplified in the ten-year follow-on open label extension studies and in increasing volumes of real world evidence supporting the sustained safety and efficacy of Ocrevus in all people with MS. So it's really quite an amazing success story. However, MS is not cured, and the part of the disease that isn't cured, as you've heard from Paulo, is the progressive phase of the disease that we now know, because of Ocrevus, is operating in most patients throughout the landscape of their life history with MS. Early on, it's very difficult to measure. Patients know they're not quite as good, but we can't see it on our neurologic exams, typically. This is called silent progression.
Later on, and in patients who have had sustained secondary or primary progression, prior to beginning treatment, it is much more evident in terms of year-on-year changes. What we've learned from the Ocrevus and other anti-CD20 trials is that the substrate of that progression is not primarily B-cells in the periphery that move into the nervous system, the mediator of attacks, but rather is due to locked inflammation within the central nervous system, mediated in chronic MS by plasmablasts and microglial cells, a form of macrophage, in the brain. Two cells that are not directly hit by CD20 because they don't have CD20 on their surface. So that is the unmet need, and I am very excited about the programs with Ocrevus and fenebrutinib that will address this unmet need, as well as better address underserved groups and patients with inadequate access to IV capacity.
Next slide, please. So let's begin with Ocrevus and the ECTRIMS data. As you've heard from Paulo, the trials of Ocrevus subcutaneous administration were presented at ECTRIMS, and these trials basically have looked at pharmacokinetics as a primary endpoint and pharmacodynamics as secondary, as well as exploratory endpoints. Looking at a non-inferiority comparison between Ocrevus subcutaneous versus intravenous, 920 mg subcutaneously, 600 mg intravenous, open-label study, 1-to-1 selection for Group 1 to 2, with a 24-week observation period, followed by an extension. But a primary endpoint that is pharmacokinetic, similar overall exposure for during the control period of the initial 12 weeks, comparing subcutaneous with intravenous administration.
What you can see on the right side of this slide is that the results showed, in terms of pharmacodynamics, rapid and sustained B-cell depletion in blood, similar in both treatment arms. The pharmacokinetics on the left side of the trial, the primary endpoint, also shows a similar overall exposure during the control period of 12 weeks with the subcutaneous compared with intravenous administration. Let us move to the next slide, please. Not a primary endpoint, but obviously a very important endpoint, is the relative effect of subcutaneous administration on clinically valid endpoints, which in this case are MRI changes, specifically evidence of new or growing lesions. Here, if we look, I don't think you can see my-- Can you see my arrow? I don't think you can.
But if you look at week 24, there was essentially zero evidence of focal brain inflammation with the subcutaneous or intravenous, compared with intravenous doses, showing comparable efficacy to the IV formulation for the new subcutaneous delivery mechanism. I will not show that no new safety concerns were identified. You can see this in a very rough way on the right side of the slide. There were more adverse effects in the subcutaneous dosing, and that was due entirely to local tissue reactions, which were mild to moderate in severity, usually mild, around the injection site. So the safety profile of the subcutaneous was clinically non-inferior to that of the intravenous dosing. Next slide, please.
So going back, of the 300, more than 300,000 patients treated with Ocrevus, we have been presenting ongoing results from the open label extension study, which is now out to 10 years of clinical experience. And in the data presented, almost eight out of 10 patients who were initially in the Ocrevus arm of the OPERA relapsing remitting Ocrevus trial, almost eight out of 10 were progression-free 10 years after onset. That is really quite remarkable. If we look at subgroups of patients, those with recent onset disease and no disability when Ocrevus is started, even do better at 10 years. In patients with primary progressive MS, they're older, they have more advanced disability on admission compared with the Ocrevus patients in the relapsing study.
More than one out of three of these patients were progression free at 10 years. Another quite remarkable result at a 10-year follow-up point. This is extraordinarily clinically significant. So very impressive long-term data with continued safety in both the OPERA and ORATORIO trials of relapsing and primary progressive MS. This is a dramatic change in the landscape of multiple sclerosis. There was also data presented from the International MS Base Pregnancy, Neonatal Outcome, and Women's Health Registry on the value of Ocrevus for family planning, and specifically its utility as a protective means of preventing MS disease activity throughout pregnancy and the postpartum period. Remember that more than three out of four people with new onset MS are female, and the majority are in the childbearing age.
This slide shows the annualized relapse rates here in green with Ocrevus, compared with platform low efficacy therapies, interferon and glatiramer, natalizumab, and dimethyl fumarate. I would make the point that it is clear from the phase II studies that the effects of Ocrevus, the benefits, the protection against relapses, is sustained even when B cells recover at about 4-8 months. That sustained protection against relapses goes out beyond 12 months, at least to 18 months, we feel. Now, Q six month dosing is essential because the protection against progression requires six months dosing for this to be maximum. But protection against relapses, the main concern for over the short term for many women with multiple sclerosis in the childbearing age, is conferred over a long period with just one dose of Ocrevus.
So one could treat patients three months before conception, and that benefit against progression will be sustained throughout the pregnancy and postpartum period. I'd also make the point that there is no rebound following B-cell repletion with Ocrevus, unlike natalizumab and the S1P inhibitors like fingolimod. So there is a rebound in a proportion of patients with a dangerous increase in MS disease activity above the level preceding treatment. Another risk for patients who are in pregnancy, unable to continue taking their other disease-modifying therapies for MS, and they are not only not protected, but they are at heightened risk because of discontinuation of other MS therapies. So the benefit of Ocrevus in this situation, in my opinion, is really quite unique. Next slide, please. Let me move from Ocrevus to fenebrutinib. Next slide.
I had mentioned the pathologic substrate of progressive MS, plasmablast and microglia. Two cell types not directly affected by Ocrevus, but both the direct targets of a Bruton's tyrosine kinase inhibitor. In addition to its effects on B cells and plasmablasts in the periphery, BTK inhibitors, if they can penetrate CNS effectively, should have active inhibitory effects on microglia. And we know well that pro-inflammatory neurotoxic microglia are a key, key component of the MS pathology underlying progression. So in many respects, a BTK inhibitor is a perfect selective therapeutic, at least in theory, for patients with MS, because in addition to inactivating disease-causing B cells, plasmablasts and microglia are also affected. The problem with BTK and with kinase inhibitors in general, as many in the audience knows, is a selectivity problem.
One of the, and perhaps the most important advantage of fenebrutinib, and you can see this on the right side of the slide, is that it is more than 100-fold selectively acting on BTK compared with any other kinase inhibitor that can be studied. Here, close to 60 kinase inhibitors were studied, and this is different from the less selective kinase inhibitors, here shown for tolebrutinib and evobrutinib. Also, the non-covalent mechanism of action of fenebrutinib, something that Paulo spoke about, and also its slow off rate, makes it a very appealing choice for chronic, daily use in patients. Next slide.
So we presented at ECTRIMS, the Fenebrutinib data from the FENOPTA clinical trial, a phase II clinical trial, and also CSF and microglial in vitro data, as well as B-cell in vitro data at ECTRIMS. And just very briefly, enrollment in the FENOPTA trial was 2 to 1, FENOPTA, Fenebrutinib over placebo. The primary endpoint was the number of gadolinium-enhancing lesions, and a number of exploratory endpoints, as you can see here. And it was the MRI scans at weeks four, eight, and 12 were summed for the primary endpoint in FENOPTA. And this is followed—this will be followed by an open label period. So let's go to the primary data now.
What you can see here in the FENOPTA study is that Fenebrutinib reduced T1 gadolinium lesions, new areas of focal brain inflammation by more than 90%, at week 12. Beginning of an effect in week four, and a quite substantial effect in week 8. The lower number of lesions at week 12 in the placebo group is due to just the variation that we typically see with small phase II studies. This greater than 90% effect is really quite striking and very significant. Next slide, please. Importantly, Fenebrutinib was also able to be detected in a nested study out of FENOPTA, at clinically significant concentrations, at levels that can impact mechanisms underlying both microglial and B-cell progressive disease biology within the nervous system in people with MS.
And here you can see the mean fenebrutinib CSF concentration in nanograms per milliliter. Here is the IC 90 and the IC 50 concentration. So very impressive maximum inhibitory concentrations achieved through twice-daily oral dosing of fenebrutinib. Next slide, please. And finally, the safety studies were also quite promising. All adverse events were mild to moderate, grade 1 or 2, except for two grade 3 asymptomatic transaminase elevations. There may be questions about this later. I think that although we will be required to see how data continues to develop in the phase III fenebrutinib studies, it appears that the hepatotoxicity seen with other BTK inhibitor, with other BTKIs, is quite modest with fenebrutinib compared with those other two compounds.
Some degree of transaminase elevation may be a class effect of BTKIs, but much of it may well be these off-target kinase effects that are not present with fenebrutinib at the dosing that is currently being used in the MS trials. Next slide, please. In conclusions, fenebrutinib was present in the CSF at levels sufficient to reduce activation of both B cells and microglia, and especially plasmablasts and microglia in vitro, suggesting that fenebrutinib may impact mechanisms underlying progressive MS, and may go beyond even what Ocrevus is able to do. The primary endpoint was met, and I would point out that by that after week four, reductions in new gadolinium enhancing focal inflammatory MRI lesions was greater than 90%, and that no new safety concerns were identified.
Unlike three other BTKIs currently in trials for MS, for which a halt has been placed because of Hy's Law, liver function elevations, this has not been the case for fenebrutinib, and this may well be due to the selectivity of fenebrutinib for BTKIs. I believe that's my last slide.
Yeah. Thanks very much, Dr. Hauser. Good evening, everybody. Good evening from Basel. My name is Luka Kulic. I'm an Expert Medical Director and Therapeutic Area Leader for the dementias at Roche Pharma Research and Early Development, based in Basel. It's my great pleasure to walk you through some of our recent data that we presented at the CTAD conference in Boston last week. We at Roche, as many of you know, and Paulo also highlighted it, in his intro, have a long-standing footprint in Alzheimer's disease. We are and remain committed to this disease and to transforming every single step of the AD patient journey.
We do this by providing tailored solutions across the breadth of the Alzheimer's disease continuum, and this includes the development of advanced diagnostic solutions and of biomarkers, as well as our efforts to develop and advance innovative therapeutic agents. Agents that target the core disease pathologies of AD, like A-beta and tau, along with novel targets and mechanisms that we are currently exploring in our earlier pipeline. If you go to the next slide. Today, I'd like to give you an update on two of our clinical stage assets, trontinemab and RG6289, our new gamma-secretase modulator. Go to the next one. So, Paulo already introduced the molecule, trontinemab, is a novel molecular entity, a so-called brain shuttle A-beta antibody. Actually, the first of its kind that is currently in clinical development.
Trontinemab combines by recombinant fusion an anti-Aβ IgG1 backbone with the so-called Brain Shuttle module that specifically binds to human transferrin receptor 1. This is a receptor that is highly enriched on the surface of brain endothelial cells. This whole Brain Shuttle Aβ antibody construct then crosses the blood-brain barrier by an active transport mechanism, by a so-called receptor-mediated transcytosis at the capillary level, to reach its target, amyloid plaques and aggregated Aβ in the brain. In comparison with standard anti-Aβ monoclonal antibodies, this is, we believe, a truly differentiated approach, which may not only enable a substantially higher brain exposure, but due to this capillary entry mechanism of the shuttle, also a more widespread and more homogeneous distribution of the therapeutic molecule in the brain, and also superior targeting engagement.
A substantially higher brain exposure is something we were able to demonstrate in various of our preclinical studies that we did with trontinemab, including so-called single-dose pharmacokinetic studies in cynomolgus monkey and non-human primates. In these studies, this is the figure in the middle, trontinemab led to a 6- to 17-fold higher brain exposure across different brain regions compared to gantenerumab. The first in-human evidence that we then obtained for a shuttling effect to CNS compartments, this evidence came actually from our first-in-human single ascending dose study of trontinemab in healthy young volunteers. In this study, this is the figure that you see on the right-hand side, trontinemab showed an approximately eight fold increase in the CSF plasma ratio compared to historical gantenerumab data. To move on, the slide.
In 2021, we initiated our first-in-human study called Brain Shuttle AD. We presented interim results from this study at CTAD last week, and allow me please to walk you through some of the key data that we shared with the scientific community. So, the Brain Shuttle AD study. The study is a global, double-blind, placebo-controlled, phase I-B/II-A, multiple ascending dose study of trontinemab in people with MCI due to AD and people with mild to moderate Alzheimer's disease. The primary objective of the study is safety and tolerability. A key secondary objective is pharmacodynamics, as revealed by the change from baseline in amyloid plaque burden measured by PET. Go to the next slide. The study uses a staggered parallel group design, with participants recruited in four sequential dose cohorts that you see here.
In the initial dose escalation part of the study, a minimum of 10 study participants per dose cohort are randomized in a 4-to-1 ratio to receive either trontinemab or placebo IV every four weeks for a total of seven doses. The study is adaptive in nature. That means that dose levels that have been tested in the dose escalation part of the study, that these dose levels may be investigated further in the so-called expansion part, in order to establish a robust PK/PD and safety profile of the molecule in a larger number of study participants. Today, we would like to share with you the interim results from the first three dose escalation cohorts in this study, and the cut-off date for this interim analysis was actually recently in on June 30, 2023. Next slide, please.
For time reasons, we will be really focusing today just on the key results, beginning with the PD, the amyloid PET results. The interim analysis of amyloid PET data that you see here revealed a dose-dependent amyloid plaque lowering across all three active dose groups. At 0.2 mg/kg, so the lowest dose level that we tested in the dose escalation part of the Brain Shuttle AD study, trontinemab led to a meaningful reduction of -20 centiloids versus baseline. The reduction in the second dose cohort at 0.6 mg/kg was -31 centiloids versus baseline, and at 1.8 mg/kg, so our third dose level, we observed a very strong and rapid amyloid PET reduction of -62 centiloids versus baseline at week 12, and -84 centiloids versus baseline at week 28.
In this third dose cohort, 36% of the study participants on active drug fell below the amyloid positivity threshold of 24 centiloids after 12 weeks. 75% of the study participants became formally amyloid negative after 28 weeks. Next slide, please. Just to put these numbers in relation to what we have previously seen with standard anti-beta antibodies. What you see here is the amyloid lowering trajectories of trontinemab at 1.8 mg/kg in blue, and of several other anti-beta monoclonal antibodies that have been tested in phase III so far. Gantenerumab is in turquoise and purple, lecanemab is in brown, and donanemab is depicted in green. Please note the different time scale on the axis on this slide, compared to the image that you've just seen on the previous slide.
The magnitude and the speed of amyloid lowering with trontinemab, as I said, trontinemab is depicted in blue, is quite impressive and exceeds the effects of the standard antibodies, even of those that read out positive in phase III, like lecanemab last year and donanemab earlier this year. In comparison with gantenerumab, there is an approximately nine-fold faster amyloid plaque clearance if we take the three-month, the three-month PET time point in the 1.8 mg/kg group as a reference. Next slide, please. Let's have a brief look at the blinded safety profile. So please note, this is an ongoing study. This study remains blinded to individual treatment assignment.
So that means that the data from participants receiving trontinemab and placebo, that these data will be presented here together as cohort-level data in order to protect the blind at an individual participant level. In brief, there were no deaths and no serious adverse events that were related to the study drug by the investigators. Among the treatment-emergent adverse events, mild to moderate infusion-related reactions, or IRRs, and a mild transient anemia, showed a dose dependency and were more common or common adverse events in the highest dose group at 1.8 mg/kg trontinemab or placebo. What we can say so far is that both IRRs and the mild transient anemia are monitorable and manageable adverse events. The vast majority of IRRs that we observed, for example, occurred after administration of the first dose of the study drug in the absence of pre-medication.
We have, meanwhile, in our study protocol, included pre-medication to effectively mitigate IRRs at dose levels of 1.8 mg/kg and higher from the outset. Next slide, please. A common, and occasionally sometimes, serious adverse event associated with anti-beta antibody therapies are the so-called amyloid-related imaging abnormalities, or ARIA. Our current data set is of course still relatively small, so this is preliminary data. In total, we have 44 participants included in the interim analysis. What we can say, though, is that the ARIA incidence of this molecule has been fairly low so far, especially if we put this in relation to the magnitude and the speed of the amyloid lowering that you've just seen at 1.8 mg/kg, for example.
In cohort one and two, we didn't see any ARIA events at all, and in cohort three, at 1.8 mg/kg trontinemab or placebo, we had in total only one radiographically mild ARIA-E case... This ARIA-E case resolved on a follow-up MRI scan four weeks later. It was associated with mild clinical symptoms, a transiently impaired attention, and these symptoms resolved after approximately one week. Another participant in this third cohort developed two ARIA-H events, so both events were asymptomatic and stable on follow-up MRI scans. Next slide, please. So to conclude on this first part on trontinemab. Trontinemab is a novel molecular entity, a brain shuttle, A-beta antibody that crosses the blood-brain barrier via active receptor-mediated transcytosis at the capillary level.
In our current study, the Brain Shuttle AD study, trontinemab demonstrated rapid and robust amyloid plaque reduction in people with AD, and at a relatively low doses, so at 1.8 mg/kg, so dose levels at which standard anti-Aβ antibodies usually have little or no effect on amyloid plaque pathology in patients. Collectively, our preliminary PD and safety results, including a so far low ARIA incidence, these results support further investigation of trontinemab in the ongoing Brain Shuttle AD study. And our encouraging amyloid PET results, moreover, provide the first pharmacodynamic proof of concept for Roche's Brain Shuttle platform approach. This may, of course, have important implications, not only for AD and the treatment of AD, but also for the treatment of other neurological disorders. Next slide, please.
Moving on from the trontinemab to our second, exciting Aβ targeting asset, namely RG6289, our new gamma secretase modulator that we investigated recently in a phase I study in healthy volunteers. So as Paulo already mentioned in his intro, RG6289 is an oral small molecule with a complementary mechanism of action to anti-Aβ monoclonal antibodies. The gamma secretase modulator acts upstream in the amyloid cascade. It shifts the processing of the amyloid precursor protein, APP, to produce less of the longer aggregation-prone and toxic Aβ fragments, like Aβ 42, and more of the shorter, non-toxic Aβ isoforms, like Aβ 38 and Aβ 37. This unique mechanism of action is expected to significantly slow down or even halt the formation of toxic Aβ aggregates and of amyloid plaques in the brain.
Importantly, there is recent evidence from two independent natural history cohorts suggesting that these shorter Aβ isoforms, like Aβ38, are protective. Aβ38 has recently been associated with better clinical outcomes in people who are at risk for AD-related cognitive decline. On the right-hand side, you see the results of two in vitro pharmacology studies highlighting the unique mechanism of action of the gamma secretase modulator. The longer Aβ species, like Aβ42, go down, the shorter species, like 37 and 38, go up. There is no change in the overall net production of Aβ. What is important to note here, and Paulo also alluded to it in his intro, is that this mechanism of action is fundamentally different from the former secretase inhibitors, including the gamma secretase inhibitors.
Gamma secretase inhibitors, as the name already tells you, inhibit, they, that means they block the cleavage and also the signaling of a number of important cellular substrates of the gamma secretase complex. For example, the cleavage of the Notch receptor, which plays a pivotal role in the central nervous system. In previous studies, this inhibition of Notch cleavage was associated with toxicity and various safety problems in the clinic. Gamma secretase modulators, in contrast, are completely different from the secretase inhibitors, gamma secretase inhibitors in particular. As you may appreciate from the figure on the right-hand side, they do not affect Notch cleavage at all. This is really important to keep in mind, and crucial also for the understanding of the differentiated safety profile of gamma secretase modulators. Next slide, please.
At ECTRIMS, we presented data from the first in-human phase I study of RG6289 in healthy volunteers. Next slide. So we share the results from the first three parts in this study that are highlighted here in blue. A single dose, a single ascending dose study in healthy young volunteers, a multiple ascending dose study in healthy young and healthy middle-aged participants, and a multi-dose study in healthy elderly individuals. The total number of participants enrolled in the whole phase I study was 127. Next slide, please. Let's have a brief look at the data, beginning with the primary objective, that is safety and tolerability. RG6289 in this study exhibited a favorable safety and tolerability profile after single and multiple oral administrations for 14 days.
All most commonly reported adverse events were of mild intensity, and there was no dose-dependent increase in adverse events in any of the study parts. Moreover, we did not observe any noticeable treatment or dose-related changes in vital signs, ECG, or lab parameters, nor in any of the clinical and neurological assessments that we performed. Next slide, please. For time reasons, we left out the PK results in this presentation. What is relevant to mention here is that the PK profile of RG6289 was well-behaved, dose proportional and supportive of daily dosing. What you see on this slide are the pharmacodynamic results after multiple oral administrations of RG6289. And as you may appreciate from the figure on the left-hand side, we observed a very nice dose-dependent target engagement and lowering of A-beta 42 levels in plasma.
At the highest and second highest dose level tested, an Aβ-42 reduction of 60%-70% was achieved. Next slide, please. These plasma results were further confirmed in CSF, cerebrospinal fluid. In the figure in the left upper corner, you see a nice dose-dependent lowering of Aβ-42 levels in CSF, similar to what you've just seen in plasma. In agreement with the gamma secretase modulating activity of RG6289, there is also a decrease in CSF Aβ-40 levels and a parallel increase in the shorter Aβ forms, Aβ-37 and Aβ-38. Lastly, when we plotted our plasma Aβ-42 results versus the CSF results, this is the figure on the right-hand side.
When we did this, we observed a very good correlation actually between the plasma and CSF levels, suggesting that plasma Aβ-42 levels may, in principle, be used as a proxy for CSF Aβ-42 levels in the clinic. Next slide, please. With this, I'm at the end of this short overview of RG6289 results. In the recently completed phase I study, the new gamma secretase modulator showed a favorable safety profile across all single and multiple doses in young as well as healthy elderly study participants. It exhibited a favorable PK profile supporting daily dosing. Importantly, we were able to confirm successful gamma secretase modulation in human and establish a proof of RG6289 mechanism in this study.
The longer toxic A-beta species, 42 and 40, decreased as expected, and the shorter protective forms, Aβ-37 and Aβ-38 , increased in a dose-dependent manner in CSF. The good correlation between plasma and CSF Aβ-42 levels, moreover, suggested that plasma Aβ-42 levels may serve as a proxy for CSF Aβ-42 levels in our future clinical studies of RG6289. And the overall positive results from this first in-human study support further clinical development of this new gamma secretase modulator for the treatment of Alzheimer's disease. With this, thank you very much, and I'll pass it over to you, Bruno.
Thanks a lot, Luka, and with that, we will jump into the Q&A session. The first questions come from Harry Gillis from Berenberg.
Hi, yes. Thank you for taking the question. So I know you touched on the fact that there were the elevated liver enzymes in Synocta, but that these may be less severe than other BTKIs. So I was just wondering how confident you are that you could receive a differentiated label versus competitors if they were to have warnings, and is there a risk of a sort of class-wide safety warning here? And then secondly, if I may, just on the gamma secretase modulator, just wondering if there's any rationales for combining even with the brain shuttle and also other anti-amyloid antibodies. Thank you for taking the questions.
Who's going to take the questions? Paulo, maybe?
Oh, yeah, I'll take a shot at it. Thank you for the question. I mean, the first one is obviously very difficult to answer because it, at the end of the day, is a result of conversations with the regulators when we have the full phase III data. What I think is fair to say now is that we are taking a very thorough approach to monitoring liver safety. And as Dr. Hauser mentioned, the few signals we have seen so far are mild to moderate. They're easily monitorable, and they're reversible, and there's no Hy's Law cases. That gives us some confidence that in approaching the regulators, we'll be able to have a good conversation around that.
Also, taking into account that the mode of action of the drug, the fact that it's, sort of that, that it's a non-covalent reversible binder, might give us credence to why those data in, you know, in fact, show that it's a differentiated mode of action. At the end of the day, of course, this is a conversation with the regulators. So I think it's very premature, first of all, to say there will be a class label. You know, secondly, I think even if that is applied, I think we would have good data to substantiate our own position. Regarding the potential of combinations, maybe, Luka, you want to comment as well. As I mentioned in the slides, it is actually one...
A key part of our strategy moving forward is that we want to build on the backbone of existing and new anti-A-beta therapies, including the antibodies. And obviously, a gamma secretase modulator would be a perfect pairing partner, if you want, to one of those, you know, medicines. But our combinatorial approach is not limited to A-beta mechanisms only. So we have other mechanisms in the pipeline that we're studying, and we'd obviously be interested in looking at the combination potential for those. Maybe, Luka, you want to add something?
Yeah, I can only echo what you just said, Paulo. So I mean, as I already mentioned also in the presentation, it's a complementary mechanism of action. I think the idea of a combination with an anti-amyloid monoclonal perfectly makes sense. So the gamma secretase modulator acts upstream in this amyloid cascade while the antibodies essentially clear you know pre-existing aggregates. So this is also what trontinemab is doing, obviously, very efficiently and rapidly. So yeah, there is a strong rationale for a combination.
Mm-hmm. Very good. With that, we would move on. The next questions would come from Steve Scala from Cowen.
...Thank you, and I have two questions for Dr. Hauser. First, this is following up on the liver tox. You suggested that other BTKs have liver enzyme elevations that meet the definition of Hy's Law. Can you say which agents do so? Roche, Sanofi, and Novartis all have said they have not seen Hy's Law, and Merck hasn't said. So which one does have Hy's Law cases of liver tox? And the second question is regarding the local reactions to subcutaneous Ocrevus. What did medical personnel do when they appeared, and would they ultimately inhibit patient administration in the absence of medical personnel? Thank you.
Yeah. For the first question, I, I am—if I said that I knew the... If I intimated that I knew the details of the, of the BTKIs, that resulted in the hold, I, I would have misspoken. I don't, I don't know the details, but the drugs that have been put on FDA hold are tolebrutinib, or orelabrutinib and ibrutinib. That is all that I know about those trials. Plus, you know, for Ivo and tolebrutinib, we know the phase II data.
We have not seen anything thus far in the phase II or in the ongoing phase III trials of Senabrutinib, that bring us to have concerns about that point, that the drugs are that we're seeing cases of Hy's Law or of less significant LFT liver function, and particularly transaminase elevations, that put us at risk for a similar FDA action. So I guess that's all that I would say about that. And with respect to the second point, Paulo, I believe that the most of these areas of erythema, warmth, some itching, some pain, can be managed with analgesics. Interestingly, they are present more with the first dose than with later doses.
and do not seem to affect the provider's impression that this is an attractive therapy, and that's anecdotal. I would say that this could be an outstanding means of delivery, should this subcutaneous formulation reach approval. For the reasons that I stated, in addition, for insurer's perspective, the cost differential, which is huge in a country like the United States, where, as you may know, the cost of infusion can be 12-15x the cost of the drug. I think it could be enormously valuable for patients.
Maybe just a brief comment. Thank you, Dr. Hauser, and I agree with you. Most of these local adverse events are pretty easily managed. They're not severe in any way. But actually, we continue to work on this technology, and the first administrations now, and in the trial, are administered in the office under physician supervision. But the goal is very much to keep de-developing that, to develop a patch pump, to do the studies that prove that comparability, to be able to move it to the home setting, in which obviously we're looking for a very clean, safe, and tolerability profile.
Thank you.
Did we answer your questions?
Yes. Thank you.
Yeah. Then let's move on. Next one would be Emmanuel Papadakis from Deutsche Bank.
Thank you for taking the questions. Maybe a couple on Trontinemab. Just curious on the rationale and indeed perhaps even the ethical basis for using a placebo, even in a phase I study. Why not use gantenerumab or one of the approved alternatives? Perhaps more importantly, just some clarity on timelines and next steps. It looks like you're continuing to run the phase I and II Brain Shuttle study, so are you going to do another separate phase II dose escalation, or is this it, and you're now going to phase III? And then what does the phase III look like? Would that be a head-to-head study? Given the speed with which you're reaching amyloid negativity, would that be a relatively short fixed duration study, so perhaps even less than six months? Any comments there would be helpful. Thank you.
Yeah, thanks very much for the question. The first question was related to the use of placebo. First of all, I mean, this is the first inpatient study and the first multiple ascending dose study, so the multi-dose study of the molecule. To really establish, you know, and the primary objective of the study is safety and tolerability. A placebo-controlled in such an early trial is really important. By the way, the study was initiated, I mentioned this at the beginning, in 2021, so I think, you know, at the time when we also didn't have these readouts that were presented last year and then earlier this year.
Yeah, in any case, in such an early study, a placebo control is important, especially also to get a good understanding of the placebo. The randomization ratio is four to one, so we really, you know, have obviously many more patients on active drug. The second question relates to the next step. I mentioned, we are, we presented today data from an interim analysis from the first three dose escalation cohorts from the Brain Shuttle AD study. We have now fully enrolled the highest dose within this dose escalation cohort, 3.6 mg/kg , and then the idea is, as I mentioned, to then expand cohorts with the most promising risk-benefit profile, essentially.
So to add additional numbers of participants to really get a robust understanding of the PK/PD and safety profile of the molecule in the so-called expansion part. And this is something that is currently underway and will also be done next year. So this is where we are currently in terms of clinical development. And from there on, of course, you know, we will take it based on what we see. There are different considerations currently in the team with regards also to the phase III development. But thanks for the question.
Emmanuel, all answered?
Yes, thank you.
Then we move on. Next one would be, Richard Parkes from Exane BNP Paribas.
Hi, thanks for taking my question. So two questions, both on trontinemab. I wondered, I didn't see anything about neutralizing antibodies in the slides. So could you talk about whether you've looked at the incidence of neutralizing antibodies, and how much comfort you've got about the immunogenicity, given the profile of the drug? And then secondly, in terms of ARIA incidence, I wonder if you could help us to understand what we know about rates of ARIA relative to amyloid removal rate of amyloid reduction for the current drugs. I wonder if there's any correlation there that might raise a concern, or given the rate of amyloid reduction with trontinemab. Thank you very much.
Thanks very much for this question. Today, indeed, we didn't have time to touch on the pharmacokinetics and immunogenicity, but we presented the data at CTAD last week. What we observed after administration of the first dose of trontinemab, you know, in this multiple ascending dose study, was a well-behaved PK profile. This was not the case after administration of the seventh dose, at the end of this treatment period, which was due to the incidence of, you alluded to it, anti-drug antibodies, PK-relevant anti-drug antibodies or ADAs. What is important to note is, yes, ADAs have been observed across the dose levels that we explored in this study.
What is really important to note is that their impact on PK appears to be dose dependent, and significantly less pronounced with higher dosing in this study. So at 1.8 mg/kg , this is the dose level, you know, with these impressive amyloid lowering results, what we observed was actually a lower incidence of ADAs, first of all, at this dose level, lower titers of ADAs, and also less of an impact on the AUC, the median AUC brain, the median AUC systemic exposure, apologies, which was reduced by approximately 25%, after administration of the seventh dose at 1.8 mg/kg . So there was a moderate effect of ADAs on exposure, systemic exposure, at this third dose level.
What is also important to note is that ADAs were not associated, what we can say so far, based on the available data, with any safety signals. Obviously, they did not prevent the, you know, the rapid and robust amyloid plaque lowering that we've observed so far with this molecule. The second question, I think, was related to the incidence of ARIA. I think this is really an interesting question, and we've been thinking also a lot about this. Obviously, amyloid lowering monoclonal, standard monoclonal antibodies are associated, they are all associated, including gantenerumab, as you know, with the incidence of amyloid-related imaging abnormalities or ARIA.
What seems to be the case is that, yes, I mean, the more amyloid you remove, the more likely it is that you get ARIA. However, there are also differences across the molecules. So we know from molecules like lecanemab from Eisai, that the ARIA rate is, you know, lower than, for example, with donanemab, or lower than with aducanumab. So, it's not only about amyloid lowering, obviously, and there are certain molecule-specific differences that appear to play a role. In our case, we believe that... I mean, of course, it's still early days, right? We have only 44 participants, and it looks like a relatively low and maybe lower than anticipated ARIA rate so far, if we put this in relation to the amyloid lowering effect....
Currently, you know, we are discussing different hypotheses why, if this really can be confirmed in the expansion part of the study, what could be an underlying mechanism? So, one of the, you know, the theories is actually that this access to the brain via the capillaries might be, you know, a major difference that could explain, you know, this lower ARIA incidences. Other aspects are, for example, that the dose that we administer systemically is significantly lower. You know, we achieve at a significantly lower dose, more amyloid and faster amyloid removal than, you know, standard antibodies with higher doses, so that might also play a role. And the third, you know, potential factor that we're currently discussing is actually the pharmacokinetic properties of trontinemab. Thanks very much for the question.
Maurice, answers. The next questions would come from Eric Le Berrigaud from Jefferies.
Yes. Thank you, Bruno. Two questions on MS. First, on Ocrevus sub-Q, and referring to one of your initial slides, looks like Ocrevus sub-Q goes with a double bullet, meaning over CHF 2 billion peak sales potential. If we think about where Ocrevus is now, i.e., around CHF 6.5 billion at the end of this year and still growing double digits, probably we might think of Ocrevus reaching CHF 7 billion by the time the sub-Q formulation is coming to the market. So if we had CHF 2 billion on top, would bring the brands to CHF 9 billion or around this. Is it what you're suggesting, or should we think about any cannibalization or any patients switching at some point from IV into sub-Q because of being in trouble finding the IV centers?
Or, and if there is any shift to, to model, could you help us maybe understand how much would that represent out of the existing Ocrevus patient base? The second question is on fenebrutinib and, the timing for the data. It looks like when we look at the, the agenda, which was on one of the, on the slides, the arrow suggests that two reporting phase III data would be in the second part of 2025. Is this your best guess, as we speak, and are the two phase III data set to report about the same time or one ahead of the other? Thank you.
Maybe, Eric, I will take the first question on the, peak sales. So in general, you know, we don't guide on peak sales for an individual, molecule. What we have outlined here with the CHF 2 billion+ opportunity is, really the totality of, the outstanding Ocrevus trials, and this is the, Ocrevus subcutaneous, opportunity, as well as the Ocrevus high-dose, opportunity. And you're right, as both, it's, we believe there is an additional, opportunity here, so there is an element of market expansion. But there probably also will be a certain element of, switching in the, in the hospitals, in the larger hospitals where Ocrevus is, primarily established today. The other question, then I, was taking this one?
Yeah. I can speak to the Dr. Hauser also, I think, has his hand up. I mean, yes, so we are putting the second half of 2025 as a readout for both the relapsing and PPMS trial. These are trials which are ongoing now, and obviously we're moving as fast as we possibly can. So these are still, you know, rough dates, if you want. These are, for now, the dates we are working towards, but obviously we want to beat those. And I don't know, Dr. Hauser, if you want to add anything.
I wanted to add, knowing nothing about the finances and being quite separate from that, myself, there is a substantial use of non-Ocrevus anti-CD20s globally being used for MS. The availability of an anti-CD20, like Ocrevus, with the best-in-class track record for efficacy and safety over time, plus now the ease of administration, not requiring the burden and cost of an infusion center, could, in my opinion, dramatically cause a shift of patients who are now on other anti-CD20s to potentially move to subcutaneous Ocrevus. That's just an opinion. I don't have much to add on the fenebrutinib studies. The primary progressive study and one of the two relapsing studies are fully enrolled.
As Paulo said, we're very much looking forward to a second, early second half, 2025, completion of these studies.
Thanks, Stephen, for adding your insights. The next one in a row would be Mark Purcell from Morgan Stanley.
Thank you very much, Bruno. Two questions. The first one on your confidence in adaptability around the Brain Shuttle technology, are you looking to use it with other antibody targets, such as tau? Can you explore this in other neurodiseases, such as Parkinson's, for example? The second question on Ocrevus patch pump, can you help us understand a little bit more about this in terms of the partner on the device, the path to Part D, and the timing of introducing this technology into the marketplace? Thank you.
... Yeah, so maybe I can take, I can take a shot at both. Well, for the first one, yes, this is very much a platform that we've been working on for, again, as I, as I mentioned, over a decade. And we have two molecules in the clinic now. Trontinemab is the most advanced one, but you might have seen in my slides in the beginning, we have a brain shuttle anti-CD20 molecule in phase I for multiple sclerosis as well. And again, the idea here is to Dr. Hauser's comments around the residual inflammation that's compartmentalized in the CNS, and that we believe is associated with either smoldering progression or, or, you know, residual progression that's not currently addressed by existing therapies. That is the purpose of that program. But this is very much a platform.
We are looking at the opportunity of anti-alpha synuclein antibodies, anti-tau antibodies. Each one of these turns out it's its own molecule, so we need to engineer it and perfect it. So it's not entirely a plug-and-play type of platform, but it is something that we're very, very keenly been developing across a range of indications in neuroscience. Your second question may be a bit premature. I mean, we have, you know, some plans that are advanced. It's premature to disclose partners, to disclose path. What we look to do now is really perfect that combination with the technology and the administration of Ocrevus subcutaneous. This will most likely employ some sort of Halozyme technology as well. Again, the patch pump is a common device.
It basically allows for at-home, easy administration of small volume of, you know, antibodies. And what we're working on now is really the approval as fast as possible of the subcutaneous formulation we have currently, and in parallel, working to do the bridging studies necessary to come to that patch pump. Now, in my experience, these bridging studies are typically just regular PK, small safety studies, so not overly cumbersome, so we hope to do them in a short amount of time. Thank you.
Thanks, Paul. Next questions would come from Emily Field, from Barclays.
Hi, I'll just ask one for Dr. Hauser. You know, a lot of your competitors in the BTK space have talked a lot about the concept of smoldering MS, and their molecules are showing a benefit there, and I think that was what you were referring to when you were talking about the silent progression. I was just wondering if you could just provide some context of what you would hope to see out of the fenebrutinib phase III studies, just to show that it's really having a benefit for those patients.
Yes. Well, you know, one of the amazing things about modern clinical trials in MS is that the phase IIs are so reliable as predictors of what we'll see in phase III in terms of the primary endpoint. I'm quite confident that the Fenebrutin trial will show very substantial benefits against focal inflammation and MRI evidence of attacks. The key... The two key questions will be what the studies show against the unmet need of progression, which with Ocrevus is about, you know, the effects on silent progression are about 42% in the clinical trials for relapsing MS. A greater effect size in the earlier patients, patients treated immediately when the MS is just beginning.
So about a 42% effect size in relapsing and about a 30% effect size in progressive MS. So those are the champions. That's Ocrevus, and our goal is to beat that or add to that benefit. These are difficult trials because on Ocrevus, fewer than 4% of patients with relapsing MS will worsen each year, and about maybe 8%-10% of patients with primary progressive MS will worsen each year. So I would like to see those progression curves for chronic disability progression attenuated. To me, that would be the home run of these trials against progressive against the progressive phase of the disease across the MS continuum. Safety is, of course, going to be a big issue and possibly a distinguishing feature between the BTKIs.
Thanks, Stephen. Next question will come from Peter Welford, Jefferies.
Hi. Yes, thanks. Just two quick ones. Firstly, just sticking with Dr. Hauser on multiple sclerosis. Curious, typically, your multiple sclerosis patients, both RMS and PPMS, how often do you typically see them and invite them back to your office? I guess I appreciate, I'm thinking, you know, with regards to the benefit of the subcut patch pump and at home, I mean, realistically, how often do these patients come in to see you for monitoring anyway? And-
Yeah.
Just secondly on, sorry, on prontosilimab. I guess curious there, when you look at the dosing, given what you said about the amyloid positivity rates being decreased from rate with the higher, with the 1.8 dose that you showed, I guess, what is the benefit, do you think, potentially, of going higher? I guess what's sort of related to that, did you see any data to show better efficacy or correlation of that amyloid reduction relative to the ability of the antibody to get into the CSF if you monitored that, or any sort of interpatient variability at all, perhaps, that could explain the effect of the drug?
... Maybe I'll start. Just quickly, we are seeing patients generally every six months, which times beautifully with the Ocrevus dose requirements, the dosing requirements. One of the other very interesting things that has happened because of Ocrevus is that we see our patients much less frequently than we used to. They're not calling us on Friday afternoon. People are really stable, and the visits are easier. MS has become an easier disease to treat. And at numerous academic medical centers, the MS services have not grown commensurate with all of the other diseases. And I think that this is a testimony to the highly efficacious nature of anti-B-cell therapy that is now conveniently administered by general neurologists and primary care docs.
If I may add just a comment on that as well, because I think the what Dr. Hauser is referring to, this, there has been really almost like a paradigmatic shift to the burden of monitoring of these patients. But what we're encountering, if you want more from a commercial setting, is that there are areas of the world, not just in the U.S., where actually, even if the burden of monitoring is very small, and therefore one might think that, yeah, you know, subQ won't make a big difference. It is actually access to IV infusion capacity that's limiting access to a high, highly efficacious therapy. So that's regardless of doctor visits or access to monitoring.
And so what we want to make sure with Ocrevus subQ as well, is that for any patient or any physician who wants to prescribe Ocrevus, in whatever geography or whatever care setting they are, there's an option that works for them. And I think that's particularly important because what we've seen with Ocrevus and other anti-CD20 is that, you know, there is an unmet need for an easy to administer subQ form that is not eating into the Ocrevus share, if you want. So clearly, there's a population of patients and physicians that would favor a subQ version for whatever reason, whether it's convenience, whether it's at home, whether it's access to IV capacity that's constrained. So that's what we're trying to fulfill here. Luka, do you want to do the trontinemab?
Yes, yes, sure. Yeah, I think it's an exciting question, actually. I mean, the question is like, if we go higher, what is the expectation? Right? I mean, what we observed at this third dose level is, and you pointed to it, is 75% of the people at this third dose level on active were amyloid negative at week 28. There was a -82, a -84 centiloid reduction versus baseline at week 20, which is quite remarkable and probably 2-3x faster than what is out there, right? If we go higher, the...
I mean, we are now entering really an uncharted territory, I think, but the expectation is that we will have even earlier and deeper clearance at the higher doses. And based on what we have learned from the field so far, is that rapid, robust, and early amyloid clearance is necessary for efficacy. So the expectation is that if we have faster and deeper amyloid clearance at an earlier time point, that hopefully this will translate into larger clinical effects. But this needs to be now shown at the next higher dose level, of course, and with the third dose level that we will be exploring in the expansion part of the study.
Thanks, Luka. The final questions today then go to Andrew Baum from Citi. Andrew?
Yeah, I'm here. Sorry. There we go. You can hear me.
Yeah.
So couple of questions. Firstly, on the hemosiderosis and the transient anemia reported with trontinemab, could you comment on putative mechanism? Is this cross-reactivity? Just thinking to explain it, or whether it's something we should be concerned about with prolonged dosing. Second, for Dr. Hauser, I know that Roche does not have any CAR T programs in development currently for MS, but curious just if he has thoughts or whether he's concerned about the autoimmune encephalitis as a reason to stay away. And then finally, I assume when you're trying to compare versus, Ocrevus, you will be enriching patients based on clinical as well as imaging parameters. I assume that to be the case in order to get a higher event rate. Anyway, thank you.
I can maybe start with the... So I assume the question was around anemia, because you mentioned hemosiderosis at the beginning, so-
Yes. Because you report the hemosiderosis and anemia with trontinemab, so I was curious as to the mechanism associated.
So the leptomeningeal hemosiderosis is essentially a form of ARIA-H. So this was observed in one participant at the higher dose level of 1.8 mg/kg trontinemab or placebo. So one individual developed. This is an imaging finding in the brain, is actually a common adverse event or imaging finding associated with amyloid-lowering therapy. So a form of ARIA, which we call ARIA-H, ARIA with hemosiderosis, or hemosiderin deposits in the brain on MRI imaging. We do not think that this is in any way related to the anemia phenotypes. I think these are two independent processes, from what we currently can say.
The anemia phenotype, as I mentioned, formally, five participants at a higher dose level, 1.8 mg trontinemab or placebo, developed a mild and transient anemia, an anemia that essentially disappeared after a few weeks. This was a mild anemia, it was not associated with any clinical symptoms and were essentially lab findings. In terms of mechanisms of anemia, the drug does, I mean, there is the Brain Shuttle module that we explained at the beginning. That module binds to the transferrin receptor 1, so there is a possibility of, obviously, a drug-related effect. What we also mentioned at the CTAD conference is additional confounders.
So in this study, we are sampling a lot of blood, and what we observed so far is that actually all those groups, including placebo, show a mild, I mean, really modest decrease overall in hemoglobin and red blood cell count. So we are, in this study, particularly, you know, stressing the hematopoietic system, but of course, there could be also an, you know, a potential drug effect. What we have also observed as a, or we're currently discussing as a third mechanism, is in those people who developed this mild and transient anemia, these people at baseline already entered the study with, you know, and were rather on the lower end with their ferritin and iron and hemoglobin levels.
So there are certain also participant predisposition factors that likely play a role, and we are currently actually exploring the potential of iron supplementation in those individuals who are at the beginning of the study. So at entry point, at entry, study entry, on the lower side with their iron levels. And this is something we're currently exploring, whether we can actually completely prevent anemia with this approach.
Should I say a few words? With respect, thank you, Andrew, for those questions. With respect to the CAR T question, numerous groups are exploring CAR T therapeutics. The Lupus data is obviously very exciting to all of us, even though it's a small number. The apparent magnitude of the effect has been very impressive. For MS, the development pipeline, I think despite the excitement about the delivery system, is going to be challenging. I believe that the regulators are requiring that the early CAR T trials in MS use patients who have failed best available treatments. In those patients, the disease mechanism, I think, will be predominantly microglial, pro-inflammatory microglia. And the CD19 targeted therapeutic, even if effective, will not be able to directly target that pathology.
I'm very excited about some of the second-generation or third-generation CAR Ts that might be able to use technologies, like synNotch, that will activate, that will sense, and then deliver the effects in a predetermined environment, for example, in the brain or in white matter, or that could deliver therapeutic payloads in addition to knocking out CD19-bearing cells, which would hit plasmablasts. I think that it will be these more sophisticated CAR Ts that will ultimately be the more interesting for MS. Your second question, I don't recall.
I think we have answered Andrew's question. Andrew?
I think I answered.
Yeah, yeah. That was it. Thank you very much.
Okay. I think with that, we are at the end of today's call. I would like to use the occasion here to thank our speakers again for their time and their commitment, and also the IRT members who contributed in preparing the event. That's Monica Baudler, Lily Trieu, and Alina Levchuk and Melanie for the event organization. I hope this event was helpful for you, providing an update here on the neuroscience franchise and especially on some really exciting new early assets. If there are any remaining questions, then please reach out to the IR team. With that, I would like to wish you a good day, and hopefully talk to you soon. Bye-bye.
Thanks, all.
Thank you.