Ladies and gentlemen, welcome to Roche Virtual Neurology Investor Event. My name is Henrik, and I'm the technical operator for today's call. Kindly note that the webinar is being recorded. I'd 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're invited to send in questions for this throughout the entire session using the Q&A functionality of Zoom. In addition to that, you may also raise your virtual hand to address your questions verbally. For participants joining via phone, to raise your hand, use star nine on your phone's dial pad. When you then get selected to ask your questions, please follow the instructions from the phone and press star six to unmute yourself.
One last remark: if you'd like to follow the presented slides on your end as well, please feel free to go to roche.com/investors to download the presentation. At this time, it's my pleasure to introduce you to Bruno Eschli, Head of Investor Relations. Bruno, the stage is yours.
Thanks a lot, Henrik. Could I have the first slide, please? Welcome to our IR call focusing on the latest clinical results for the neurology franchise and especially on the latest data which were presented at MBA and ADPD. Let me quickly take you through today's agenda. We have today three speakers with us. First will be Azad Bonni, our Global Head of Neuroscience and Rare Diseases from pRED. Azad will provide a quick update on our neurology franchise portfolio before taking us through the phase II PADOVA data for Parkinson's disease, which have been presented yesterday at ADPD. Our second speaker will be Luka Kulik, Global Head of Early Development Neuroscience and Rare Diseases at pRED. He will lead us through the updated phase I and phase II results for trontinemab, our 2+1 bispecific Brainshuttle antibody in Alzheimer's disease.
These data just got presented at ADPD and were the basis for our decision to move fenebrutinib into late-stage development with the phase III start planned now for later this year. Finally, we have with us Dr. Alex Murphy, a Senior Clinical Director within Product Development for neuromuscular disorders and stroke. He will provide an update on the two-year follow-up data from the phase III EMBARK study for gene therapy, Elevidys, and DMD. Overall, we have 90 minutes for this call, around 60 minutes planned for the presentations and 30 minutes for Q&A. Could I have the next slide, please? This is just as a quick reminder to our neurology franchise. Roche has more recently become the number one in neurology in terms of sales. Neurology sales account now for 20% of our 2024 pharma sales.
For this franchise, we expect to continue to show double-digit growth in coming years, driven by the already launched portfolio, but also from the pipeline which is emerging. Let me use this occasion here just to make two quick comments on two very recent newsflow items from our late-stage neurology pipeline. Firstly, on Ocrevus high dose, where we just communicated negative results on Wednesday. A few comments here just to put the phase III, the negative phase III outcome into a broader Ocrevus franchise perspective. Previously, we have communicated for Ocrevus high dose and Ocrevus in general that the drug substance patent is to expire around 2029. There are other patents on the subcutaneous formulation, the high-dose formulation, on a high-concentration formulation and devices, for example, the on-body device, which is currently in development. These patents go far beyond 2030.
We have communicated that we have modeled the total Ocrevus franchise to peak around 2029, and we do not expect the cliff situation afterwards due to the Ocrevus subcutaneous providing some level of protection for the franchise. We have also communicated we feel comfortable with the Ocrevus consensus peak sales, which currently stand at about $8.5 billion in 2029, which includes the $2 billion incremental sales opportunity for Ocrevus subcutaneous, which we have called out before. Just to be clear and make you aware, we expect the Ocrevus subcutaneous opportunity to be larger than $2 billion in total, as there will also be some switching over from IV. Also to clarify here, we have never provided peak sales or quantified the incremental sales opportunity for Ocrevus high dose.
We have previously communicated only once we would have had positive study data for Ocrevus high dose, we would have provided this information. Based on the results, there will be no significant revision to our internal business plan assumptions. The second topic I quickly wanted to cover here is on Elevidys. Following the tragic news announced last week of a 16-year-old non-ambulatory DMD patient passing away from acute liver failure, the EMA has required that Roche and Sarepta put temporary clinical holds on three ongoing studies. This includes the studies 104, 302, or EMBARK , and 303 ENVISION. Patient safety is Roche and Sarepta's top priority, and an investigation into the cause of these tragic fatalities is ongoing, and we are working with our partner Sarepta with the utmost urgency to gather information and make a full assessment of the event.
Infection was suspected by the treating physicians as a contributing factor. We are also working in close collaboration with all relevant health authorities, and it is premature to speculate at this stage on any potential impact to the program or any of the program timelines. Can I have the next slide, please? Since diagnostics is not mentioned in any of the other sections of today's call, I just wanted to quickly highlight our diagnostics efforts in the space of neurology and how this ties into our ongoing drug development efforts, especially with Alzheimer's disease. As you know, we aim to build integrated diagnostic solutions along the patient journey, and AD is a key example of this approach where we innovate on both the diagnostics and the pharma side, and where we also have presented several data sets at ADPD.
For AD, you can see here our current product portfolio and the pipeline. Let me quickly take you through the solutions we are developing for the initial screening and triaging of patients, and then also for getting a final diagnosis done. The Elecsys pTau181 test, formerly part of the Elecsys Amyloid Plasma Panel, is used as a rule-out test requiring confirmatory testing through our CSF tests. I will share the performance data of the pTau181 test on the next slide as we present it here in update at ADPD. Second, we have the Elecsys Beta Amyloid pTau ratio test for CSF samples, which is already commercially available and used for confirmatory testing of the amyloid pathology. Finally, I would like to point out the Elecsys pTau217 test, which received FDA breakthrough device designation in 2024.
pTau217 will be used as a triage test initially and has the potential to become the first blood-based rule-in test in a second step, thereby revolutionizing the timely diagnosis of Alzheimer's disease. Next slide, please. At ADPD 2025, we shared the recent interim clinical study results for our Elecsys Amyloid Plasma Panel, which consisted of two blood-based biomarkers, the pTau181 and Apolipoprotein E4. In this study, we enrolled 492 highly diverse patients with suspected cognitive impairments across 30 different study sites. Our results demonstrated excellent clinical performance and negative predictive value of over 90% independent of comorbidities and demographics for both the [EAP Panel] as well as for pTau181 as an individual biomarker. Pending regulatory clearance, we hope this test will provide a minimally invasive blood-based test to rule out Alzheimer's disease and decrease the time to definite diagnosis.
This will have a significant impact on patients, their families, and healthcare systems worldwide. Can I have the next slide, please? This is just the unchanged keynote flow slide for 2025, as it was previously presented at the full year results. Highlighted in yellow are the remaining readouts for the neurology franchise with Elevidys approval still expected for later in the second half. The fenebrutinib readouts expected at the very end of 2025 in Q4, and also the GYM329 anti-eleven neurostatic antibody readouts in SMA and FHSD expected for later this year. Next slide, please. Just to close from my side on the upcoming IR events, as you know, we have the Diagnostics Day on May 22nd again as a live event in London coming up.
On June 23rd, we will host a hematology IR call covering all the relevant data from the hematology summer conferences and ASCO. We will have no separate call for ASCO this year. With that, let me hand over to Azad for an update on our neurology pipeline. Azad, please.
Thank you, Bruno, and good afternoon. It's a pleasure for us to bring you this update in neurology. As Bruno alluded to, we are in the privileged position of leading the field in neurology, therapeutics, and diagnostics, and this includes the portfolio. As this slide shows, we are focused in a number of areas in neurology, including Alzheimer's disease and MS, which together represent our two within neurology to what we call end-to-end disease areas representing strongholds for us at Roche. Today, I'm going to give you a very brief overview of our portfolio and a few quick updates on just a few projects. For the main part, as Bruno mentioned, we will, as the next slide shows, focus on three projects. Alex Murphy will focus on providing a recap of results on Elevidys and Duchenne muscular dystrophy.
Bruno alluded to the recent developments there. Luka Kulic will focus on trontinemab in Alzheimer's disease, and I will provide you the recent results on prasinezumab. As Bruno mentioned, both tronti and prazi were shared; the results were shared at the ADPD in Vienna, and this is what we will be talking to you about. Before we do that, let's go to the portfolio slide that shows our projects in clinic. I want to make three points here. First, we are focused on neurology, and as the legend in the right lower part of the slide shows, we are in a number of areas within neurology. The second point is that, as depicted in the left lower part of the slide, we are actually using innovative technologies already in clinic, including the Brainshuttle technology, which Luka will elaborate on.
Not shown on the slide in the third point is that we actually have a large and growing portfolio and research in neurology that feeds this clinical portfolio. I'm going to give you three updates quickly in MS and neurodegenerative diseases. Let's start with MS. This is on the next slide. We are building on the success of Ocrevus in MS. In one area, we are focused on fenebrutinib, which is a BTK inhibitor. BTK is a tyrosine kinase that has attracted a lot of attention in MS because it's activated in B cells and myeloid cells. It's activated in the periphery and in the central nervous system. As such, it's been attractive for both relapsing disease as well as progressive aspects of the disease.
Among the BTK inhibitors, fenebrutinib stands out because it's the only reversible non-covalent inhibitor of BTK that's currently tested in phase III trials in MS. On the slide, you see results of the FENopta phase II results. On the left panel, you see the primary endpoint that was met with robust reduction of T1-enhanced lesions. In the middle panel, you see that in a subset of patients, CSF concentrations of fenebrutinib were measured, which show that where the mean is higher than the IC90, indicating that there is sufficient exposure in the CNS. On the right side of the slide, you see results of the open label extension, which are equally striking to what we found in the double-blind period. Here, what we find at 48 weeks is that 96% of the patients were relapse-free, and nearly all patients were free of new T1-enhanced lesions.
We should also add that the safety profile is favorable, consistent with previous studies. The 96-week data will also be from the OLE, will be presented later this year. Currently, we have three phase III trials in MS with fenebrutinib, two in relapsing MS, and one in primary progressive MS, the latter with a comparator arm of Ocrevus. Readouts are expected later this year. Let's move on to the next slide where I'm going to tell you about Alzheimer's disease. You will hear a lot more about Alzheimer's from Luka Kulic and the results of trontinemab, which target the amyloid plaque. Here, I'm going to tell you about a molecule called gamma secretase modulator, which acts on the other end of the amyloid cascade, the beginnings, actually.
Gamma secretase, as shown on the left in the left panel, acts on this protein, amyloid precursor protein, and cuts it at several sites processively. This leads to the generation of multiple types of A beta peptides, including the amyloidogenic A beta peptides 40 and 42, but also other peptides, including A beta 37 and 38, which are non-amyloidogenic. Previously, people have been interested in gamma secretase and used what I would call a sledgehammer approach of inhibiting it. Often, this was not selective. Gamma secretase modulator, on the other hand, is an incisive approach to modulate gamma secretase once it binds to this enzyme and modulates it such that you produce less of the amyloidogenic peptides, A beta 40 and 42, and more of the 37 and 38 non-amyloidogenic peptides.
These results have been confirmed in phase I trials in healthy volunteers, as shown in the middle panel, where you see in CSF and cerebrospinal fluid reductions of the amyloidogenic peptides, A beta 40 and 42, and a concomitant increase of A beta 37 and 38. Currently, we're in a phase II- A trial focused. This is in people who are accumulating amyloid and who are either cognitively normal or have mild cognitive impairment. The focus of this trial is on safety, tolerability, PK, and pharmacodynamic effects. The update that I can give you here is that recruitment is going ahead of schedule and is about to complete with interim data expected next year. Let's move to Parkinson's disease now. Here, what I want to illustrate with this slide is that we're, of course, interested in neurodegenerative diseases beyond the core pathologies.
I'm going to talk about alpha-synuclein and prasinezumab, and Luka will talk about amyloid in his part of the talk, but there are other targets, of course. There are co-pathologies. There are also targets within microglia that involve what's called the innate immunity and neuroinflammation. On this slide, what I'm showing you is that we are already moving on this and have an NLRP3 inhibitor. NLRP3 inflammasome has emerged as a key player in neuroinflammation and from preclinical studies. Here we have a phase I- B study where we've characterized the [Selnoflast] , which is an NLRP3 inhibitor, and characterizing the effect of this inhibitor on measures of brain inflammation and microglial activation. The other thing that this slide shows on the right side is that we are interested in NLRP3 across different areas, including also in immunology and cardiovascular disease.
This, of course, presents us with synergies across the therapeutic areas. Now, let's go to the next slide and moving toward, I'm going to tell you about prasinezumab and the readout of phase II-B PADOVA trial, which was shared earlier this week at ADPD. Before I go into the results, I want to show you a couple of sort of introductory slides leading up to the PADOVA phase II-B trial. On the first next slide, you will see a very brief introduction to Parkinson's disease. Parkinson's is a progressive neurodegenerative disease. As you know, the key cell type that degenerates in Parkinson's disease are these dopaminergic neurons that are in the midbrain. By the time people are diagnosed and symptoms are found, about nearly half of these dopaminergic neurons have already degenerated.
What we are learning is that this cell type continues to degenerate with progression of the disease. The other aspect of this that I want to convey to you is that Parkinson's disease, as the second most prevalent neurodegenerative disease, is also age-associated, similarly to Alzheimer's. The expectation is that the prevalence will continue to rise in the coming decades. This, of course, leads to enormous costs to people and their families and to the healthcare systems. What's interesting about Parkinson's disease is that there have been symptomatic treatments for quite some time, dating back to the early 1970s when Matterport was launched from Roche, and there have been a number of other symptomatics since then. Until now, we still don't have treatments that actually alter the course of the disease.
This is where prasinezumab comes in, as shown on the next slide, with the potential to be a first disease-modifying treatment. Now, what prasinezumab is is a monoclonal antibody that targets and binds specifically aggregated alpha-synuclein. Alpha-synuclein is a protein that's found within neurons, and it aggregates within dopaminergic neurons. As the panel on the left shows, once these neurons degenerate, aggregated alpha-synuclein is released from neurons, and then it's thought to lead to the further degeneration of other dopaminergic neurons in the vicinity. With prasinezumab, what we're testing here is the idea that by binding to aggregated alpha-synuclein, we would prevent the cell-to-cell spread of aggregated alpha-synuclein and consequent degeneration and further progression of the disease.
Now, prior to the PADOVA trial, we had another phase II trial, and that is the PASADENA trial, where we saw evidence of signals suggesting that prasinezumab slows down the progression of the disease. Here, I'm just showing you one piece of data, which is actually in the open label extension part of the trial. This is shown on the right side. Here, because we're in the open label extension, we're comparing to a natural cohort shown in the gray line, which represents the PPMI cohort propensity match population to our population. As expected, you see that there's progression of the disease, meaning that the scores increase on the scale, the MDS-UPDRS part III. What you're seeing with the patients, participants who are on prasinezumab, you see that there appears to be flattening of this progression as compared to the natural cohort.
One other thing to mention here, and of course, we have to remember this is open label, so it comes with its caveats. One thing you can see is that you see the separation begins after year two, suggesting that it takes longer or some time to see the effect of prasinezumab on slowing of the progression of the disease. Now, let me move to PADOVA and tell you about what we found here. This is a phase II-B trial where we tested prasinezumab on Parkinson's disease patients who were already on symptomatic treatment. Here, we needed to use an innovative approach to measure this, a novel time to event to measure this to mitigate the masking, potential masking effects of the symptomatic treatments. We took 586 patients or so in Parkinson's disease who were randomized one-to-one to placebo or prasinezumab.
These patients were already on symptomatics with either L-DOPA or MAO-B inhibitors. This was a randomization factor to allow us to ensure that they are balanced across the treatment arms. What's really important on this slide to convey is that how we, when the end of the sort of the trial, the double-blind period of the trial, and that required a minimum number of events and the minimum duration of 76 weeks. The last patient in was treated for 76 weeks. Because of a common closed design, that meant that all of the previous patients were treated longer. In fact, the first patient in would have been on for about three and a half years. Patients were rolled over in the open label extension. What I'm going to present are the results at the end of the double-blind period.
Let's go to the next slide. These are the baseline characteristics, which basically shows that they are well balanced across the treatment arms. The key point from the slide is actually in the title of the slide, the byline. You see that nearly three-quarters of the participants were on L-DOPA. Now, let's go to the next slide and begin to tell you about the results. As I mentioned, we used a time to event endpoint. Let me go through this briefly to explain this. Here, as you can see in the blue rectangular box, this was defined as a change of five or greater points on the MDS-UPDRS part III scale. This is motor signs. This reflects a clinically meaningful change. As we have shared with you earlier, the primary endpoint was missed in that the statistical significance was missed.
As you can see, however, there are trends toward delaying motor progression. In the primary analysis, as you can see, the hazard ratio is 0.84 with a p-value of 0.0657, just missing the 0.05 threshold. This was done incidentally where the covariates were not taken into account. These are covariates that are taken at baseline that predict progression. Now, when you take that into account in pre-specified analyses, supplementary analyses, you see that the hazard ratio improves to 0.81 with a nominal p-value of 0.03. We also looked at the difference of medians, which is shown here, a difference between placebo and prasinezumab, which is just under 12 weeks, which means that it took, on average, 23% longer for participants on prasinezumab to reach this event as compared to placebo. These trends were also seen in the L-DOPA subgroup, this large cell L-DOPA subgroup shown here.
Now, just a comment about L-DOPA. This is a common symptomatic. In fact, in some countries, it's used in 70% of the patients. Here, as you can see, the hazard ratio improves to 0.79 in the primary analysis for those where the covariates were not adjusted for the covariates and to 0.76 for those in the supplementary analysis where this was taken into account. All of these measures are pre-specified. In terms of difference of medians, this comes to just under 16 weeks. In other words, it takes about 32% longer for the participants on prasinezumab to reach this event as compared to placebo. Now, let's move to another measure where we actually looked beyond part III, which is motor signs, which is what a neurologist would be able to see.
Here, we looked at a measure of patient-reported function in the part II of the scale. Here, we used a time to event again, in part because actually, we know that part II, it takes quite some time for an effect to be seen. Here, we define this as time to a change of three or greater points on this part of the scale. This represents clinically meaningful change. I should add that here, what we looked at to reduce the variability in those participants where there was a confirmed motor event. As you can see here, there are trends towards delaying the decline of function. You see the numbers shown on the right side for the hazard ratio and the difference in the medians between prasinezumab and placebo, about 27%. Let's go to the next slide.
As you can see now, you see the pattern. We see that trends that are in favor of prasinezumab across time to event endpoints, so beyond those that I mentioned, as well in time to meaningful worsening in clinician and patient global impression of change. Now, I'd like to move beyond these endpoints and actually go to some exploratory markers that, actually, before I go to that, let me tell you about the change in baseline. The change in baseline is something that is for the MDS-UPDRS part III. As I mentioned at the beginning, with this scale, it's challenging to see a change for disease-modifying treatments because of the masking effect that takes place with symptomatic treatment. Consistent with that, you see that at 76 weeks, actually there's no change between prazi and placebo.
Now, and this is the whole reason that we innovated for time to event, and you saw the trends on time to events. Even here, what's interesting to note is that from disease modeling, as you can see note on the right side of the slide, this disease modeling suggests that you need more than two years to see a potential treatment effect of a disease-modifying therapy with a 30% effect size. Sort of consistent with that corroboratingness, you will recall, I showed to you from the PASADENA open label extension that there actually, you see the flattening of this scale as you go beyond year two. Because in this trial, in the PADOVA trial, we had a common closed design, we actually had a number of patients who had gone well beyond 76 weeks, well beyond 18 months.
It turned out that we actually had more than half, about 56% of participants or 435 participants who had completed two years or 104 weeks. These results are shown here on the next slide, which are again pre-specified. As you can see, as you go beyond 76 weeks, you begin to see the trend, the separation of lines. By 144 weeks or two years, you see that with prasinezumab, you see about 35% relative reduction versus placebo of motor progression. It is important to note that the baseline characteristics in the subsets were also balanced between the treatment arms. Within the L-DOPA subgroup, which represents 3/4 of the group, you see that this is maintained. Indeed, we see 40% relative reduction in prazi versus placebo with a nominal p-value of 0.0177.
Let me go to the exploratory markers that I wanted to tell you about. It is going to come here. Here, I want to take just a minute to explain this. These are exploratory. We know that in Parkinson's disease, there are a couple of pathological changes that take place. Neuromelanin, which is a pigment that you see in the substantia nigra, actually giving the name substantia nigra. In particular, in substantia nigra pars compacta, which is a part of the midbrain that contains the dopaminergic neurons that are critical for the pathogenesis of Parkinson's disease from a circuitry perspective, over time, you see reduction in the intensity and volume of neuromelanin in the substantia nigra. We looked at this.
As shown here in the gray bar columns, you see that as expected in the placebo participants, you see a reduction of intensity in the left panel and the volume of neuromelanin in the substantia nigra pars compacta in the placebo group. However, interestingly, as you can see in the prazi participants, you see that actually this does not appear to occur. In fact, if anything, you see a trend in the opposite direction. The other change that you see in pathology is accumulation of iron in the substantia nigra as well as in the putamen, which is a target for the dopaminergic neurons from the substantia nigra. It is known that iron deposition accumulates. This is, as expected, you see this in the placebo.
There is a change accumulation of iron in the putamen, as shown on the left side, and the substantia nigra in the right panel in the placebo group. With prazi, we are seeing again stabilization or a change in the trends in the opposite direction. All of these results suggest trends toward reduction of iron accumulation and trends from the previous slide of reducing neuromelanin reduction. Let me go to the summary slide. What I have shown to you from the PADOVA trial is, although the primary endpoint was missed, the time to event analyses showed trends toward delaying motor progression in Parkinson's disease. This was more evident in the L-DOPA treated subpopulation, which represents 3/4 of the population. We saw consistent trends across secondary endpoints, including patient-reported function.
I also showed to you that although we don't see changes in baseline at 76 weeks, we do see trends toward reduced motor progression, particularly at 104 weeks, which suggests that longer times may be needed to measure a treatment effect or to capture such an effect of a DMT, a disease-modifying treatment on top of symptomatics. One thing I didn't cover but important to convey here is that prasinezumab continues to have a favorable safety and tolerability profile. We do see high retention. In fact, we see over 90% of participants who rolled over in the open label extension. This will be important as this will provide us with longer-term data. Finally, I showed to you the first biomarker evidence of a potential impact of prasinezumab on the underlying pathology in Parkinson's disease. We are currently considering next steps for the prasinezumab program in Parkinson's disease.
I'd like to thank, as shown on the next slide, acknowledge first and foremost all of the participants and their families, investigators, the staff for really a tremendous amount of effort to this program. With that, I'm going to turn it over now to Luka Kulic, who will tell you about trontinemab.
Thank you very much, Azad. I hope you can hear me well. It's indeed a great pleasure to provide you here with an update on our trontinemab program and share with you the most recent interim data from our ongoing phase I- B/II-A study of trontinemab in people with Alzheimer's disease. Next slide, please. Alzheimer's disease, as many of you know, is the most common form of dementia and represents one of the biggest healthcare challenges of our time. This disease is characterized by early aggregation and pathological accumulation of amyloid beta peptide and of amyloid plaques in the brain. The central role of a beta in Alzheimer's disease pathology is well established and strongly supported by both neuropathological and human genetic evidence. Consequently, a beta has long been the primary focus of efforts to develop drugs that might slow or delay the progression of Alzheimer's disease.
In recent years, as you all know, there has been lots of excitement in the AD field. We have seen the very first positive phase III trials with anti-A beta targeting monoclonal antibodies. What we have learned from these positive trials is that both the speed and the amount of amyloid lowering appears to be critical for efficacy. This diagram on the left-hand side shows the distribution of amyloid plaque burden measured by PET imaging. At the beginning of an AD trial, the participants usually have an amyloid burden that is in the range of approximately 75-100 so-called centiloid units. The trials that ultimately read out positive are highlighted here in green. These trials, interestingly, push the amyloid plaque load below a threshold of approximately 24-30 centiloids at trial endpoint. Trials falling just short of that were negative.
Rapid and deep amyloid plaque lowering obviously critically matters with these therapies. Next slide, please. A major hurdle for these therapies, as well as for many other treatments of neurological disorders, is and remains, of course, the blood-brain barrier. The blood-brain barrier acts as a gatekeeper. It limits the access of all kinds of molecules, especially of large molecules like antibodies, to the brain. Roche's proposed solution to overcome this problem is our Brainshuttle technology platform. Our lead shuttle molecule, trontinemab, that you see on this slide, targets aggregated forms of amyloid beta and amyloid plaques and is specifically engineered to overcome the blood-brain barrier by an active transport mechanism called transferrin receptor-mediated transcytosis. This novel approach allows for more effective and rapid clearance of amyloid beta deposits and has great potential to improve therapeutic outcomes for people living with Alzheimer's disease. Next slide, please.
In the following, I'd like to walk you through some of our key results that we presented here in Vienna at ADPD yesterday. Both presentations were based on interim data from the ongoing Brainshuttle AD study of trontinemab. Next slide, please. Just as a quick recap, the Brainshuttle AD study is a randomized global double-blind placebo-controlled phase 1-B/II-A study in participants with mild cognitive impairment due to AD or mild to moderate AD. The Brainshuttle AD study uses a staggered adaptive study design and has four different parts. There is an initial dose escalation part or part one of the study. In each of the cohorts in part one, approximately 15 study participants are randomized in a four-to-one ratio to receive either the active drug, trontinemab, or placebo once every four weeks for a total of seven doses.
Following review of emerging data, then we've got the option to investigate promising dose levels further in the so-called dose expansion part or part two of the study. This is currently ongoing with cohort three and cohort four, so the two higher dose cohorts that showed favorable results in part one. The goal of the part two is to establish a more robust understanding of the pharmacodynamics and safety profile of trontinemab in a larger number of study participants, namely an additional approximately 60 study participants per expanded cohort. Without going too much into detail, there is also a partthree of the study in which we are currently assessing the effects of different dosing regimens on PK/PD and a part four, an open label extension part that is offered to all study participants who have successfully completed the first three parts of the study. Next slide, please.
Today, we would like to share with you the interim results from a most recent data cut that we did in November last year. These interim results included data from the meanwhile completed part two of cohort three, so 1.8 mg/kg , as well as data from approximately 1/3 of the cohort four participants, so participants on 3.6 mg/kg or placebo who had the opportunity to complete the double-blind treatment period of 28 weeks in part two. Next slide, please. You see the baseline characteristics of the study population at interim analysis. In total, 114 study participants were included in this analysis. In the combined part one and two data set in cohort three, we had 76 study participants on 1.8 mg/kg trontinemab or placebo and 38 study participants in cohort four who had the opportunity to complete the double-blind treatment period of 28 weeks.
Next slide, please. Let's have a look at the data and begin with the amyloid PET results. Again, as a quick recap, you see the results from the completed part one, the so-called dose escalation part of the study. We shared these results at CTAD of last year. At the two higher dose levels, 1.8 mg/kg and 3.6 mg/kg , trontinemab rapidly and robustly reduced amyloid plaques. A majority of the study participants fell below the amyloid positivity threshold after only 28 weeks of double-blind treatment. This is the part two data. What about part two? Go to the next slide. Next slide, please. Would it be possible to move to the next slide? Thank you very much. You just saw the part one results. This is now let me introduce to you the part two.
In part two, similar to part one, all participants underwent amyloid PET imaging at baseline and at the end of the double-blind treatment period of 28 weeks. What is special about this part two is that the study participants were randomized in a one-to-one-to-one ratio to three different intermediate PET time points, namely a day 50 PET after administration of two doses of the study drug, a day 78 PET. This is the same time point that we also used in part one after administration of three doses of the study drug, and a day 106 PET, a PET scan that was done after administration of four doses of the study drug. The objective of these different intermediate PET time points was to obtain a more refined understanding of the amyloid lowering trajectory and inform our PK/PD modeling activities. Next slide, please.
This is the results from these different PET randomization groups in part two. In the upper panel in blue, you see the results from the 1.8 mg/kg dose cohort. In the lower panel in purple, the preliminary results from 3.6 mg/kg . In agreement with what we previously shared from part one, there is a clear time and dose-dependent effect of the therapy on amyloid PET. We see a particularly early and deep amyloid plaque depletion at 3.6 mg/kg , so the higher dose level. At 3.6 mg/kg , you see that a near-complete amyloid plaque depletion appears to be achieved already at day 106, so after administration of only four doses of trontinemab, based, of course, on these still preliminary results from part two. Next slide, please.
This is the MMRM analysis of the combined part one and two amyloid PET results at interim analysis in November 2024. The adjusted mean change from baseline to week 28 is - 78 centiloids at 1.8 mg/kg and - 96 centiloids at 3.6 mg/kg . You see that the majority of the study participants, this is the table on the right-hand side, at 3.6 mg/kg is formerly amyloid PET negative, actually after 12 weeks of treatment already. Approximately 60% of the study participants are amyloid PET negative at 3.6 mg/kg. At study endpoint at 28 weeks, it's more than 80%, 81% of the study participants are amyloid PET negative at this higher dose level. Next slide, please.
If we now take a look at the participants who were treated with this higher dose, so 3.6 mg/kg in part one and two combined, and have a look at the distribution of the amyloid PET load at the different PET time points, this is the violin plot on the left-hand side, it becomes obvious that the depletion of amyloid is very robust at this higher dose level, even in participants who did not become formerly amyloid PET negative during the double-blind treatment period. The amyloid PET reduction in these participants is quite substantial. All of them are pretty close to the 24 centiloid amyloid positivity threshold by the end of the treatment period at 28 weeks. As you may appreciate from the violin plot on the right-hand side, there are essentially no non-responders to trontinemab treatment.
The minimum change from baseline that we observed at 3.6 mg/kg was - 47 centiloids, which is truly different from what we have seen so far with other agents, standard anti-amyloid monoclonal antibodies. Overall, very impressive effects on amyloid PET, especially at 3.6 mg/kg. We see a particularly rapid and early amyloid plaque depletion. Now, what about other markers of AD pathophysiology, including so-called downstream biomarkers in cerebrospinal fluid and plasma? Next slide, please. At the most recent interim analysis, we had the opportunity to look at multiple Alzheimer's disease biomarkers in cerebrospinal fluid, including the a beta 40/ 40 ratio and phospho-tau or pTau181 levels, two core markers of AD pathology, which are closely related to amyloid plaque deposition as well as to early tau pathology.
What we observed in the combined part one and two data set were dose-dependent, early, and pronounced effects of Trontinemab treatment on both of these markers, with both markers trending towards normalization at week 25 when we did the post-baseline CSF sampling in the study. Next slide, please. Importantly, we observed a very similar picture with neurogranin and total tau in CSF. These are two markers of synaptic and neuronal or axonal integrity, so markers reflecting neurodegenerative processes that are more downstream of the amyloid plaque pathology. These markers are significantly elevated in AD, and the observed early and marked decreases with trontinemab treatment that you see on this slide are, again, encouraging and reassuring, suggesting that trontinemab has indeed an early impact not only on amyloid, but also on important downstream biomarkers of AD pathophysiology, including markers of neuronal integrity and neurodegeneration. Next slide, please.
Last but not least, we also assessed plasma downstream biomarkers at the most recent interim analysis. What you see here are our preliminary results from the combined part one and two data set for the two key downstream biomarkers in plasma, namely pTau181 and pTau217 in plasma. In contrast to the CSF, where we had only one post-baseline time point, we were able to collect plasma samples more frequently in the ongoing study, in total at four different post-baseline time points, namely on day 22. These are the blue boxes that you see on this slide. On day 78, these are the purple boxes, on day 134, gray boxes, and on day 183 in green.
You may appreciate from this slide the dose and time-dependent effects of trontinemab treatment on both plasma p-tau markers, and again, quite pronounced and early effects with a median percent change for 181 of - 36% versus baseline and a median percent change for pTau 217 of more than minus of more than 50% versus baseline. The magnitude of the effects on these plasma p-tau markers is quite substantial and similar to what we've just seen on amyloid PET. The effects occur very early with trontinemab treatment. Next slide, please. Let's now shift gears and have a brief look at the blinded safety profile. The Brainshuttle AD study, as previously discussed, is an ongoing study. The data from participants receiving the active drug and placebo, these data are presented here together as cohort-level data to protect the blind at an individual participant level.
At CTAD of last year, we already shared that there were two serious adverse events in cohort three and part two that were deemed related or potentially related to the study drug by the PI. One was a grade one infusion-related reaction. The other, a fatal case of cerebral microhemorrhage that unfortunately occurred in a participant with evidence of probable cerebral amyloid angiopathy on screening MRI. We discussed the case extensively in our CTAD presentation. As you might remember, this serious adverse event led to a protocol amendment and the decision to exclude participants with superficial siderosis. This was the lesion that was present in this patient from the ongoing study, a decision that we made in agreement with the recently published appropriate use recommendations for other anti-amyloid therapies.
Apart from these two previously reported cases, there were no new relevant safety aspects at the most recent data cut in November 2024, and no related or unrelated SAEs in cohort four in part two. Next slide, please. What is and remains, of course, encouraging is the sustained low ARIA incidence with trontinemab treatment. The number of ARIA-E cases at the most recent data cut in November is unchanged from our last interim analysis that we did at the beginning of September 2024. We had in total only three mild or mild-plus ARIA-E cases. All of these cases occurred in cohort three on 1.8 mg / kg or placebo. There were no ARIA-E cases that were reported in the higher dose cohort four on 3.6 mg/ kg trontinemab or placebo as of cut-off date in November.
Interestingly, and this is important to note here in this fourth dose cohort, we had more than 75% APOE4 carriers and 18% homozygous APOE4 carriers. Next slide, please. Let's have a look at the two other relevant treatment emergent adverse events, which are infusion-related reactions and anemia. The anemia incidence in part two that we've seen has been limited so far, in particular in cohort four, so the higher dose cohort, where we only saw one out of 22 participants developing a transient and mild anemia. The infusion-related reactions, or IRRs, are still relatively common adverse events. They are generally mild to moderate in severity. Most of these events occur after administration of the first dose of the study drug and in the absence or with incomplete pre-medication. This has been the case both in part one and in part two of the brain shuttle AD study.
Our preliminary analysis of the study data, however, suggests that both the incidence and the severity of infusion-related reactions can be successfully mitigated and further reduced with corticosteroid pre-medication. This is something we have now implemented in the study protocol, which we recommend prior to administration of each dose of the study drug. Next slide, please. This is essentially the summary. The most recent interim data from part two of the ongoing Brainshuttle AD study confirm our previously shared results, namely rapid and deep amyloid plaque lowering and a particularly early amyloid plaque depletion at 3.6 mg / kg. At 3.6 mg / kg, more than 81%, more than 80% of the study participants, or 81% of the study participants were formerly amyloid PET negative after only 28 weeks of treatment.
Nearly all participants were near or below the amyloid positivity threshold at the end of the double-blind treatment period, and there were no amyloid non-responders to trontinemab treatment. Early and pronounced effects were also observed on several key downstream biomarkers in CSF and plasma. In plasma, we saw a remarkable reduction in plasma pTau 217 levels of more than 50% at 3.6 mg/ kg after only six months of treatment. Trontinemab continues to show a favorable safety and tolerability profile with very few ARIA cases, limited anemia, and manageable infusion-related reactions. These results are encouraging and support the continued development of the molecule, including our recently announced plans to initiate a phase III clinical program later this year. With this, it's my pleasure to pass it on to Alex.
Great. Thank you very much. My name is Dr. Alex Murphy, I'm going to take you through the Elevidys, the recent data that we've had from the Elevidys program in Duchenne muscular dystrophy. This is a gene therapy and was presented at MDA in March recently. If you move on to the next slide, please. Duchenne muscular dystrophy is a disease, inherited muscle disease, and the unmet need remains critical. This is a progressive, irreversible disease and leads to a very limited lifespan. DMD affects approximately one in 3,500 to one in 5,000 newborn males worldwide, and it's caused by a mutation in the Duchenne gene, which then encodes for dystrophin, which is a protein that plays a key structural role in preserving muscle function and stabilizing the sarcolemma. You can see in the diagram in the middle here really what patients go through.
From zero to four years of age, they may have some motor delays and other issues, but as they reach five to seven and then eight to eleven years of age, they really start to slow down, and it becomes much more obvious compared to the other children of their age, their peers. Eventually, they start to lose ambulation in their early teens or before. This is really where they start to become more dependent on caregivers at a time when their peers are becoming more independent. As they get to their late teens and their twenties, they start to have more cardiac and respiratory problems before an average lifespan of 28 years of age on average. If we move on to the next slide, please.
Elevidys is the first approved gene therapy, which is shown in a phase III trial functional benefit in a large number of patients. You can see on the left here, we have the overall gene therapy and what it's aiming to do. It is made up of broadly three parts. There is the vector, which is AAVrh74. This drives the safety and transduction of the molecule. We have the promoter, which is seen on the left. This is aiming to drive expression of the protein within tissues of interest. In our case, this is skeletal and cardiac muscle. In the middle, you can see the transgene, and this is using a shortened version of the dystrophin protein, which retains all of the important parts and therefore is functional to provide muscle stabilization, muscle cell stabilization, and then a functional benefit. Elevidys is a one-time application.
As I mentioned before, it's a first approved gene therapy, which has shown a functional benefit and gives you a potential broader patient population that can be treated than mutation-specific therapies, none of which are available worldwide. You can see on the right the clinical development program. We're going to mostly be talking about the EMBARK trial today, which is study 301. This is for patients who are four to less than eight years of age. We also have two other studies which are highlighted on this slide, the 302 EN VOL study. This is a Europe-only study for younger patients of zero to four years of age. We have the 303 trial, also known as ENVISION, which is patients who are older than eight years of age and is looking at late ambulatory, primarily non-ambulatory patients. This is a randomized control trial.
Elevidys meets the urgent unmet medical need for Duchenne muscular dystrophy for a disease-modifying treatment that can address the underlying cause of the disease. If you move on to the next slide, please. What did we show with the first part of the EMBARK trial? You can see kind of a summary of those results, which is on the forest plot, which is seen in the middle. Anything which is to the right of that line, which is over zero, you can see favors Elevidys, the gene therapy. You can see that all of these different endpoints, both primary, our key secondaries, and our other time secondaries, they all favor the gene therapy.
You can see for the North Star score, this was not statistically significant, but you can see that for four out of the five secondary endpoints, you can see that these were statistically significant and again in favor of the gene therapy. To the right, you can see that we have plotted the patients who we have followed up for the longest. These are our four patients from study 101. They have five years of data, which has been presented previously. What we have tried to do here is put this on centile charts, which is what patients with Duchenne muscular dystrophy would usually do. You can see if we just take, for example, the patient, the blue patient who starts off at just below the 25th centile, they get an initial gain, and then they stabilize their muscle function on the North Star score over a period of those years.
You can see that they end up on the 75th centile. What we are aiming really to do for these patients is to stabilize their muscles and to really move them across this graph so that they retain their ambulation for as long as possible. This is felt to be the most important thing for these patients. We have over 800 patients who have now been dosed with Elevidys globally in either clinical trials or in the commercial setting. There is U.S. approval for the treatment for ambulatory patients four to five years of age for Sarepta in 2023, with an expansion for patients who are greater than four years old in 2024. To date, this gene therapy has been approved in seven countries ex U.S., with the EU filing submitted in patients between three to seven years of age. If you move on to the next slide, please.
Without further ado, we'll move on to what's been presented at MDA. The two-year EMBARK results and the pooled three-year analysis. If you move on to the next slide, please. Here is the overall study design for the EMBARK study. Patients were randomized in a one-to-one ratio, 125 in total, to either receive the gene therapy or the placebo in part one. At the end of part one, as it's a crossover design, the patients in the gene therapy group then receive placebo, and those in the placebo group receive gene therapy. This means after the end of part one, we no longer have a placebo to compare against. We're going to be showing you some of our external control analysis to try and contextualize the results over two years.
You can see as well that our patients had a muscle biopsy at both week 12 and then 64 weeks after the start of the trial. This was for a subgroup of patients. On the right are the inclusion criteria, where you can see we've looked at patients between four to less than eight years of age and those who had a North Star score of greater than 16 or less than 29, with a time to rise of less than five seconds at screening. Again, we're going to talk about the two-year functional results. I'm going to show you our expression and sarcolemmal localization for those patients who were treated in part one. If you move on to the next slide, please. As I mentioned, we need to contextualize our results. We have developed an external control.
We've done this following the guidance from both the FDA, EMA, and ICH to try and make this as robust as possible. We use the following studies, which you can see highlighted on the left for DMD, BioMarin, and [Synergy] to make up our data sources. We use propensity score weighting using the entry criteria, which is on the right. We based our overall propensity score weighting on the very important clinically relevant things, which are below. If we move on to the next slide, please. This just shows the baseline characteristics for the two groups. You can see in the EMBARK trial, the patients who were treated, you can see in the middle column, and then to the right of them are the patients in external control after propensity score weighting.
You can see that for the majority of these endpoints, these characteristics, that we are reasonably well balanced, both in terms of the average and also the range, which you can see in the brackets. This is particularly relevant for the North Star score, the time to rise, and the 10 m walk run, as these are the most important things which help to decide on the trajectory of these patients. If you move on to the next slide, please. These are the overall results, again, using standardized statistics to compare these three endpoints compared to external control. You can see for the primary endpoint here, the North Star score was 2.88 points difference between the external control and the treated group. You can see that this is highly statistically significant.
We also see that for the time to rise and 10 m walk run, again, that these are favoring the gene therapy group and highly statistically significant. These are also considered to exceed the minimum clinically important differences. We believe they are providing a clinically meaningful functional benefit even after only two years. If you move on to the next slide, please. Just to give you an idea again of the trajectory of these patients over time. Here you can see the data which is kind of showing the external control versus the treated group. The external control here are the purple bars. You can see that our patients have gained over one year and then kept those gains over to the second year. This is in comparison to the gray bar, which is the external control, who are declining on the North Star score.
Now, the time to rise is a time to function test. It's how long it takes you to get up from the floor. Here you can see that both groups are beginning to decline. The treated group are declining at a much slower rate than is being seen in the external control cohorts there. If we look at the 10 m walk run, again, this is how long it takes to walk or run 10 m. Here again, you can see that our patients are relatively stable over those two years, whereas the patients in the external control have really begun to decline. You can see the delta which is being generated here is statistically significant. If you move on to the next slide, please. Moving on then to the expression results and the biological activity of the medication.
Here you can see the expression, which is measured by Western Blot. You can see that for the patients who were treated in part one, we have week 12 data and then week 64 data. You can see that we produce 34% on average percent of healthy dystrophin. You can see that that is 34% there. When we get to week 64, we see a stable expression of that protein, 45%, even a year after treatment, a year and three months after treatment. Below that, you can see the PDPF. This is the percentage of dystrophin-positive fibers. You can see at week 12, this is 28%. By week 64, you can see that that has increased up to 38.6%.
We're seeing not just expression being durable, but we're seeing this also that it's localizing to the correct place into the sarcolemma over the same time period. If you move on to the next slide, please. We wanted to show you this slide, which has been highlighted by key opinion leaders as being some of our most compelling evidence. It's an objective endpoint. It's using MRI to look at our patients and how much fat is being deposited in the muscle. In Duchenne, more fat is a sign of the disease progressing. Here you can see we've highlighted in particular, although we have shown you all of the different muscles we look at using MRI, you can see the vastus lateralis has been selected here particularly because in the literature, this is the one that's been most closely associated with prognosis and loss of ambulation.
If you have more fat, you can see if we look at the bar chart, you can see that the pink bar is the patients over one year. They gained 0.72% of extra fat over that one year, whereas the placebo group gained almost 4% of fat in the same time period. If you look then after the second year, those patients who were treated in part one, and that is the kind of purple bar, you can see that they've still only gained 1.56%. You can see that even after two years, these patients haven't gained what those placebo patients gained in one year. You can see again, objective evidence here that we're altering the trajectory of this disease. If you move on to the next slide, please. Just to touch briefly on the safety results. Primarily, we're going to talk about the two-year.
Between the weeks 52 and 104, we saw 15 patients experienced 34 treatment-related adverse events. One patient experienced two felt to be treatment-related SAEs of rhabdomyolysis, which both resolved. There have been no treatment-related AEs leading to death or discontinuation, and there were no clinically significant complement-mediated AEs. If you move on to the next slide, please. Here we have again, just showing you really when these adverse events tend to happen. Typically, this is within the first 90 days after infusion. We saw very few treatment-related adverse events after those 90 days during this trial up to the year time point again. We really know when the most important part of measurement and assessment for these patients is. If you move on to the next slide, please. Again, we're just going to touch on the three-year functional outcomes.
If you move on to the next slide, here we've taken three different early phase studies. Study 101, 102, and then study 103, also known as ENDEAVOR. We took patients who received the target dose, who were four to less than nine years of age, and had both baseline and year three assessment values. This is 50 patients in total across those different studies. You can see that we use a very, very similar method, as I've described to you previously, using the same studies for DMD, BioMarin, and [Synergy]. We use propensity score weighting again following those guidance that I mentioned earlier on. If you move on to the next slide, please. Here you can see the baseline demographics were really quite nicely balanced after propensity score weighting. You can see that's especially true again for the North Star time to rise 10 m walk run.
If you move on to the next slide, please. After three years, these patients, which it was a wider group of patients in terms of function at baseline, but you can see here that for the North Star score, our patients in the treated group, they are declining, but again, at a lower rate than the patients who were in the external control cohort. You can see there is a difference here of three points on the North Star score, and this is statistically significant. We can see for the time to rise and 10 m walk run a very similar appearance that you're seeing a decline for these patients, but less than you're seeing for the external control cohort. If you move on to the next slide, please.
Overall, if we just look to the right of this, you can see that we think as our understanding is developing, you can see that actually at different times, you may see a slightly different treatment effect. Treating at an earlier point in the disease, you may see an increased score or higher peak of the North Star score, for example. If you treat at a later time, we're aiming more for stabilization and slow decline. Even at a later stage, after loss of ambulation, there's plenty of muscle which still needs preserving. We're still looking at upper limb function. We're still looking at cardiac and respiratory function. We do believe that all patients could potentially benefit from this gene therapy.
What we've shown you today overall is that we see the results of the two-year and the three-year gold analyses versus external control are showing a clinically meaningful stabilization and a slowing of disease progression compared with well-matched DCs. We see a sustained microdystrophin expression and localization to the sarcolemma along. Effect up to 64 weeks. We also have shown you some safety outcomes here, which were consistent from our previous work on the Elevidys clinical development program. If you move on to the last slide, I think this is just QR codes for the host to soil handbag to our host.
Thanks a lot, Alex. I think we are ready to open the Q&A session. Besides our speakers, we will have four additional panelists. Let me quickly introduce them. There is Lauren Boak, life cycle leader for prasinezumab. There is Hanno Svoboda, life cycle leader for trontinemab, Jill Maria Thompson, life cycle leader at Elevidys, and Samir Megateli, our Global Disease Area Head for Alzheimer and neurodegeneration for the late-stage development. With that, we'll give the first question to Colin White from UBS. Colin, please. He seems to have dropped out. Let's go to Emmanuel Papadakis from Deutsche Bank. Emmanuel.
Thank you for taking the question, sir. Maybe one from trontinemab. Can you just remind us your late, in terms of next steps on the clinical development program, just remind us of your latest thoughts on a fixed duration approach in the phase III and where we are in terms of the phase III initiation timelines and what that study might look like? Maybe prasinezumab, it sounds like you're continuing to see some opportunity for continued development of the molecule despite two missed phase II studies. Just give us your latest thoughts in terms of where you go from here and potential future further clinical development. Thank you.
I can maybe start with trontinemab. The plan is to initiate, as shared at ADPD, the phase III study by the end of this year. Details on the design, duration, study population, etc., will be shared at upcoming conferences. We cannot comment at this point in time on these details.
I can jump in for the prasinezumab question. Yeah. We're just at the moment really looking into the data that we have. We are also awaiting some more mature open-label data, and then we will make a decision on next steps. We're not ready yet to share this. It will be happening sometime this year.
Understood. [Obligation]. Thank you.
Emmanuel, all questions asked?
All good. Thank you.
Yeah. We give it a second try. Colin White from UBS. Colin, please.
Hi. Can you hear me?
Yes, we can hear you.
Sorry about that. I don't know what happened. Just on trontinemab, I wanted to ask about the decision to move into phase III. Clearly, Brainshuttle technology is a new technology. Assuming that you move to phase III with 3.6 mg/k g dose, we've got data on about 38 patients. I just wanted to ask about moving straight to phase III as opposed to doing a larger phase II-B study with a dose that you might potentially take forward into the phase III and the confidence behind moving into phase III.
The second question, I guess, on prasinezumab is when we might expect to hear a decision on the program, are we waiting to the end of the OLE to get the data on that? I guess if you did make a decision on that, what the study would look like in terms of length, biomarker, human stage, etc. I'll stop there just now.
I can start maybe with the trontinemab question. Obviously, the decision to move into phase III is based on the totality of data from the ongoing study, which is still actually generating data. We will have more, as we speak, actually, we are generating data and data is emerging throughout this year. It is also based on the totality of data from the field as also shared in my presentation.
These insights from the field really suggest that this early and deep amyloid removal appears to be a prerequisite for efficacy. Everything that we have seen so far from the ongoing study with our molecule is actually very reassuring. The speed, the magnitude of the amyloid removal, as well as the effects on various downstream biomarkers that we are looking at, we shared some of those in this presentation, that also show early and pronounced effects. Markers that are closely associated with key aspects of the AD pathophysiology. All these together with the totality of data from the field is reassuring and, yeah, provides confidence in our decision to move ahead with the expedited development.
Yeah, I just wanted to add that at the ADPD conference, we have shown data from 114 subjects on two relevant high doses that show pharmacological activity and lead to amyloid plaque reduction to a great extent. We have looked at it extensively at the safety profile. We think that we know sufficiently enough to move this into the phase III trial.
I can jump in.
If you can just cover, I'm sorry, did you want to go?
No, go ahead, please.
I was just on the prasi question. We're looking at data this year and making a decision this year. It's premature to share any details of potential future study plans.
I just want to add for the prasi part also, of course, similar to each of these programs, we look at the totality of the evidence. That's important to keep in mind. As Lauren mentioned, we'll make the decision in due course.
Thank you. Colin, any additional questions?
I mean, yes, I guess I don't have another question on Elevidys. I wanted to ask, I know you said it's too early to speculate on how it might affect approval timelines and such, but obviously, Sarepta has come out today talking about the decision of the DMC that met on April 3rd. I just wondered if you could perhaps comment a little bit on that, what happens next. Also, if there's perhaps an acknowledgement from the EMA about the relative risk by age group, because obviously we're talking about EMA's looking at patients four to seven years old. Potentially there is higher safety risk at older age groups. I just wondered if you could comment on that.
Hi, this is going to you, Jill or Samir.
Yes, I'm happy to take the question. Thanks for the question, Colin. First of all, I just want to acknowledge that our partners, Sarepta, indeed posted today about the Independent Data Monitoring Committee that, of course, have been engaged yesterday to evaluate the impact of the tragic acute liver failure case on the ongoing clinical trials, which, to reiterate, are currently on hold. These are studies 104, 302, and also study 303, the ENVISION study. To address your question, what happens next? Certainly, we will be submitting the DMC's conclusions, which were essentially that this should not impact the ongoing clinical studies, and they should actually continue without any changes to the protocol. We will submit that to the European regulators within a week.
Of course, that is part of a broader investigation, which is ongoing in order to try to lift the temporary clinical hold, which, of course, is at the ultimate discretion of the EU regulators. We will continue to work closely with the relevant health authorities. To address your question around any acknowledgement by EMA and regarding the, is there a sort of discussion or acknowledgement perhaps of relative risk by age group, what I can say today is that obviously the tragic totality for the liver acute failure has been reported to EMA, and we are working very closely with them. You are absolutely right that within the current procedure in Europe, we are going for an indication between four to seven years of age in the ambulatory segment.
In terms of what happens next, Colin, we still, we have not changed our sort of direction that we're anticipating the CHMP opinion by the end of the year. Obviously, the filing submission by the EMA is ongoing, as well as other territories like Japan and other international territories. We do remain confident in the clinical benefit of Elevidys, which I think, as Alex mentioned earlier, in addition to the four to seven-year-old ambulatory segment, we've dosed over 800 patients today, both clinically and commercial settings of all age ranges and different sort of ambulatory status.
Thank you.
Very good. We move on in the queue. Next one would be William Wood. Can you please identify yourself?
Yes. Thank you for taking our questions. William Wood from B. Riley Securities. Very nice day today. We have two on trontinemab. For the first, could you speak to the cohort five dose and what you may be looking for in this dose, given the rapid CL clearance already demonstrated with a 3.6 mg/ kg dose? I have a follow-up.
Sure. Yeah. We cannot speak to the details of that dose. The dose, I mean, is also shared actually at CTAD, allows us to test, obviously, the same objectives that we are testing in part one or used to test for the other doses as well, which is PK, safety, PD. This is what we will be looking at, immunogenicity. These are the outcomes that will be of interest for that dose. Having this higher dose, so it is a higher dose than 3.6 mg/ kg being tested in part one, allows us to test a broader range, obviously, of doses and assess. Yeah.
I mean, yes, you mentioned that the effects on amyloid are quite impressive at 3.6 mg/kg. We will be testing the effects on amyloid at this higher dose level as well. At this higher dose level as well. Yeah, the objectives that we'll be looking at are the same as for the other doses.
Got it. Also, sticking on trying to just for one more, we were curious as to what your team might be seeing in terms of dropout rate, whether it might be related to IRR or maybe anemia related. Any color that we could receive on if there is an increase in anemia rate with longer-term follow-up, that could also be very helpful. Thank you.
Yes. No, thank you for this question. We had in part one of this study in cohort three, two discontinuations that were associated with grade two infusion-related reactions. However, in both cases, the participants were not premedicated at all, so not even with paracetamol. You might recall that we then in the course of the study introduced premedication, first with paracetamol, then meanwhile also with corticosteroids, and now also actually at each dose. Since then, there have been no discontinuations due to IRRs. Yes, I mean, they occur. They're relatively frequent, mild to moderate in severity. Most of them occur at the first dose, however, we do not see in the larger part two any discontinuations. Actually, anemia, there are, I am not aware of any discontinuation due to anemia. This is, and regarding potential incidents with chronic dosing, we have not seen this.
The 28-week treatment period, as you have seen also in my presentation, includes essentially monthly doses of the study drugs, so seven doses. The participants have the opportunity to transition into an open label extension study. We have meanwhile enrolled, just looked at the numbers, 110 study participants into part four into the OLE, and we have not seen any discontinuations due to anemia.
Got it. Very helpful. I appreciate it. Thank you.
Sure.
Okay. Next one would be David Evans from Kepler.
That's great. Thank you very much, Bruno. Hopefully, you can all hear me. Some questions all on trontinemab as well. Firstly, on the ARIA rates, I mean, remarkably low, less than 3% ARIA-E rates. I mean, would you say that that rate is able to be roughly compared cross-trial to the 13%-24% rates we've seen with the other two marketed amyloid antibodies, or are there any reasons that these rates are really not comparable? Also with the ARIA-H, less than 6%. Could you just remind us how regulators and doctors view the relative and absolute importance of both ARIA-E and H? Thanks.
We do not have head-to-head data, right? This is important to say. We are not comparing to other molecules here. It's also important to note that each trial has obviously a monitoring procedure with MRI scans taking place at different time points. In this study, we have very specific time points where we do the MRI scan to monitor for ARIA. As you rightly said, the ARIA incidence is pretty low.
In the overall datasets, clearly below 5%, potentially rather in the range of 3%-4%. Whether this is now in the ballpark of 13%, I mean, you need to tell me. I mean, I think this is what we see in that dataset that we are looking at today. Regarding ARIA- H, what we should mention here, ARIA- E is obviously the ARIA that is commonly also mentioned in the context of anti-amyloid treatments. We have not seen any ARIA- E that was associated with ARIA- H. The combination as of cut-off date in November. This is what you can also see in the table. ARIA- H occurs with a certain background incidence in the Alzheimer's disease population.
If you see a certain number of ARIA-H cases occurring in the different cohorts, you also have to take into account that ARIA-H incidence of microbleeds or also leptomeningeal hemosiderosis or superficial siderosis lesions can occur spontaneously in this population. Currently, we have an incidence of ARIA-H in the ballpark of, I think, 3-7%, which is pretty much the background incidence that we see in such a population.
The only thing I may want to add to Luka, just for transparency, this is the blinded safety profile that we reported. It includes both on active as well as on placebo in a four-to-one randomization, just in order to not overcalculate ARIA rates. The second point I wanted to make that Luka also pointed out during the presentation. This is a population, especially in the 3.6 mg/ kg dose, that should be at risk of ARIA due to the high number of APOE4 carriers and also homozygous. As we have reported in the data, we haven't seen cases so far. That makes us really confident in the safety profile moving forward. Clearly, these are still small numbers. We'll need more patients exposed to trontinemab to get to a more accurate point estimate. It's very, very encouraging data.
I just want to add too, because David, you asked, is it comparable? Luca said, well, you decide. Actually, I'm going to tell you. Of course, these are not head-to-head. However, we believe that that's one of the features of trontinemab that's there, and that is the low ARIA-E rates and less than 5%. It is also important to note that this is likely due to sort of there are biological reasons for this. Here we have a Brainshuttle anti-A beta antibody. I mean, it might be speculative, but the route of entry of trontinemab is likely to be different from conventional antibodies. This could well explain the low ARIA rates. The bottom line is that although it is not head-to-head, these are clearly low numbers.
Yeah. Excellent. Maybe if I could ask another question, just, I mean, in terms of other endpoints that you are tracking in the study, I mean, are you tracking actual cognitive functional endpoints? If so, might we see those towards the end of the study, or is that not being tracked at all?
Yeah, I can speak to it. Yes, we are collecting also clinical endpoints as exploratory outcomes in the study. What should be mentioned here is the study is not designed as such to, neither powered nor designed to properly, adequately assess clinical efficacy. The study, the double-blind treatment period of 28 weeks is very short, as you might know. Also, the study population is relatively broad, so it includes also a certain number of people with moderate Alzheimer's disease. It is a broader study population. We have a four-to-one randomization ratio. There are several aspects that essentially limit what we can do with these clinical outcomes, but we are collecting these clinical outcomes, and we will be sharing the results at upcoming conferences once we have completed part two of the study.
Okay. Excellent. Thanks very much. I'll get back in the queue, I think.
Yeah. Thanks. Very good. Next questions go to John Priestner from JP Morgan.
Hi, John Priestner, JP Morgan. Thank you very much for taking my question. Maybe one on trontinemab and also maybe one on Ocrevus as well. For trontinemab, how are you thinking about that potential phase III design, really in terms of what you may need to show for approval, but what you may also need to show for kind of broad reimbursement and uptake, and how that might actually differ? For Ocrevus, just wondering how the recent MUSETTE readout in RMS has changed your thinking about the GAVOTTE readout in PPMS and any kind of thinking around that. Thank you very much.
Hanno, would you like to take the question on phase III?
Yes, of course. As Luka has already outlined, we will not comment on the study or study plans at the moment. We will share this in the future and upcoming scientific meeting. I think it's very clear that we are very pleased to see that the first anti-amyloid therapies have been approved in a number of territories. However, we think there is still a very high unmet need when it comes to treatment of Alzheimer's disease, in particular for patients looking for more efficacious and safer therapies. I think that we are aiming to demonstrate this in upcoming studies, which will both facilitate approval, but importantly, will facilitate the access in a number of territories to the market.
Maybe I take the question on Ocrevus. Let me say that the results of the MUSETTE tell us about relapsing MS. The GAVOTTE trial is continuing in primary progressive MS, so that will continue until we see the readout.
What we have learned, though, in terms of what we've learned from MUSETTE, is actually in relapsing MS, we have been at an optimal dose. This is really important to convey here. There is a lot of evidence now for Ocrevus playing a very prominent role in relapsing MS with now over 11 years of work and over 400,000 patients treated with very favorable benefits and safety profile. Also, one other thing to say is that, of course, we have a rich pipeline. You heard about fenebrutinib. We also have other projects, other molecules in early development, including Brainshuttle CD20 and MAGL inhibitor. To your question, to repeat, the GAVOTTE trial will continue until we get the readout for that for primary progressive MS with a high dose.
John, do these answers help?
That's great. Thank you very much for taking my questions.
Yeah. And then we go back here to Colin White. Colin, do you have another question? Oh, seems that Colin, are you on? No, did not work. Maybe the final questions go to Matthew Barkus. Can you please identify yourself?
Hello, this is Matt Barkus on Andrew's [side. See Matt Jefferies. Just following up on your earlier question on Elevidys, you indicate that there is no change in direction, that the temporary study hold could be withdrawn soon with no material change in timelines. Do you remain confident in your prior peak sales guidance for the program, or is that something you plan to revisit?
Thanks for the question. Yeah, we have not changed our proposal of we are still guiding on $2 billion-$3 billion at peak at this stage. No change in our guidance there.
Appreciate it. Thank you.
Yeah. Then we will try it again. Colin White from UBS.
Hi, I'm so sorry about the technical difficulties I've been having. Just wanted to ask a question about the phase III study in general, because you get such rapid reductions in amyloid and bring patients to amyloid negativity. I know you're not sharing a trial design, but would you have to potentially incorporate something that would take patients off treatment of drug once they reached amyloid negativity, or would you just continue to treat them at that point for the duration of the trial? A second quick question was just if you could quickly remind us again, we've got upcoming data of your anti-latent myostatin. If you could just remind us how that's different from Scholar Rock's anti-latent myostatin, that would be helpful. Thank you.
I can maybe start with the trontinemab. As already said, it is really premature to comment on the details of the dosing strategy or the dosing regimen in phase III. Generally speaking, I think there are obviously different opinions in the field regarding the need for continuous dosing. There are actually many experts in the field who believe that some sort of maintenance therapy is required to keep the pathology of Alzheimer's disease low. Some sort of maintenance treatment will be required. Pathology may reoccur or reaccumulate in the absence of treatments with anti-amyloid therapies. This is what I can say on that. We cannot comment on any details of the plan design at this point in time.
I can take GYM329 question and others. If you'd like to add, please go ahead. Basically, the difference with Scholar Rock is that here we have an antibody that deploys a really innovative technology, the recycling sweeping antibody. That makes it very potent. We have actually a sub-queue approach to this. That differentiates it from Scholar Rock. Basically, what we're doing is we have a trial called the MANATEE trial, where it's a phase II component looking for a dose that would then be used in a phase III. Of course, we'd need to see the results of that. I don't know if Samir or others want to add to that, but that's basically where things stand for.
Maybe I can add. I don't know, Colin, whether you also asked about 329 in obesity. Oh, or was it only neuromuscular disease?
No, please go ahead with about obesity as well, please.
Yeah. You might know we've been doing a dose finding in obese patients, but otherwise healthy patients. We got these data in-house at the end of last year, December. It's a small sample. I think it's 1,000 patients, not more. Based on the data we have seen, we took the decision to take GYM329 in combination with one of the external incotrin-based drugs into phase II development. This is then either one of the two approved drugs on the market. The reason for that is that this just accelerates the development progress because these are approved medicines for a phase III program. We would, of course, have a development program where we would go with internal obesity molecules, but also eventually on top partner with externals as well. This phase II is thought to initiate, will start somewhere around mid-year.
One other feature that we should point out is actually that the GYM329 targets latent myostatin. So it is sort of that also differentiates it from the other antibodies that are out there, including from Scholar Rock.
Yeah. Maybe just the last compliment is that we expect these data later in 2025.
Thank you very much.
Yeah. Good. We have, I think, one final question, which goes again to David Evans from Kepler. I think we will close the call. David, please.
Excellent. Thanks. Thanks, Bruno. Just a quick last one, but just on the benefit that you see of getting to really low amyloid levels in the brain, again, on trontinemab. I mean, you kind of talked about your confidence that getting below, say, 24 centiloids is crucial. Do you have the same level of confidence or evidence that halving that level again to say below 10 centiloids and then halving it again to below 5 centiloids? I mean, are you very confident that that could correlate with better outcomes, or is there a kind of baseline level below which you think the incremental benefits would be limited? Thanks.
I mean, I can briefly comment on this. I mean, we do not have such detailed data at this point in time, whether a threshold of 5 or 10 centiloids. What we know based on our actually own meta-regression work that included essentially data from various phase III trials and that we presented at CTAD actually two years ago is that getting below the positivity threshold of 24 centiloids at an early time point is important.
The more people we get below this threshold, and that's, of course, a meta-regression of data and kind of an extrapolation. But based on this analysis, the larger the effects are on clinical outcomes. However, we do not have this, and that's actually something for future work to be done on the depth, like whether an even deeper threshold is more relevant or not. This is a work in progress. Yeah, currently, we know this for the 24 centiloids.
I just want to highlight that actually when we say evidence from the literature, this is a large body of evidence. It's not one study or two studies. It's sort of the entire field that it's been going at it for over two decades. What it tells us, as Luka mentioned, is the deeper you go, as you get to below that threshold of 24, and the faster you get to that, that gives you a good prediction of favorable clinical outcome. That gives us the confidence together with the fact that we see such low ARIA rates. These are the key results.
Maybe a comment. I mean, the more people you have, of course, very deeply cleared, right, the more likely you will have a higher proportion of people below the 24 centiloids. That is obviously a relationship that is obvious. In that regard, one could say that, yeah, it does matter how deep the clearance is at an early time point.
We have seen reports at ADPD from others that have shown also this relationship in trials, which makes us very confident. Getting back to John's questions earlier, that really makes us confident to position trontinemab as a best-in-disease therapy, both in terms of the effects that we want to achieve as well as the safety profile, backed by some of the low ARIA rates that we have been observing so far, as we discussed earlier. This should greatly help with both approval as well as access in the relevant markets around the world.
Excellent. Thank you very much.
Okay, very good. I think with that, we will close the call. I would like to thank again all our speakers for their engagement and the effort they put into the call, and also from the IR team members who worked on the individual slide decks, Sabine Born, Correba, and Richard Selvig. Last but not least, also Melanie Wolf, who was responsible for the overall call organization. I hope the event was helpful, providing the latest update on our neuroscience franchise, including some exciting early, now even late-stage assets. If you have any remaining questions, please reach out to the IR team. We're happy to assist you with any additional questions you might have. Wishing you all the best in these turbulent times and talk to you soon. Bye-bye.
Bye.
Thank you.