Roche Holding AG (ROG) Earnings Call Transcript & Summary

Ladies and gentlemen, welcome to Roche’s [indiscernible] Investor Event. My name is Henrik, and I'm the technical operator for today's call. Kindly note that the webinar is being recorded. [Operator Instructions] After the presentation there will be questions and answers session. [Operator Instructions] One last remark if you'd like to follow the presented slides 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. And could I have the first slide, please? So welcome to our IR call focusing on latest clinical results for the neurology franchise and especially on the latest data, which were presented at MDA and ADPD. And let me quickly take you through today's agenda. We have today 3 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 prasinezumab in Parkinson's disease, which have been presented yesterday at ADPD. Our second speaker will be Luka Kulic, Global Head of Early Development Neuroscience and Rare Diseases at pRED. He will lead us through the updated Phase I, 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 [ trontinemab ] into late-stage development with the Phase III start planned now for later this year. And 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 2-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 #1 in neurology in terms of sales. Neurology sales account now for 20% of our 2024 pharma sales and 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 news flow items from our late-stage neurology pipeline. Firstly, on Ocrevus high dose. MUSETTE, 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. And 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 development, and these patterns go far beyond 2030. So we have communicated that we have modeled the total Ocrevus franchise to peak around 2029, and we do not expect a 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. And 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. And also to clarify here, we have never provided peak sales or quantify the incremental sales opportunity for Ocrevus high dose. We have previously communicated only once we have would have had positive study data for Ocrevus high dose. We would have provided this information. So 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 Evrysdi. Following the tragic news announced last week of a 16-year-old non-ambulatory DMD patients passing away from acute liver failure, the EMA has required that Roche and Sarepta put temporary clinical holes on three ongoing studies. This includes the Study's 104, 302 or ENVOL and 303 ENVISION. Patient safety is Roche and Sarepta's top priority and an investigation into the course of this tragic fatality is ongoing, and we are working with our partner, Sarepta with the uttermost urgency to gather information and make a full assessment of the event. Infection was expected 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 time lines. And with that can we have 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. So 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 pTau 181 test, formerly part of the Elecsys amyloid plasma panel is used as a rule out test requiring confirmatory testing for the CSF test. I will share the performance data of the pTau 181 test on the next slide as we presented here an update at ADPD. Second, we have the Elecsys better amyloid pTau ratio test for CSF samples, which is already commercially available and used for confirmatory testing of the immediate pathology. And finally, I would like to point out the Elecsys pTau217 test, which received FDA breakthrough device designation in 2024. pTau 217 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. 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 prospectus 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 EAAP panel as well as for pTau181 as an individual biomarker. Pending regulatory clearance, we hope this test will provide a minimally invasive block-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 health care systems worldwide. And to the next slide, please. This is just the unchanged key newsflow slide for 2025, as it was previously presented at the full year results. Highlighted in yellow are the remaining readouts for neurology -- for the neurology franchise with Elevidys approval still expected for later in the second half. The fanobrutinib readout expected at the very end of 2025 in Q4, also the GYM 329 anti-latent myostatin antibody readouts in SMA and FHSD expected for later this year. Next slide, please. And just to close from my side on the upcoming IR events. As you know, we have the Diagnostics Day on May 22, again, as a live event in London coming up and on June 23, we will host now a hematology IR call covering all the relevant data from the hematology summer conferences and ASCO. So we will have no separate call for ASCO this year. And 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. So as Bruno alluded to, we are in the privileged position of leading the field in neurology, therapeutics and diagnostics and this includes the portfolio. And 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, two of what we call end-to-end disease areas representing strongholds for us at Roche. And today, I'm going to give you a very brief overview of our portfolio and a few quick updates on just a few projects. And for the main part, as Bruno mentioned, we will, as the next slide shows, we'll focus on three projects, Alex Murphy will focus providing a recap of results on Elevidys in Duchenne muscular dystrophy. And 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. And as Bruno mentioned, both tronti and prasi 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. And I want to make 3 points here. So 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 left lower part of the slide, we are actually using innovative technologies already in clinic, including the brainshuttle technology, which Luka will elaborate on. And not shown on the slide and the third point is that we actually have a large and growing portfolio in research in neurology that feeds this clinical portfolio. And so let's -- I'm going to give you 3 updates quickly in MS and neurodegenerative diseases. So let's start with MS and this is on the next slide. So we are building on the success of Ocrevus in MS, and in one area, we are focused on fenebrutinib, which is a BTK inhibitor. So 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. And as such, it's been attractive because for both relapsing disease as well as progressive aspects of the disease. And 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 this slide, you see results of the FENopta Phase II results. So 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's sufficient exposure in the CNS. And on the right side of the slide, you see results of the open-label extension, which are equally striking to what we found in a double-blind period. And 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. I should also add that the safety profile is favorable, consistent with previous studies. And 96-week data will also be -- from the OLE will be presented later this year. And currently, we have 3 Phase III trials in MS with fenebrutinib, 2 in relapsing MS and one in primary progressive MS the latter with the comparator arm of Ocrevus and 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, and 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 beginning actually. So gamma secretase, as shown in the left panel, acts on this protein amyloid precursor protein and cuts it at several sites processively, and this leads to the generation of multiple types of Abeta peptides, including the amyloidogenic Abeta peptides, 40 and 42, but also other peptides, including Abeta37 and 38, which are non-amyloidogenic and previously, people have been interested in demo secretase and used what I would call a sledgehammer approach of inhibiting it. And 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 modulate it such that you have -- you produce less of the amyloidogenic peptides, Abeta40 and 42 and more of the 37 and 38 non-amyloidogenic peptides. And these results have been confirmed in Phase I trials in healthy volunteers, as shown in the middle panel, where you see in CSF in cerebrospinal fluid, reductions of the amyloidogenic peptides, Abeta40 and 42 and a concomitant increase of Abeta37 and 38. And currently, we're in a Phase IIa trial focused -- this is in people who are accumulating amyloid and who are either cognitively normal or have mild cognitive impairment. And the focus of this trial is on safety, tolerability, PK and for macro dynamic effects. And 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. So here, what I want to illustrate with this slide is that we're, of course, we're interested in neurodegenerative diseases beyond the core pathologies. So I'm going to talk about alpha-synuclein and prasinezumab and Luka will talk about amyloid in his part of his talk, but there are other targets, of course. There are co-pathologies, there are also targets within microglia that involves what's called the innate immunity and neuroinflammation. And so on this slide, what I'm showing you is that we are already moving on this and have an NLRP3 inhibitor. So NLRP3 inflammasome has emerged as a key player in neuro inflammation and from preclinical studies. And here, we have a Phase Ib the study that -- 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. And that, 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 IIb PADOVA trial, which was shared earlier this week at ADPD. And before I go into the results, I want to show you a couple of sort of introductory slides leading up to the PADOVA Phase IIb trial. So on the next slide, you will see a very brief introduction to Parkinson's disease. So Parkinson's is a progressive neurodegenerative disease. And as you know, the key cell type that degenerates in Parkinson's disease, are these dopaminergic neurons that are in the midbrain. And by the time diagnosis, people are diagnosed and symptoms are found, about nearly half of these dopaminergic neurons have already degenerated. And what we are learning is that this cell type continues to degenerate with progression of the disease. And 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. And so the expectation is that the prevalence will continue to rise in the coming decades. And this, of course, leads to enormous cost to people and their families to enter the health care systems. What's interesting about Parkinson's disease is that there have been symptomatic treatments for quite some time, dating back to the early '70s when madopar was launched from Roche, and there have been a number of other symptomatics since then. But until now, we still don't have treatments that actually alter the course of the disease. And this is where prasinezumab comes in, as shown on the next slide, with the potential to be the first disease-modifying treatment. Now what prasinezumab 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. And as the panel on the left shows once these neurons degenerate, aggregated alpha-synuclein and then it's thought to lead to the degeneration -- further degeneration of other neurons -- other dopaminergic neurons in the vicinity. And so with prasinezumab, what we're testing here is the idea that by binding to aggregated alpha-synuclein, we'd prevent the sell-to-sell 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. And here, I'm just showing you one piece of data, which is actually in the open-label extension part of the trial. And this is shown on the right side. Now here, we're compared -- 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 as population to our population. And as expected, you see that there's progression of the disease, meaning that the scores increase on the scale of the MDS-UPDRS Part III. And 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. But one thing you can see that you see the beginning -- the separation begins after year 2, suggesting that it takes longer or some time to see the effect of prasinezumab on slowing of the progression of the disease. So now let me move to PADOVA and tell you about what we found here. This is a Phase IIb trial where we tested prasinezumab on Parkinson's disease patients who are already on symptomatic treatment. And here, we needed to use an innovative approach to measure this a novel time to event to measure this to mitigate the effect, the potential masking effect of the symptomatic treatments. So 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-Bi inhibitors. This was a [ randomization ] factor, so 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 duration -- minimum duration of 76 weeks. So the last patient in was treated for 76 weeks. And 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 3.5 years. And then patients were rolled over in the open-label extension. And what I'm going to present are the results at the end of the double-blind period. So let's go to the next slide. So these are the baseline characteristics, which basically shows that they are well balanced across the treatment arms. And the key point from this slide is actually in the title of the slide, the [ by-line ], you see that nearly 3/4 of the participants were on L-DOPA. And now let's go to the next slide and begin to tell you about the results. So as I mentioned, we used a time to end point. Let me go through this briefly to explain this. So here, as you can see in the blue rectangular box, this is was defined as a change of 5 or greater points on the MDS-UPDRS Part III scale. This is motor signs. And this reflects a clinically meaningful change. And now as we have shared with you earlier, the primary endpoint was missed in that the statistical significance was missed. And as you can see, however, there are trends toward delaying motor progression. So in the primary analysis, as you can see, the hazard ratio is 0.84 with a p-value of 0.0657, so just missing the 0.05 threshold. This was done incidentally with where the co-variates were not taken into account. These are co-variates areas that are taken at baseline that predict progression. Now when you take that into account in prespecified analyses, supplementary analyses, you see that the hazard ratio improves to 0.81 with a nominal p-value of 0.03. And we also looked at the difference of medians, which is shown here at 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 to comment about L-DOPA. This is a common symptomatic. In fact, in some countries, it's used in 70% of the patients. And here, as you can see, the hazard ratio improves to 0.79 in the primary analysis for those where the co-variates were not adjusted for the co-variates and to 0.76 for those in the supplementary analysis where this was taken into account. All of these measures are prespecified. And in terms of difference of medians, this comes to just under 16 weeks or in other words, it takes about 32% longer for the people on -- 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. And here, we looked at the measure of function patient-reported function in the part II of the scale. And here, we used a time to event again in part because actually, we know that Part II, it takes quite some time. And for an effect to be seen -- and here, we define this as a time to a change of 3 or greater points on this part of the scale. Again, this representing clinically meaningful change. And I should add that here what we looked at to reduce the variability in those participants where there was a confirmed motor event. And as you can see here, there are, again, trends towards delaying the decline of function and 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%. And let's go to the next slide. And 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. And now I'd like to move beyond these endpoints and actually go to some exploratory markers that -- well, actually, before I go to that, let me tell you about the change in baseline. Now the change in baseline is something that is for the MDS-UPDRS part III. And as I mentioned at the beginning, it is -- 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. And so consistent with that, you see that at 76 weeks that actually there is no change between prasi and placebo. And this is the whole reason that we innovated for time to event, and you saw the trends on time to events. But even here, what's interesting to note is that from modeling disease modeling, as you can see a note on the right side of the slide, suggests -- this disease modeling suggests that you need more than 2 years to see a potential treatment effect of a disease-modifying therapy with a 30% effect size. And sort of consistent with that corroborating this, you will recall, I showed to you from the PASADENA open-label extension that they're actually -- you see the flattening of this scale as you go beyond year 2. And 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. And it turned out that we actually had more than half, about 56% of participants or 435 participants who had completed 2 years or 104 weeks and these results are shown here on the next slide, which are again prespecified. And as you can see, as you go beyond 76 weeks, you begin to see the trend, the separation of lines and by 104 weeks or 2 years, you see that in this -- with prasinezumab, you see about 35% relative reduction versus placebo of motor progression. And it's important to note that the baseline characteristics in the subsets were also balanced between the treatment arms. And within the L-DOPA subgroup, which represents 3/4 of the group, you see that this is maintained. And indeed, we see 40% relative reduction in prasi versus placebo with a nominal p-value of 0.0177. And now let me go to the exploratory markers that I wanted to tell you about, and now it's going to come here. So here, I want to take a couple of -- just a minute to explain this. These are exploratory. So 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. And in particular, in substantia nigra pars compacta, which is a part of the mid-brain that contains the dopaminergic neurons that are critical for the pathogenesis of Parkinson's disease from a circuitry perspective, that over time, you see a reduction in the intensity and volume of neuromelanin in the substantia nigra. And this actually, we -- so we looked at this. And 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 a substantia nigra pars compacta in the placebo group. However, interestingly, as you can see in the prasi participants. You see that actually this does not appear to occur. In fact, if anything, you see a trend in the opposite direction. And 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. And it's known that iron deposition accumulates. And this is, as expected, you see this in the placebo. So there's a change accumulation of iron in the putamen, as shown on the left side and the substantia nigra on the in the right panel, in the placebo group. And with prasi, we're seeing, again, a stabilization or a change in the trends in the opposite direction. So all of these results suggest trends toward reduction of iron accumulation and trends from the previous slide of reducing neuromelanin reduction. So let me go to the summary slide. So what I've shown to you from the PADOVA trial is although the primary endpoint was missed the time-to-event analysis show 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. And 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 maybe 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. And in fact, we see over 90% of participants who rolled over in the open-label extension. And this will be important as this will provide us with longer-term data. And finally, I showed to you the first biomarker evidence of a potential impact of prasinezumab on the underlying pathology in Parkinson's disease. So we're currently considering next steps for the prasinezumab program in Parkinson's disease. And with that, I'd like to thank, as shown on the next slide, acknowledge most and -- first and foremost, all of the participants and their families, investigators, the staff for really a tremendous amount of effort to this program. And 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 Ib/2a study of trontinemab in people with Alzheimer's disease. Next side, please. Alzheimer's disease, as many of you know, is the most common form of dementia and represents one of the biggest health care 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 Alzheimer's -- of Abeta in Alzheimer's disease pathology is well established and strongly supported by both neuropathological and human genetic evidence. Consequently, Abeta 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-Abeta targeting monoclonal antibodies. And 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 to 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 to 30 centiloid trials falling just short of that were negative. So 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 and our lead shuttle molecule trontinemab that you see on this slide, targets aggregated forms of Abeta 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 at Ghana at ADPD yesterday. Both presentations were based on interim data from the ongoing Brainshuttle study of trontinemab. Next slide, please. Just as a quick recap. So the Brainshuttle AD study is a randomized, global, double-blind, placebo-controlled Phase Ib/IIa study in participants with mild cognitive impairment due to AD or mild to moderate AD. The brain travel AD study uses a staggered adaptive study design and has 4 different parts. There is an initial dose escalation part or part 1 of the study. In each of the cohorts in Part 1, approximately 15 study participants are randomized in a 4:1 ratio to receive either the active drugs or trontinemab or placebo once every 4 weeks for a total of 7 doses. Owing review of the emerging data then we've got the option to investigate promising those levels further in the so-called dose expansion part or part 2 of the study. This is currently ongoing with Cohort 3 or cohort 4, so the 2 higher dose cohorts that showed favorable results in part 1. The goal of the Part 2 is to establish a more robust understanding of the pharmacodynamics and safety profile of trontinemab in a larger number of study participants, mainly an additional approximately 60 study participants per expanded cohort. Without going too much into detail, there is also a Part 3 of the study in which we are currently assessing the effects of different dosing regimens on PK/PD and a Part IV, an open-label extension part that is offered to all study participants who have successfully completed the first 3 parts of the study. Next slide, please. Today, we would like to share with you the interim results from the most recent data cut that we did in November last year. These interim results included data from the meanwhile completed Part 2 of Cohort 3, so 1.8 milligram per kilogram as well as data from approximately 1/3 of the Cohort 4 participants. So participants on 3.6 milligram per kilogram or placebo who had the opportunity to complete the double-blind treatment period of 28 weeks in part 2. 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 I and II data set in cohort 3, we had 76 study participants on 1.8 milligram per kilogram trontinemab or placebo and 38 study participants in Cohort 4 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, here you see the results from the completed Part 1, the so-called dose escalation part of the study. We shared these results at CTAD, end of last year. At the two higher dose levels, 1.8 and 3.6 milligram per kilogram trontinemab rapidly and robustly reduced amyloid plaques. And a majority of the study participants fell below the amyloid positivity threshold after only 28 weeks of double-blind treatment. This is the Part II data. But what about part 2? Go to the next slide. Next slide, please. So you just saw the Part 1 results and this is now -- let me introduce to you the part 2. In part 2, similar to Part 1, 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 2 is that the study participants were randomized in a 1:1:1 ratio to 3 different intermediate PET time points. So mainly a day 50 PET after administration of 2 doses of the study drug. At day 78 PETs. So this is the same time point that we also used in Part 1 after administration of 3 doses of the study drug and a day 106, a PET scan that was done after administration of 4 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. And this is the results from these different PET randomization groups in Part 2. In the upper panel in blue, you see the results from the 1.8 milligram per kilogram dose cohort and in the low panel in purple preliminary results from 3.6 milligram per kilogram. In agreement with what we previously shared from part 1, there is a clear time and dose-dependent effect of the therapy on amyloid PET. And we see a particularly early and deep amyloid plug depletion at 3.6 milligram per kilogram, so the higher dose level at 3.6 milligram per kilogram, you see that a near complete amyloid plaque depletion appears to be achieved already at day 1 and at 6. So after administration of only four doses of trontinemab based, of course, on these still preliminary results from Part 2. Next slide, please. This is the MMRM analysis of the combined Part 1 and 2 amyloid PET results at interim analysis in November 2024. The adjusted mean change from baseline to week 28 is minus 78 centiloids at 1.8 milligram per kilogram and minus 96 centiloids at 3.6 milligram per kilogram. You see that the majority of the study participants, this is a table on the right-hand side at 3.6 milligram per kilogram is formally amyloid PET negative actually after 12 weeks of treatment already. Approximately 60% of the study participants are amyloid PET negative at 3.6 mg per 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 of 3.6 milligram per kilogram in Part 1 and 2 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 formally amyloid PET negative during the double-blind treatment period. The Amyloid PET reduction in these participants is quite substantial. And all of them are pretty close to the 24 centiloid amyloid positivity threshold by the end of the treatment period at 28 weeks. And as you may appreciate from the violet plot on the right-hand side, there are essentially no nonresponders to trontinemab treatment. The minimum change from baseline that we observed a 3.6 milligram per kilogram was minus 47 centiloids, which is truly different from what we have seen so far with other agents to standard anti monoclonal antibodies. So overall, very impressive effects on amyloid PET especially a 3.6 milligram per kilogram. 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 [ Abeta 42:40 ] ratio and phospho-Tau or pTau181 levels, 2 core markers of AD pathology, which are closely related to amyloid plaque deposition as well as to early Tau pathology. And what we observed in the combined Part I and II data set were dose-dependent, early and pronounce the effects of trontinemab treatment on both of these markets, with both markets 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 2 markers of synaptic and neuronal or axonal integrity. So markets reflecting neurodegenerative processes that are more downstream of the amyloid plaque pathology. These markets are significantly elevated in AD and 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 an important downstream biomarkers of AD pathophysiology including markers of neuronal integrity and neuro degeneration. Next slide, please. Last but not least, we also assess plasma downstream biomarkers at the most recent interim analysis. What you see here are our preliminary results from the combined Part 1 and 2 data set for the key downstream biomarkers in plasma namely phospho-Tau181 and phosphoTau217 in plasma. In contrast to the CSF where we had only 1 post-baseline time point, we were able to collect plasma samples more frequently in the ongoing study in total at 4 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 a day 183 in green. You may appreciate from this slide the dose and time-dependent effects of trontinemab treatment on both plasma pTau markers. And again, quite pronounced in early effects with the median percent change for 181 of minus 36% versus baseline and a median percent change for pTau 217 of more than 50% versus baseline. The magnitude of the effects on these plasma pTau 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, end of last year, we already shared that there were 2 serious adverse events in Cohort 3 and Part 2 that were deemed related or potentially related to the study drug by the PI. One was a grade 1 infusion-related reaction. The other, a fatal case of cerebral micro hemorrhage 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. So this was the lesion that was present in this patient from the ongoing study, a decision that we made an agreement with the recently published appropriate user recommendations for other anti-amyloid therapies. And apart from these 2 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 4 in Part 2. Next slide, please. What is and remains, of course, encouraging is the sustained low ARIA-E incidents 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 beginning of September 2024. We had in total only 3 mild or mild plus ARIA-E cases. All of these cases occurred in cohort 3 on 1.8 milligram per kilogram or placebo. There were no ARIA-E cases that were reported in the higher dose Cohort 4 or 3.6 milligram per kilogram trontinemab or placebo as of cutoff date in November. Interestingly, this is important to note here in this fourth dose cohort, we had more than 75% ApoE4 carriers and 18% homozygote ApoE4 carriers. Next slide, please. Let's have a look at the 2 other relevant treatment-emergent adverse events, which are infusion-related reactions and anemia. The anemia incidents in Part 2 that we've seen has been limited so far, in particular, in cohort 4. So the higher dose cohort, where we only saw 1 out of 22 participants developing a transient in 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 premedication. And this has been the case both in part 1 and in part 2 of the Brainshuttle AD study. Our preliminary analysis of the study data, however, suggests that both the incidents and the severity of infusion-related reactions can be successfully mitigated and further reduced with corticosteroid premedication. This is something we have now implemented in the study protocol and which we recommend prior to administration of each dose of the study drug. Next slide, please. So this is eventually the summary. The most recent interim data from the Part 2 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 milligram per kilogram. At 3.6 milligram per kilogram, more than 80% of the study participants -- so 81% of the study participants were formally 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 nonresponders 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 milligram per kilogram after only 6 months of treatment. Trontinemab continues to show a favorable safety and tolerability profile with very few ARIA-E cases, limited anemia and manageable infusion rated 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.

So my name is Dr. Alex Murphy, and I'm going to take you through the Elevidys, the recent data that we had from the Elevidys program in Duchenne muscular dystrophy. This is a gene therapy and was presented at MDA in March recently. Can we move on to next slide, please? So Duchenne muscular dystrophy is a disease inherited muscle disease and the unmet need remains critical. This is a progressive, irreversible disease and it leads to a very limited lifespan. DMD affects approximately 1 in 3,500 to 1 in 5,000 newborn males worldwide and is caused by a mutation in the Duchenne gene, which then encodes for dystrophin, which is a protein which 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. So from 0 to 4 years of age, may have some motor delays and other issues. But as they reach 5 to 7 and then 8 to 11 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. And then eventually, they start to lose ambulation in their early teens or before -- and 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 20s, they start to have more cardiac and respiratory problems before an average lifespan 28 years of age on average. If we can move on to the next slide, please. So Elevidys is the first approved gene therapy, which 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 3 -- broadly 3 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 [indiscernible] cardiac muscle. And 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 onetime application. As I mentioned before, the 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. And this is for patients who are at 4 to that's in 8 years of age. We also have two other studies, which are highlighted on this slide, the 302 ENVOL study. This is a Europe-only study for younger patients, so 0 to 4 years of age, have the 303 trial, also known as ENVISION, which is patients who are older than 8 years of age and is looking at [indiscernible] primarily non-ambulatory patients. This is a randomized controlled trial. The 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. Can we move to the next slide, please? So what do we show with the first part of the EMBARK trial, so you can see the kind of 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 or key secondaries and our timed, other timed secondaries, they all favor the gene therapy. You can see for the North Star score this wasn't statistically significant, but you can see that for 4 out of the 5 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've plotted the patients who were followed up for the longest. These are 4 patients from Study 101. They've got 5 years of data, which has been presented previously. And what we try to do here is put this on centile charts, which is what patients with Duchenne Muscular dystrophy would usually do. And 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, and you can see that they end up on the 75th centile. So what we're 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, and this is felt to be the most important thing for these patients. We have over 800 patients who have now been dosed with a Elevidys globally in either clinical trials or in the commercial setting. There's U.S. approval for the treatment for ambulatory patients 4 to 5 years of age for Sarepta in 2023 with an expansion for patients who are greater than 4 years old in 2024. To date, this gene therapy has been approved in 7 countries, ex U.S., with the EU filing submitted in patients between 3 to 7 years of age. Can we move on to next slide, please? So without further ado, we'll move on to what's been presented at MDA. So the 2-year EMBARK results and the pooled 3-year analysis. So here is the overall study design for the EMBARK study, so patients were randomized in a 1:1 ratio, 125 in total to either receive the gene therapy or the placebo in part 1. At the end of Part 1, we then -- is it a crossover design, the patients in the gene therapy group, then received placebo and those in the placebo group received gene therapy. This means after the end of Part 1, we no longer have a placebo to compare against. And so we're going to be showing you some of our external control analysis to try and contextualize the results over 2 years. You can see as well that our patients had a muscle biopsy at worth week 12 and then 64 weeks after the start of the trial. And this was for a subgroup of patients. On the right of the inclusion criteria, where you can see that we've looked at patients between 4 to less than 8 years of age. And those had a North Star score of greater than 16 or less than 29 with a time to rise of less than 5 seconds at screening. And again, we're going to talk about the 2-year functional results. I'm going to show you our expression in cycle localization for those patients who were treated in Part 1. If we can move to the next slide, please. As I mentioned, we need to contextualize our results. And so we have developed an external control. We've done this following the guidance from both the FDA, EMEA 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 CINRG to make up our data sources. And then we use propensity score weighting using the entry criteria, which is on the right. And then we based our overall propensity score weighting on the very important clinically relevant things which are below. If we can move on to the next slide, please. So 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. And this is particularly relevant for the North Star score, the time to rise and the 10-meter walk run as these are the most important things which help to decide on the trajectory of these patients. If we can move on to the next slide, please. So these are the overall results, again, using standardized statistics to compare these 3 end points compared to external control. So 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. And you can see that this is highly statistically significant. We also see that the time to rise and 10 meter walk run, again, that these are favoring the gene therapy group and highly statistically significant. And these are also considered to exceed the minimum clinically important differences. So we believe they are providing a clinically meaningful functional benefit even after only 2 years. If we can move on to the next slide, please. So just to give you an idea again of the trajectory of these patients over time. So 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. And you can see that our patients have gained over 1 year and then kept those gains over to the second year. And 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 very -- is a time to function test, how long it takes you to get up from the floor. And so 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 external control cohort there. And then if we look at the 10-meter walk run, again, this is how long it takes to walk or run 10 meters. Here, again, you can see that our patients are relatively stable over those 2 years. whereas the patients in the external control have really begun to decline. And you can see the delta which is being generated here is statistically significant. If we can move on to the next slide, please. Moving on then to the expression results and the biological activity of the medication. So here, you can see the expression which is measured by Western blot. You can see that for the patients who were treated in Part 1, we have week 12 data and then week 64 data. So you can see that we produced 34%, on average, percent of healthy dystrophin. You can see that it's 34% there. And then when we get to week 64, we see a stable expression of that protein at 45%, even a year after treatment, a year and 3 months after treatment. Below that, you can see the PDPF, this is the percentage of dystrophin-positive fibers. And you can see at week 12, it's 28%. And then by week 64, you can see that, that has increased up to 38.6%. So we're seeing not just expression being durable, but we're seeing this also that it's localizing to the correct place into sarcolemma over the same time period. If we can 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. So here, you can see we've highlighted in particular, whether we have shown you all of the different muscles were looked 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 1 year. They gained 0.72% of extra fat over that 1 year, whereas the placebo group have 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 1, and that is the kind of purple bar, you can see that they've still only gained 1.56%. So again, here, you can see that even after two years, these patients haven't gained what those placebo patients gained in one year. So you can see, again, objective evidence here that we're altering the trajectory of this disease. If we can move on to the next slide, please. Just to touch briefly on the safety results. So primarily, we're going to talk about the 2-year. So between the weeks 52 and 104, we saw 15 patients experienced 34 treatment-related adverse events. One patient experienced two [indiscernible] treatment related SAEs of rhabdomyolysis was both resolved. There have been no treatment-related days leading to death or discontinuation and there were no clinically significant complemented mediated AEs. If we can move on to the next slide, please. Here, we have, again, just showing you really when these adverse events tend to happen. And typically, this is within the first 90 days after infusion. So we saw very few treatment-related adverse events after those 90 days during this trial up to the year time point, again. So we really know when the most important part of measurement and assessment for these patients is. If we can move on to the next slide, please. So again, we're just going to touch on the 3-year functional outcomes. So if you move on to the next slide. Here, we've taken 3 different early phase studies. So Study 101, 102 and then Study 103, also known as ENDEAVOR. And we took patients who received the target dose who are 4 to less than 9 years of age and have both baseline and year 3 assessment value. So 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 CINRG and we use propensity score weighting again following those guidance that I mentioned earlier on. If we can 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-meter walk run. If we can move on to the next slide, please. So after 3 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 are patients in the treated group, they are declining, but again, at a lower rate than the patients who are in the external control cohort. You can see there is a difference here of 3 points. On the North Star score and this is statistically significant. We can see if the time to rise and 10-meter walk run are 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 we can move on to the next slide, please. So 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. So treating at an earlier point in the disease, you may see an increased score a higher peak of the North Star score, for example. If you treat it a later time, we're aiming more for stabilization, slow decline. But 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. So we do believe that all patients could potentially benefit from this gene therapy. But what we've shown you today overall is that we see the results of the 2-year and the 3-year called analysis versus external control is showing a clinically meaningful stabilization and a slowing of disease progression compared with well matched DCs. We see a sustained micro-dystrophin expression and localization to sarcolemma, prolonged effect up to 64 weeks. And then we also have shown you some safety outcomes here, which were consistent from our previous work on the Elevidys clinical development program. If we move on to the last slide. I think this is just QR codes for the host. So I'll hand back to our host.

Thanks a lot, Alex. And I think we are ready to open the Q&A session. Besides our speakers, we're going to have 4 additional panelists. Let me quickly introduce them. There is [indiscernible], life cycle leader prasinezumab; there is [ Hannah Swoboda ], life cycle Leader trontinemab; Jill Maria Thompson, life cycle Leader Elevidys; and then [indiscernible] our all global disease area head for Alzheimer's and neurodegeneration for the late-stage development. And with that, we'll give the first question to Colin White from UBS. He seems to have dropped out. Then let's go to Emmanuel Papadakis from Deutsche Bank.

Maybe one in trontinemab. Can you just remind us you're late in terms of next steps in the clinical development program. Just wanted to see your latest thoughts on a fixed duration approach in the Phase III and where we are in terms of the Phase III initiation time lines and what that study might look like? And then maybe prasinezumab, it sounds like you're continuing to see some opportunity for continued development of the molecule despite two missed Phase II studies. So just give us your latest thoughts in terms of where you go from here and potential future further clinical development.

I can maybe start with trontinemab. So 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, et cetera, will be shared at the upcoming conferences. So we cannot comment at this point in time on these details.

I can jump in for the prasinezumab question. Yes. So 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 and we're not ready yet to share this. But it will be happening sometime this year.

Then we give a second try. Colin White from UBS.

So 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 milligram per kilogram dose, there's -- that's -- we've got data in about 38 patients. And so I just wanted to ask about moving straight to Phase III as opposed to doing a larger Phase IIb study with a dose that you might potentially take forward into the Phase III and the confidence behind moving in Phase III? And then 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. And I guess if you did make a decision on that, what this study would look like in terms of length by medication [indiscernible], et cetera, I'll stop there just now.

I can start maybe with the trontinemab question. So 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. So we will have as we speak, actually, we have -- when we are generating data and data is emerging throughout this year. But also it's based on the totality of data from the field as also shared in my presentation. And these insights from the field really suggest that this early and deep amyloid removal appears to be a prerequisite for efficacy. And everything that we have seen so far from the ongoing study with our molecule is actually very reassuring. So 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 earlier pronounced effects. So the markets that are closely associated with key aspects of the AD pathophysiology. So all these, together with the totality of data from the field is reassuring India provides confidence in our decision to move ahead with the expedited development.

Yes. I just wanted to add that at the ADPD conference, we have shown data from 114 subjects on 2 relevant high doses that show a pharmacological activity and lead to amyloid plaque reduction to a great extent, and we have looked at it extensively at the safety profile. So we think that we know sufficiently enough to move this into a Phase III trial?

I can just cover -- did you want to go?

No, go ahead, please.

I just -- on the prasi question. We're looking at data this year and making it a decision this year. and it's premature to share any details of potential future study plans.

Yes. I just want to add for the prasi part. Also, of course, we -- similar to each of these programs, we look at the totality of the evidence. So and that's important to keep in mind. And as Lauren mentioned, we'll make the decision in due course.

Yes, I guess, I don't have another question on Elevidys and I wanted to ask -- I know you said it's too early to speculate on how it might affect approval time lines and such. But obviously, Sarepta come out today talking about the decision of the DMC that met on April 3. And so I just wondered if you could perhaps comment a little bit on that, what happens next? And then also, if there is perhaps an acknowledgment from the EMA about the relative risk by age group because obviously, we're talking about EMAs looking at patients 4 to 7 years old. And it's obviously potentially there is higher safety risk at older age groups. So I just wondered if you could comment on that.

I assume this is going to you, Jill, or Samir.

Yes, I'm happy to take the question, and thanks for the question, Colin. So first of all, yes, I just want to acknowledge that our partner, 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. So to address your question, what happens next. Certainly, we will be submitting the DMC's conclusions, which were essentially that this should 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. So we'll continue to work closely with the relevant health authorities. To address your question around any acknowledgment by EMA and regarding the -- is there a sort of discussion or acknowledgment perhaps of relative risk by age group. What I can say today is that, obviously, the tragic fatality for the liver failures being reported to EMA, and we're working very closely with them. And you're absolutely right that within the current procedure in Europe, we are going for an indication between 4 to 7 years of age in the ambulatory segment. So in terms of what happens next, Colin, we will -- we still -- we have not changed our sort of direction that we're anticipating the CHMP opinion by the end of the year. And obviously, the filing submission by the EMA is ongoing as well as other territories like Japan and other international territories. So we do remain confident in the clinical benefit of Elevidys which I think, as Alex mentioned earlier, in addition to the 4- to 7-year-old ambulatory segment, we've dosed over 800 patients to date, both clinically and commercial settings of all age ranges and different sort of ambulatory status.

Next one would be William Wood.

William Wood from B. Riley Securities. Very nice data today. We have 2 on trontinemab. For the first, could you speak to the Cohort 5 dose and what you may be looking for in this dose given the rapid CL -- clearance already demonstrated with a 3.6 mg per kg dose? And then I have a follow-up.

Sure. So we cannot speak to the details of that dose. The dose -- I mean, has also shared -- actually, CTAD allows us to test, obviously, the same objectives that we are testing in Part 1 or used to test for the other process as well, which is PK, safety, PD. So this is what we will be looking at immunogenicity. So these are the outcomes that will be of interest for that dose. Having this higher dose, so it's a higher dose than 3.6 milligram per kilogram being tested in Part 1 allows us to test a broader range, obviously, of doses and assess. I mean, yes, you mentioned that the effects on amyloid are quite impressive at 3.6 milligram per kilogram. We will be testing the effects on Amyloid at these higher dose level as well. But yes, the objectives that we'll be looking at are the same as for the other doses.

And then also sticking on [indiscernible] for 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. And then 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.

Yes. No, thank you for this question. So we had, in part 1 of the study in cohort 3, 2 discontinuations that were associated with grade 2 infusion-related reactions. However, in both cases, the participants who are not premedicated at all. So not even with paracetamol. So 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. And since then, there have been no discontinuations due to IRRs. So yes, I mean, they occur, they are relatively frequent mild to moderate in severity. Most of them occur at the first dose, however, we do not see in the larger part to any discontinuation. And actually, anemia, there are -- I'm not aware of any discontinuation due to anemia. So 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 are 7 doses. And then the participants have the opportunity to transition into an open-label extension study. And we have meanwhile enrolled, just looked at the numbers, 110 study participants into Part 4 into the OLE, and we have not seen any discontinuations due to anemia.

Next one would be David Evans from Kepler.

So 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 rate is able to be roughly compared cross trial to the 13% to 24% rates, we've seen with the other 2 marketed amyloid antibodies? Or are there any reasons that [ these ] right to really not comparable. And also with the ARIA-H less than 6%. And could you just remind us how regulators and doctors view the relative and absolute importance of both ARIA-E and H.

So we do not have head-to-head data, right? So this is important to say. So we are not comparing to other molecules here. It's also important to note that each trial has obviously monitoring procedure with MRI scans taking place at different time points. So 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. So in the overall data set so clearly below 5%, potentially rather in the range of 3% to 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 data set that we are looking at today. So regarding ARIA-H, and so what we should mention here. So ARIA-E is obviously the ARIA that is commonly also mentioned in the context of anti-amyloid treatment. We have not seen any ARIA-E that was associated with ARIA-H. So the combination as of cutoff date in November. So this is what you can also see in the table. ARIA-H occurs with a certain background incidents in the Alzheimer's disease population. And so 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 incidents of microbleeds or also leptomeningeal [indiscernible] or superficial siderosis lesions can occur spontaneously in this population. And currently, we have an incidence of ARIA-H in the ballpark of, I think, 3% to 7%, which is pretty much the background incidents that we see in such a population.

The only thing I may want to add to Luka. So just for transparency, this is the blinded safety profile that we reported. So it includes both on active as well as on placebo and a 41 randomization just in order to not over-calculate ARIA rates. The second point I wanted to make that Luka also pointed out during the presentation. So this is a population, especially in the 3.6 mg per 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. So that makes us really confident in the safety profile moving forward. But clearly, these are still small numbers, so we'll need more patients exposed to trontinemab to get to a more accurate point estimate, but it's very, very encouraging data.

I just want to add to because David, you asked, is it comparable? And Luka said, well, you decide [indiscernible] so 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 quite -- that today, and that is the low ARIA-E rates and less than 5%. And it's also important to note that this is likely due to sort of there are biological reasons for this. Here, we have a Brainshuttle anti-Abeta antibody. And so I mean, it might be speculative, but the route of entry of trontinemab is likely to be different from conventional antibodies, and this could well explain the low ARIA rates. The bottom line is that although it's not head to head, these are clearly low numbers.

And maybe if I could ask another question. I mean in terms of other endpoints that you are tracking the study, I mean, are you tracking actual cognitive functional end points? And if so, might we see those towards the end of the study? Or is that not being tracked at all?

Yes, I can speak to it. So yes, we are collecting also clinical endpoints as exploratory outcomes in the study. So 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 very short, as you might know. And also the study population is relatively broad, so it includes also a certain number of people with moderate Alzheimer's disease. So it's a broader study population. We have a 4:1 randomization ratio. So 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 the Part 2 of the study.

Next questions go to John Priestner from JPMorgan.

Maybe one on tronti and then also maybe one on Ocrevus as well. So 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. And then for Ocrevus, just wondering how the recent MUSETTE readout in RMS has changed your thinking about the [ Gazyva ] readout in PPMS? And any kind of thinking around that?

[indiscernible], Would you like to take the question on Phase II?

Yes, of course. So as Luka has already outlined, we will not comment on the study or study plans at the moment. We will share this within the future then coming scientific meeting. But 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. And 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. And 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. So let me say that the trial -- the results of the MUSETTE tell us about relapsing MS. The [ Gazyva ] trial is continuing in primary progressive MS. So that will continue until we see the readout. What we have learned though as -- in terms of what we've learned from [indiscernible] is actually in relapsing MS we have been at an optimal dose. And this is really important to convey here. And so basically, 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. And also one other thing to say is that, of course, we have a rich pipeline. You've heard about fenebrutinib. We also have other projects and other molecules in early development, including Brainshuttle [ CD20 ] and [indiscernible] inhibitor. But to your question, to repeat, the [indiscernible] trial will continue until we get the readout for that for primary progressive MS with a high dose.

And then we go back here to Colin White. Colin, do you have another question? Colin, are you there. So then maybe the final questions go to -- Matthew Barcus, can you please identify yourself?

Hello. This is Matt Barcus on [ Andrew Seisein ] at Jefferies. Just following up on your earlier question on Elevidys, you indicate that there's no change in direction that the temporary study hold could be [ soon ] with no material change in time lines. But do you remain confident in your prior big sales guidance for the program? Or is that something you plan to revisit?

Thanks for the question. Yes, we haven't changed our proposal of -- we're still guiding on $2 billion to $3 billion at peak at this stage. So no change in our guidance there.

Then we try it again, Colin White from UBS.

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. Would you -- I know you're not sharing a trial design, but would you have to potentially incorporate some something that would take patients off treatment of drug once they've reached amyloid negativity or would you just continue to treat them at that point for the duration of the trial. And then a second question was just if you could quickly remind us again, you've got upcoming data of your Anti-latent myostatin and if you could just remind us how that's different from a [ Scholar Rock ] anti-latent myostatin that would be helpful.

I can maybe start with the trontinemab. So as already said, so it's 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. And there is actually many experts in the field believe that some sort of maintenance therapy is required to keep the pathology of Alzheimer's disease low. And that, yes, some sort of maintenance treatment will be required and that pathology may occur or reaccumulate in the absence of treatments with anti-amyloid therapies. So this is what I can say on that, but we cannot comment on any details of the planned design at this point in time.

I can take GYM 329 question and others if we'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. So that makes it very potent. And so we have actually a subcu approach to this. and that differentiates it from Scholar Rock. And basically, what we're doing is we have a trial called the MANATEE trial, where -- it's a Phase II component looking for adults that would then be used in a Phase III. But of course, we need to see the results of that. And I don't know, Samir or others you want to add to that, but that's basically where things stand for.

Maybe I can add -- I don't know, Colin, what you also asked about 329 in obesity or was it only new [indiscernible] disease?

Yes. Please go ahead on obesity as well, please.

So you might know, we have been doing a dose finding in obese patients. But otherwise, healthy patients, we got these data in-house at end of last year, December. It's a small sample. I think it's one dozen patients, not more. And based on the data we have seen, we took the decision to take GYM 329 in combination with [indiscernible] drug into Phase II development. So this is then either one of the 2 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, then we would, of course, have a development program where we would go with internal obesity molecules but also eventually on top partner with external as well. So this Phase II is [indiscernible] to initiate, will be -- will start somewhere around midyear.

One other feature that we should point out is actually -- is that the GYM 329 targets latent myostatin. So that also differentiates it from the other antibodies that are out there including from Scholar Rock.

And maybe just the last [indiscernible] as we expect this data later in 2025.

Good. Then we have, I think, one final question, which goes again to David Evans from Kepler and I think then we will close the call. David, please?

Just a quick last one, but just on the benefit that you see of getting into 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 which is crucial. But do you have the same level of confidence or evidence that halving that level again, say, below 10 centiloids and then having it again to blow 5 centiloids, is that -- I mean are you very confident that, that should correlate with better outcomes? Or is there a kind of baseline level below which do you think the incremental benefits would be limited.

I mean I can briefly comment on this. So I mean we do not have such detailed data at this point in time whether like a threshold of 5 or 10 centiloids. What we know based on our actually own matter regression work that included essentially data from various Phase III trials and that we represented at CTAD actually 2 years ago is that getting below the positivity threshold of 24 centiloids at an early time point is important. And the more people we get below this threshold at the -- and that's, of course, a meta-regression of data and kind of an extrapolation. But based on this analysis, the larger 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 like an even deeper threshold is more relevant or not. So this is a work in progress. Yes, 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. So it's not one study or two studies, sort of the entire field that it's been going at it for over two decades. And what it tells us, as Luka mentioned, is that the deeper you go and as you get below that threshold of 24, and the faster you get to that, that gives you a good prediction of favorable clinical outcome. And that gives us the confidence together with the fact that we see such low ARIA rates. So really [indiscernible] key results.

And maybe a comment. I mean, the more people you have, of course, very deeply clear, right? The more likely you will have a higher proportion of people below the 24 centiloids. That's obviously a relationship that is obvious. And in that regard, one could say that, yes, 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 make us very confident. And getting back to John's questions earlier, so that really makes us confident to position like trontinemab as a [ destine ] disease therapy, both in terms of the effect 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, and this should greatly help with both approval as well as access in the relevant markets around the world.

Okay. Very good. I think with that, we will close the call. I would like to thank again all of 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, [indiscernible]. And then last but not least, also [ Melane 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. And if you have any remaining questions, then please reach out to the IR team. We are happy to assist you with any additional questions you might have. And wishing you all the best in these turbulent times and talk to you soon. Bye-bye.

Bye.

Thank you.