At this time, it's my pleasure to introduce you to Karl Mahler, Head of Investor Relations and Group Planning. Karl, the stage is yours.
Yes. Thanks a lot, Henrik. Welcome, everybody, to our 5th science call this year. We have 1 hour reserved for you, half an hour for presentation and half an hour for the Q and A. And of course, I mean, if you I have difficulties to enter into the Zoom system, which I don't assume now, but you can also, of course, drop me an e mail directly Karl.
Mahler roche.com. So I'm joined today by Katharine Wagner. She is the Vice President of Neuromuscular Disorders, clinical development with Roche. Many of you may know her from her previous jobs and engagement. She was a Director of the Center of Genetic Muscle Disorders of the Kennedy Krieger Institute.
She was professor at the Johns Hopkins University, and she's well known for her initiatives in the whole CNS field, but in particular, on the Duchenne disease research. I'm sure you will also may have some We have during the Q and A session also Paulo Ventura with us. He is the Head of the Development for CNS Simona Stjerdzernik, Head of CPS CNS section, so basically the marketing part. Paolo is doing the development part. We have also Kamita Patel with us.
She is the life cycle leader for Everest. Actually, we if you look at the key late stage news flow, we had a really good a year so far. I mean, we are in a very good way to file for this map by first half. So that is all on a good way for AMD and DME, 2 good readouts for the dual antibody to fight COV-two, the outpatient data and the post exposure prophylaxis. Tecentriq Was one of the focus of the last ASCO, the past ASCO, EdiVent non small cell lung cancer, actually received a very good feedback from ASCO.
And today, we are focusing on every Steve, type 1, 2 and 3 in SMA, a few data which we will focus a bit on. Just to do a bit of an advertisement for the rest of the year. We still have the Farmer Day upcoming at 14th September. An ESG event, We haven't done one for long, I have to say. It could be the worst one actually.
This year, we do a lot In ESG, we haven't done a lot of public announcements on it. And I think this is but we are really, let's say, doing a lot, Placing ourselves in the Dojo and Sustainability Index every year now as a number one position. So we felt that it's a good time to share some of those efforts with you. Then And we have ASH upcoming and also our digital event, which we do basically every year. If you look at the broad pipeline, which we have, In CNS, you can see that I dare to say we have the broadest and deepest pipeline in the and also a portfolio in the industry.
OCREVUS is launched. Feliputinib is in the Phase III. We have ENSPRYNG launched. This is in neuroimmunology. Neurodegeneration Alzheimer.
I'm sure you will have some questions on that part later on in Phase III reading out next year, Parkinson's Phase 2, 3 neuromuscular disorders, every is the focal point today. And one of the Prior research also from Katherine, DMD Duchenne, muscular atrophy and disease. So here, we have Also, we received some positive data, I have to say, from our partner recently and a bit in earlier stage pipeline neuro Development psychiatry, Engleman syndrome, which we just moved into Phase 1 in schizophrenia. So there is a lot to do. So if The focal point for today is basically on Eversity, meaningful evidence being generated across the fraud program this.
Spending types from 1, 2 and 3 SMA naive and pretreated patients, newborns to 60 years old. We have included also real world spectrum SMA data, which is good because here we have really an intensive research done over the past. And the focus today is on rainbow fish. This is basically infants from birth to 6 weeks old. Smaller patient numbers, I have to say, in the trial, but really, really nice data, very encouraging for patients.
And the JEWELFISH first trial in patients from 1 to 60 years old, a wide range of disease severity being presented at this year's conference. And with this one, I wanted to hand over to Catherine. Catherine, over to you, please.
Hello. It's a pleasure to talk to you today about interim data of Roche's JUULFISH and RISK rainbow fish at risky 4 SMA. And These findings add to a growing body of evidence or of RISD in a wide range of ages and types of SMA and help lead us in our understanding of how we can continue to Meet the ongoing unmet medical needs of the diverse SMA population. Next slide. So JEWELFISH is the first study of its kind.
Next slide. This study is in a broad age range types 1 through 3 and a diverse Heterogeneous population in terms of disease severity with many more severely affected patients that are usually enrolled in a clinical trial of SMA. And these patients were all previously treated with a disease modifying therapy for SMA. And our Primary analysis will be at 24 months, but we are presenting now some 12 months data on the safety, PD and exploratory efficacy data for the dual fish population. Next slide.
So here, you can see the study design and The primary objective of this trial, as I mentioned, is safety, but we will also obtain data on PK, GD relationships and some exploratory functional endpoints such as the MFM32. Next slide. This slide shows the baseline characteristics of the dual fish population, and I will just call your attention to final column where you can see, again, the ages range from 1 to 60, the types included types 1, 2 and 3, estimate copy numbers from 1 to 4. And the motor function Was diverse and more severe, as I mentioned, than many SMA trials. So for example, 63% of patients had a baseline Hammersmith Motor Scale expanded score of less than 10, And that is frequently an exclusion criteria for clinical trials.
And again, High degrees of scoliosis, 83% and severe scoliosis in almost 40%. So, this represents The real world, this represents what physicians will be seeing in their clinics. Next slide. So why would a patient or a caregiver enroll in Zulfish to receive Risdiplam. The reasons varied somewhat depending on what the previous treatment was.
So for those who had previously received a risk sorry, new to nursing, They chose to switch to primarily to treatment related tolerability concerns, Such as intrathecal administration, which was followed by lack of efficacy or a loss of efficacy and those Two comments on efficacy total of 30% of the population. Other reasons were caregiver In terms of those who have previously been treated with Zolgensma, The primary reason to enroll in JUULFISH and receive Risto plan was the hopes of an additional benefit in 57% caregiver preference and a lack of efficacy of the gene therapy were other reasons. Next slide. So there were very low rates of discontinuation in the JEWELFISH study, only 9 out of 174 enrolled patients Discontinued, this is 5%. And there were 76 patients who enrolled who had previously received nusinersen, 4 withdrew, and you can see their reasons for withdrawal below and then 14 patients had previously received Zolgensma and there have been No withdrawals from that cohort.
Next slide. There were no treatment related safety findings that led to withdrawal in any dual fish patients. And on this slide, you can see a total number of AEs and SAEs. There was only one Treatment related SAE. This was a child who had supraventricular tachycardia that the investigator felt might be related to the drug.
However, it resolved despite Risk transplant dosing continuing. Next slide. So the SAEs and VAEs In the JUULFISH population, we're very similar to what we have seen in previous SUNFISH The trials and are just reflective of the underlying disease. So remember, these patients have had SMA and the manifestations of SMA for many years from up to 60 years. And so, they have the morbidities associated with that including among the most high upper and lower respiratory illnesses.
Treatment with risdiplam. Their AE profile was very similar to that of other cohorts who have received different treatments and again very similar to naive SMA patients We received Ristiplam. Next slide. So, Ristiplam led to a rapid and sustained increase in the SMN protein levels in blood. And here you can see that SMN protein levels approximately doubled in the 1st month of treatment and then remained stable the year.
Next slide. After the presentation to now receive CRISTA plan, but we did also look at some exploratory efficacy measures And an interim data analysis demonstrated an overall stabilization in motor function at month 12 in patients who began to receive risdiplam following previous treatments. So this shows the change In the MFM32, which is a measure of both spine and gross muscle function, The importance of stabilization in this population, many of whom are older, many of whom, as I've mentioned, are severely affected. In fact, the SMA of Europe recently published a paper in neuromuscular disorders, where of 1500 responses, 97% of them said stabilization is indeed progress. Next slide.
So in conclusion, the dual fish population is broad and heterogeneous with a high degree of motor impairment at baseline, Reflecting the real world SMA population. The AEs and SAEs were reflective of underlying disease. Risk displaying treatment is shown as sustained greater than twofold increase in median SMN protein levels versus baseline. There were low rates of discontinuation and interim exploratory of efficacy data show that overall stabilization And motor function was observed in patients who began treatment with risdiplan following previous treatments. Again, the JEWELFISH study is ongoing and primary analysis will be conducted at month 24.
Next slide. So let's switch gears to talk about rainbow fish. This is a study of risdiplam in individuals with pre symptomatic spinal muscular atrophy. And as I'm sure you are well aware that Abristi has been approved in 44 countries for individuals 2 months older. However, ideally, We would really like to be able to treat babies before they had substantial motor neuron loss and before they manifest weakness.
And this is becoming more and more possible as newborn screening is adopted. So rainbow fish is looking to see what is the appropriate dose and the efficacy and safety of treating presymptomatic individuals. So, we can go on to the next slide. So this is a multicenter, open label, single arm study of risdiplan in infants with genetically diagnosed And pre symptomatic SMA, and they could enroll up to 6 weeks or 42 days at the time of their first dose. And the primary endpoint will be when this.
The population that is being studied for The primary endpoint, which is able to hold one's head for greater than 5 seconds at this month 12 has been reached. And there are a number of secondary endpoints, which include Functional and PKPD and safety. So we're going to report here the first Time of just the first five patients to reach this 12 month endpoint. Next slide. So the baseline characteristics of the 12 infants currently enrolled show that they have an age 16 to 40.
5 of them had 2 SMN2 copy numbers And 7 had greater than 2 copy numbers. And of the 5 infants that have been treated for Greater than 12 months, 2 of these infants had 2 SMN copy numbers And 3 infants had greater than 2 SMN copy numbers. Next slide. So we are just really pleased to see that infants treated with cresdiscipline for at least 12 months achieve motor milestones on par with their healthy peers. So 100% Have head control, 100% of sitting, rolling, crawling, 4 out of 5 Can stand unaided, 4 out of 5, walk independently.
1 is standing with support and balancing, and we have every reason to hope that he will also achieve these motor milestones. So 80% of the infants scored a maximum on the high knee 2 with a total score of 26. And this included 1 infant with 2 SMN copies And one infant with 2 SMN copies had a high knee 2 score of 23. And just to put this in perspective, An individual with 2 SMN copy numbers would most likely manifest as the Type 1 SMA baby who would have a high need to score of 0. Okay, next slide.
So another way of looking at this data is by looking at motor milestones over time. And the gray bars are the WHO windows of achievement in healthy individuals. And the symbols are the achievement of motor milestones As observed at the study visit, they're not necessarily when the motor milestone was first Demonstrated, but it's when they were first demonstrated in the clinic. And Some of the clinic visits were delayed because of COVID. But notwithstanding that, you can see that majority of individuals reached very complex motor function milestones, So just crawling on the hands and knees, standing, walking independently within the range of normal healthy infants.
Next slide. And the infants treated with risdiplam for at least 12 months this. Reached a near maximum CHOP INTEND score by 4 to 5 months of age. 4 out of 5 infants scored the maximum score of 64 and one infant scored A score of 63. And again, to put this in context, babies with 2, 3, 4 Estimate copy numbers rarely go above 40 on the TOPN10 score at any time And then dramatically decline in function.
So this is really showing us that Ristiplam has rescued the SMA phenotype from these individuals. Next slide. So there were no treatment related SAEs reported in pre symptomatic individuals treated with risdiplam. Again, here you can see the total number of AEs and SAEs. Next slide.
And interestingly, the AEs now were reflective of symptoms and signs that normal individuals under the age of 1 have. So Not reflective of underlying SMA, so nasal congestion, cough, teas being vomiting, etcetera. Next slide. So in summary, Rainbow Fish, this. Most of the infants treated for greater than 12 months achieved motor milestones Within the WHO windows for healthy children and as of the data cut, all 5 who had received VISTA plan for 12 months Reached the maximum score of 64 on the top intent.
There were no treatment related SAEs Reported in pre symptomatic infants treated with risdiplam now for up to 18.1 months. And so I think the risdiplam story is really the future of SMA where we treat individuals prior to their manifesting disease and allow them to grow up Last slide, I think. So just to summarize, DUALFISH was the first trial in a diverse SMA population ages from 1 to 60 who received prior treatment, Which showed a consistent safety profile and a greater than twofold increase in SMN protein levels and stabilization In motor function, in rainbow FISH, pre symptomatic babies with SMA treated with IBRISTA for at least 1 year were able to sit, And so, we are looking forward to completing These trials do fish and rainbow fish with speed and with quality and fulfilling our commitment to the SMA
Many thanks. Maybe Henrik, we can very good. We have now all of us here on stage in brackets. And I have already seen lots of interest in Q and A. Let's start with Emmanuel Papadakis.
Emmanuel, I open your line.
Thank you for taking the question. Emmanuel Papadakis from Deutsche Bank. Perhaps just a question on dual fish. You hopefully gave that one presented that one chart with functional benefit by MFM32. You didn't provide the split by patients that previously received Zolgensma versus SPINRAZA.
So could you just give us any kind of qualitative direction? Did it differ? Was it very similar regardless of what And then just your thoughts on the implications of that for justifying, I don't know if you call it combination use, but subsequent use of EVRISD for patients that have Previously received Solgen about either lack of apparent improvement in functional status. Does that Influence your thinking about whether that will be justified. And then second question, we saw some very interesting data at conference from apategromab Combination with SPINRAZA.
I would love to hear your thoughts on the potential implications of that and indeed whether you will now consider Collaborating, supporting a trial combination of risdiplam with apotecromab. Thank you.
So I think your question had 3 parts. The first question was whether we have seen differences in improvement or stabilization in function depending on which pre treatment or previous treatment the individuals have had. And as you saw, we have some fairly small Subgroups such as those who had soldesma were 14 patients. So we really haven't Done that type of subgroup analysis on the preliminary efficacy measure. Your second question, I believe, was to comment on the combined use of Zolgensma and risdiplam.
And I would first say that the wide range of Abrisci studies across ages, types and disease severities has shown efficacy So monotherapy of risdiplam. That said, there are currently families and physicians who are choosing to put children who have received gene therapy also on risdiplam. So that is part of the real world that is out there. We have hoped that JEWELFISH, we do hope that JEWELFISH will continue to provide us data on The efficacy and safety of doing so. We believe at this point that that is safe.
And as I've mentioned, we have just preliminary data on efficacy. I think the third question of SPINRAZA and RECISPLAN, I'm going to see whether my colleague, Kavita,
So with SPINRAZA and risdiplam, I mean, we've seen that Currently in the market, that 2 thirds of patients that have been previously treated are being switched from Spinraza for risdiplam today. So that does exist, as Catherine said that we do see previously treated patients being moved to Risdiplam.
And the potential agent which is here to do any kind of trial. So I have to admit, I have to skip this one. Maybe Paolo, do you have any idea? Or I'm not sure if there's anything planned here in terms of combination studies. If I heard it correctly.
Emmanuel, if you could
Yes, sorry. I mean, you can skip it if you don't have an answer. It was apategromab
Obviously, we don't have an answer to this one. So that means also most likely we have Anything planned at this point in time, I think the answer is given by the non answer, I guess. Okay. Did we address your question?
The Escolar Rock, It's the ColorROC
Exactly. That's the one. Yes,
sorry. Sorry, I just I wasn't quite aware you had an INN yet. But yes, so this is an interesting mechanism. We do have an internal program targeting myostatin, actually a really good molecule that's in Phase I trials right now. I mean, there's no firm plans yet, but certainly it's a mechanism that we think might be interesting as a potential combination partner for any of these therapies because it works via different mode of action.
So we're looking at those data. It's still pretty early. I don't know, Catherine, if you want to add anything on that.
I would just reiterate what you said that it is an interesting possibility to be able to continue to grow the atrophied muscle of SMA patients after the
Thank you.
Thank you. Thank you, Emmanuel. Richard Richard Folsom from JPMorgan. I open your line.
Hi. Thanks, Karl. Thanks, everyone. So just a question, firstly, looking at the JEWELFISH data by age, was there any benefit in younger patients. So stabilization in the overall population, any benefit if the patients were younger?
Second question on the stabilization of disease. Just any sort of payer feedback on their positivity about that sort of level of benefit. Clearly, patients like it, as you say, But any level of feedback there? And then just finally on the motor milestone benefits past 12 months. Are you continuing to see beyond 12 months?
I know it's early, but continuation of most milestone gains in the Rainbow Fish study. Thanks very much.
So I can dispense with the first and the last pretty quickly. And then the payer feedback, maybe Simona can address. So again, we have not Subdivided or done subgroup analysis on the efficacy, The exploratory efficacy of the dual fish. And in the rainbow fish, We do not have the data yet on post 12 months.
Maybe just this was payer feedback on Erisdi, right?
Payer feedback on Erisdi for the stable this, stabilization of the disease, yes.
I think Kavita has probably the best handle on these things. So I just would suggest maybe she provides that answer, yes.
Kavita, please, yes.
Yes. No, for sure. And I would say that you know from SMA Europe that patients are really excited about stabilization, 96%, 97% of patients See stabilization as an outcome that they're very excited about. And as it relates to payers, As these are early data, we haven't approached payers extensively, but we do see coverage Now in the U. S, where we're launched, we do see coverage in patients that are previously treated amongst U.
S. Payers.
Okay. So it's moving. Does did that address your questions, Richard?
Yes. Thanks, Karl.
Thanks very much. Thank you. Next one would be Simon Baker. Simon, I open your line.
Great. Thanks very much, Karl. A couple of questions on dual pitch. Just really going back To Richard and Emmanuel's questions. Do you have any data at this stage on efficacy by SMN2 copy number?
And will that be date if you don't have it now, will that data be presented when the trial is concluded? I'm just going back to Slide 18 With the just looking at the patient numbers there, I'm assuming those patient numbers have been impacted by missed appointments rather than dropouts. So can you confirm that there is still 165 patients in that study, I. E, 174 minuteus the 9 that have dropped out?
So, your first question about SMN copy number, Was that in reference to Jewel Fish or Rainbow Fish?
Jewel Fish, yes.
Jewel Fish. No. So, we have not broken that down by a copy number. In terms of assessment of patients in the JEWELFISH, this. There were only 9 withdrawals.
However, you are right that there were many this study visits because of missed study visits because of COVID. So for the manual sorry, the MSM32, for example, there were 134 patients assayed for that.
Michael Leuchten from UBS. Open your line. Michael?
Taking the same question backwards. Can you hear me, sorry?
Now we can hear you, yes.
Yes. Taking the same question backwards. Doubling of the SMN, but you do not see a change in functional score, At what level would you have expected there to be a change in functional score? Is that doubling a number that you thought might have triggered that? And if not, why not?
And then just because Paolo invited a question, I'll sign this. Paolo, for you. Given the change in the FDA stance to Potential future approvals, does that make any difference in the way you think about trial programs from your perspective? Thank you.
Katharine?
Yes. So I think I need a little clarification on the first question. So is the question, if we doubled the SMN The protein level would we have expected an improvement in function? Is that the question?
Michael?
And maybe what we could do is we could maybe go for the Alzheimer one. And I could Open your question later on, Michael, when the line is a bit more stable. Maybe, Paolo, you can go over the Alzheimer's one, please.
Yes, of course. I mean, it is an interesting question for speculation, I would say. I mean, the decision by the FDA around aducanumab is obviously precedent setting and opens up all sorts of new possibilities. It's the first time that the medicine is approved for a neurodegenerative condition based on a surrogate endpoint, essentially unchanged on the biomarker with supportive clinical evidence. And of course, up until now, this has been a little bit the dream of a lot of us who've been working in this area that you might be able
Now we seem to have an issue with the line for yes.
So maybe in the while Paolo
Maybe you could take it, Dixit.
So maybe I can just take a little bit since Paolo and I tend to talk about these Thanks quite a bit, right, apart from it. So maybe just I think where Paolo had left it. We've this is an interesting point in time where this point in time where potentially in neuroscience, the ways of getting approval Can potentially be based on surrogate, which is not an unknown path from the FDA, as we all know, right? It just has not happened in neuroscience so much. I think from our perspective, we're excited about this because that brings a new potential medicines to patients faster.
Asked. But it is going to be important to make sure that the surrogates are clearly correlated with clinical outcomes so that we end up generating the right data, short term and long term and be able to have the sustainable benefits to patients. We'll definitely be looking at these things ourselves in programs that make sense. I don't know if that answers the question, but it is an exciting time in neuroscience, I would say.
Yes. I mean, it's also a bit difficult to comment on those things at the moment as we didn't have any contact with the FDA since the approval of the aducanumab data and we take it now, let's say, take it from there. And we will keep you updated as discussions evolve. But I mean, what we have shared with investors in the meantime, I mean, unless we have now any other information for you, we would advise the market, let's Just go for the full line of a readout. At this point in time, that would be, let's say, prudent to do.
And then if there is something We keep you updated. So that's and our continuum update, I will read out in 2022. So this is anyway not too long time out from here. But just to give you a bit of perspective where answered.
Karl, could
I try to answer Michael's first part of his question? Sure.
No, please.
Yes. There may be a nuance to that, that I missed. But I think what he was asking with the doubling of SMN protein, would we have expected an improvement in strength rather just stabilization. And So we saw a doubling of SMN protein levels in all the FISH studies. And what is different about the dual fish is that there are patients who have severe weakness, low muscle mass, contractors, severe scoliosis and those all play a role in the response to treatment.
And so, no, I don't necessarily think that a very severe individual who is treated with risdipline will necessarily have the same response
Hi, Carlo. Sorry, I'm back. My laptop decided to die on me suddenly.
Gosh. Yes. It happens sometimes in this new world. Michael, I hope you could yes, I see that you are at a That's fine. No worries.
Michael, I hope we could address your questions. And I would Jo Walton. Jo Walton, open your line.
Thank you. My guess is Jo Walton from Credit Suisse. I I guess my question is along the same lines, and I'm looking at Slide 17. Forgive my ignorance here, but you've managed to double the level of SMA protein levels. How close do you get then to a normal healthy child?
And secondly, given that you appear to be able to double the protein levels in those patients who've Had prior treatment with Zolgensma, isn't this the ideal slide to show that you should be using dual treatment? And that if you can take Zolgensma, because presumably these were only the younger end of the range who were able to take that, you can that in itself must improve the protein. Then on top of that, you're doing it again. Isn't that an absolute shoo in for dual treatment?
Unfortunately, it's a little more complicated than that in that Our SMN2 protein level is measured in the blood because risdiplan Is delivered systemically and affects multiple organs. However, other treatment options such as Zolgensma, nusinersen have either targeted to CNS this. Or muscle or a different route of administration that would not Neither one of those would show up as SMN2 protein levels in the blood. The reason that we use SMN The protein level in the blood is that it is a non invasive way for us to measure, to have a biomarker of efficacy of risk discipline. So we don't need to do a lumbar puncture, for example, to look at SMN protein levels in the cerebral spinal fluid.
However, our preclinical data has suggested that ESAMEN levels in the blood are highly correlated to that in the CSF to brain to muscle.
And can I just ask if there's any view from the regulators or the payers about the concept of if you've taken the Zolgensma approach, are you finding that patients are finding it difficult to then add this on top or such a devastating disease that the payers are likely to accept
I'm happy to address that, Joe? And I think It's a great question from Ampere Lens. And as I said previously, I mean, in the U. S, the first market that we've launched, We have seen patients that were given Zolgensma gene therapy being treated with risdiplam. So there is some access in the U.
S. For this patient population. And as we see more data and now hopefully with JEWELFISH, there's even greater confidence in the safety that Risdiplam can provide in this population.
So there is a question from the chat, which I just read to you. Basically, I think, Kavitha, this is going to you. The question is from Diana Na, and she was asking about the Eversky uptake so far in the United States. Could you perhaps provide more color where patients are mainly switching from, are they more coming from SINAZA? Are they coming more from SORCENSMA?
And which uptake. Are you seeing evolistinarship being prescribed? So basically, if you could kindly give us an update on the U. S. Market dynamics.
And she was also asking about the Europe approval, a recent approval, if you could give us an update on where we stand at the moment with the first signs of the launch.
For sure. So I'll speak to the U. S. First, and we're really happy with what's happening in the U. S.
We see a really strong uptake of risdiplam plan across a broad range of patients. So similar to in our trials where we've been studies in a broad range of patients, we're seeing that In the market play out as well. And so what we're seeing is similar to what you see in the prevalence of Type 1, 2, 3, 25% of our patients are Type 1, 50% are Type 2 and the other 25% are Type 3. Question. You asked about what does it look like in terms of treatment naive versus previously treated.
We see about onethree of our patients are treatment naive. We see about on the SPINRAZA side answered. As Olgensma, it's still early in terms of the number of patients that are on gene therapy today in the U. S. So overall, a very strong uptake.
We are the fastest, I would say DMT post in this market, the fastest uptake we've seen thus far with the DMT in the U. S. Market. And we're seeing very similar performance now in Europe as well. So the most recent approval in March, we our first Country to launch is Germany.
And what we're seeing there is also very strong uptake In Germany, similar as we're seeing in the U. S, thus far, over 200 patients have been treated question. In Germany, within 24 hours of approval, we got a patient on product, which is fantastic and shows you that It's accessible to those patients in that market. And now we're seeing 6 weeks out, we're already over 15% market share. Again, very strong performance in Germany.
And as the other markets get up and running, we'll be sure to
Very good. Thanks a lot for the update. Next one would be Stephen Skalla from Cowen.
Two questions and actually they're both on Alzheimer's. But the answer to the gantenerumab question had all the appropriate conservatism, But there has been a major change in the landscape and Roche is best positioned to take advantage. So perhaps you can lay out the range of possible alternative pathways to approval that Roche is now exploring. And would one of them include a possible approval of gantenerumab this year? And secondly, initial Roche data on tau was disappointing, but Roche is another candidate in development.
Several competitors are following. Does Roche think tau is a failed target? Or are you optimistic that different agents with different target engagement could
The good news is, Paolo, that you are back online. So I would say we get calls to you.
That sounds good, Carly. And it's a good challenging question. I don't want to evade it. We are certainly looking at the full range of options right now, Okay. And the extremes, if you want, one of them is obviously a wait for the data readout from our graduate program, which should be coming second half of twenty twenty two.
And that obviously is the full data package, includes all the safety, all the efficacy, all the biomarkers, everything else. And that is still our base plan, by the way. That's still what we're doing. But we are looking at all the other options. And the other extreme range of the options is considering something like an accelerated approval based on biomarker evidence.
Of course, we don't know what that looks like. And this would require some sort of dialogue with the FDA, with the agencies to find out what data Standards will be want to have. And it's something that, yes, we're keeping open as an option for sure. But again, our base case continues to be that we want to have a full robust data set that includes the clinical data because that is what in the long term will matter to physicians and to patients. Of course, we understand it's a brave new world since last week and we're not blind to the multiple Regarding the question on tau, yes, I mean, we reported out the data from our Toriel study, which was the first ever attempt of using a monoclonal antibody against tau to try and have an impact on cognition and function.
And as you mentioned, the results were disappointing. Are a number of open questions even regarding that trial and also regarding another trial with the same antibody called LORIATE, which is being studied in moderate Alzheimer's the question. And the questions are around target engagement. We're still looking at our biomarker data to see whether we had enough drug on target and if there's any correlation with that. Secondly, we are we really don't know what the best population is to try these drugs in.
And of course, with amyloid, the general mantra has been that the earlier, the better. But it is really something we've learned along the years. And for TAO, we're just in the beginning of that journey. And regarding it being a failed target. I think it'd be incredibly premature to say that based on the evidence of 1 single Phase 2 study with 1 monoclonal antibody targeting one of the epitopes.
We are looking at other epitopes on Tau. We have other programs looking at Tau. I think generally to answer your question, Tau is Without a doubt, at least as far as I'm concerned, a super important target for Alzheimer's first and neurodegenerative conditions broadly. Yes. So we're still very, very hopeful about that.
Okay. If you could just continue here, I have one more from Marc Bessel, which goes into the same direction. If You could maybe talk about the advantages of any potential, the challenges of a subcutaneous administration approach with cantinerumab versus, let's say, IV aducanumab or Lilly's compound.
Yes, I'm wondering if maybe Sivan and I can share this one because I can speak from a physician patient standpoint. I mean, It's building in the 5 gs capacity is going to be a challenge necessarily. And obviously, in terms of convenience for patients, especially patients who are, yes, usually older and more incapacitated and need to be accompanied to visit, etcetera, etcetera, being able to administer at home, whether self administration or administration by a caregiver or by a nurse, I think it's going to be very, very relevant clinically, right? And we do have data showing actually have a lot of data showing that it's safe, it's well tolerated, You get the same exposure. So provided the data looks robust, I'd see it as a big advantage, especially for such a big population.
We're not talking about the rare disease with a few 100 patients. We're talking about millions of patients, but potentially globally. So I'd say that's a big advantage. But maybe Simone, you want to add comments from your side?
Yes. Just continuing where you are. So to me for me, asked if in this particular disease because the prevalence is so high, the I think finding ways to bring these patients out of the treatment. I think it's really, really important. Also from given the disease and the caregiver burden here, I think that's the other aspect that brings value to alternative ways to administer and to continue and to have appropriate compliance.
So I think this there's to me the differentiation on the administration side, I think it's really, really important and for patients and for the families. So I see that as a big advantage for us.
Thank you. We do have 5 more minutes. We have 2 more questions in the line. One is for the for us. One is from Peter Wolford.
Peter, I open your line
Hi. Thanks so much for taking my questions. I've really got just 2, but I'm basically still on the broader neurodegenerative Firstly, I think it was mentioned by Paolo, I think, Simona, I can't remember, that there are a number of surrogates that are well established. Curious which surrogates in your view are well established in euro as being correlated to clinical benefit and therefore could now be considered surrogates For an expedited approval. And then secondly, I guess, looks to know any comment that Roche may have on PET scans for Alzheimer's with regards to not so much thinking in clinical trials, but more your view on how that is evolving and availability of that in the real world?
Thank you.
Before you answer the question, Paul, I guess, this is coming to you. Michael Deuchten just was asking a similar question I just wanted to complete the line of questions. Paolo, please.
I'm sorry. So, surrogacy is It is okay. So there's a regulatory concept of surrogacy, which requires a certain level of evidence and obviously that the health authority declares it as a surrogate. And amyloid is the only one so far that has been declared as a surrogate, meaning that you can take that to substitute for clinical endpoint and get approval on, in this case accelerated approval on, okay? Scientifically, there are many other that have quite extensive evidence.
For example, tau levels Neurodegeneration are well known marker of axonal loss. Neurofilaments like chain in MS and in other conditions our well known market that is again associated with progression with neuronal loss. Some of the imaging markers that we see, whether those Our brain atrophy or hippocampal volume or ventricular volume, they've never migrated, if you want, to the level So you can see that the health authority would say, I'll give you approval based on this evidence. But for example, even in neuromuscular disorders. The precedent of using the expression of dystrophin in Duchenne for the Exxon Skippers is essentially a surrogate which has been used for an approval at least in the U.
S. Now one can argue and I think there are legitimate doubts and questions about the value of all these surrogates and how much They do correlate with clinical evidence. But I think the general point for neurodegenerative conditions has been that one of the key problems that we've had as a field in terms of making progress is the fact that we need very long, very large studies using endpoints which have a big signal to noise sorry, very small signal to noise ratio because of just the heterogeneity in these patients. Having surrogates that one can base, let's say, either an approval on or development on that are recognized by health authorities is or could be a really big development for all of us for this field, okay? The second question around PET scanning.
Well, it's certainly becoming more prevalent or more available for a variety of patients. It's still pretty much reserved though to tertiary health care centers because it requires pretty advanced technology, right? So it's never going to be as widespread, I would imagine, at least in the foreseeable future as CT scanning or even MRI scanning. So it's all going to be limited just because you need to have the ability to manufacture and distribute the radionuclides pretty fast. So for, again, millions of patients needing a diagnosis or qualification via PET, That is going to be a challenge.
That's actually one of the reasons why from the beginning, we developed a CSF diagnostic that could be used and is being used in our graduate program as the eligibility criteria for treatment. Because again, CSF testing is a much more widely spread technology that can be easily done. And now we have actually a diagnostic, which is after breakthrough designation by the FDA and is approved as a standalone diagnostic. So anybody can use that. So I do think for a broader based population screening, those types of tests are going to be more and more relevant.
Simona, anything to add from your side or?
No, no. I think I just said earlier, I think that was probably me when I said that we are excited about the possibility, right, that this approach Opens for not only for in Alzheimer's disease, but in other diseases. And since we are committed to neuroscience at Roche, I think that obviously is something that we're going to be looking at across. At the same time, making sure that we have the right science supporting it, right, Which ends up being important at the end to show the clinical outcomes. That's what matters to patients and to doctors and to payers.
So So I think it's important to do the whole package at some point or underway, but really do take advantage of this potential opportunity because it's not So easy to get to that clinical data. It takes a long time.
Absolutely. Last but not least, Sachin, I'll open your line from Noel Lynch, please.
Hi, there. Thanks for taking my questions. I have a few just quick ones on Alzheimer's again, if I may. So you've mentioned you're pending a meeting with the FDA. Have you requested that meeting as yet?
And do you have any timelines in mind? Secondly, Paolo, you mentioned one range is a Potentially accelerated file on biomarker. So I wonder if I could just explore that further. What biomarker data would that be? Is that the OpenRoad data, which contains some amyloid reduction at the highest dose rather than the Phase III scarlet and margarite data.
And if you could just comment on how you look at the quality of that data versus the amyloid reduction data that Biogen has in. The reason I asked the question is some of the physician feedback that we've had on that data is very strong given that you're getting amyloid negativity in a high percentage of patients. And then the third question is, as you discussed with the FDA, one assumes that they're open to some sort of proposal. So I ask a question as you think about the Brain Shuttle Gantt program, which is in the sort of sweet spot of potentially benefiting here. So just I'm sure you've discussed this internally, but what sort of proposal or thoughts do you have around an accelerated sort of Phase Q3 program when you think about level of amyloid reduction, number of patients and what cognition data would be given at this accelerated stage.
So apologies for those questions, but would love the thoughts.
Yes. Thanks, Seijin. And I think you may be over interpreting a little bit what I said, because I said we are thinking about having meetings with the FDA, right? So we've not We're not on the flight to Washington. There's nothing like that.
And of course, these are delicate conversations that we want to make sure to respect the regulators' time and viewpoints as well. So we are considering right now, okay? We have The range of options, we are thinking about them. So anything else is speculation right now, okay? Now regarding biomarker data, I mean, there's lots of data that we've been showing throughout the years and which is public.
As you mentioned, Marguerite Road, Scarlet Road data, now Open Road data. We think there's very interesting data there showing amyloid negativity after not so long of treatment period and after 3 years about 80% of people being amyloid negative. So and there's a dose response relationship. We've shown a lot of our modeling data that underlies are those predictions for the graduate studies. So there's quite some data, which is robust and public.
We've not had any conversations with the FDA, and therefore, we don't really know what type of data. If we were to explore that option, they would be interested in. I would imagine that data, which is public, might be a part of it. I don't know if it would be enough or if there would be requirements for, let's say, more safety data because it's a new material, it's G4 and the ROAD studies were done with So there's a number of technical complications, right? And then again, if we were to approach the agencies with this, we would be approaching it in a spirit for the option of working together to see what could be possible, right?
But I do think that it is a very interesting time right Because of the acceptance of amyloid biomarkers as a surrogate potentially for clinical outcomes, I mean, does beg the question, what type of data would be required, right? So again, we're just we're entering into this conversation with open hearts and open minds, knowing that this is going to be something if we explore that will take a lot of collaboration between the agency and ourselves. And it's sponsored by that now.
Yes. Thanks a lot. Yes. Thanks for your interest in Roche. I think what we could present to you today is really very exciting new data for Making good inroads in all markets, where it's already a bit established like in the United States, but also the first signs and signals in Europe With a 15% market share in a very, very short period of time actually speaks for the drug, speaks for the receptors In the market, there is clear evidence of best in class for type 1, type 2 and type 3 Data building here more and more.
We will hear more about the next weeks months on it. I'm not surprised that we had a lot of questions on Alzheimer, I have to say. As I said before, there is so much we can say at this point in time. It's a bit of a limitation on our side as well. I think you will understand it.
But clearly, the field is moving More fast than we would have expected 2, 3 weeks ago. So that is actually encouraging. And that brings me to a big thank this or Katherine for presenting the risdiplam data. Thanks to Kavitha. Thanks to Simona.
Thanks, Paulo. I also wanted to thank Jared from our team for taking the lead on that call, this, putting the Q and A together and the slides and the storyline and also Melanie for helping with the organization. Wishing all of you a nice day. It