To the live discussion of the symposium, a a beta targeting therapies in AD number one. So my name is Yonah Levites. I'm from Center for Translational Research in Neurodegenerative Diseases in University of Florida. And my co moderator is doctor Luca Kulik, and he will introduce himself, and then all the members of our discussion will introduce themselves.
Thank you very much, Edona. Yes. I'm Luka Kulic. I'm a neurologist by training and am a medical director working at Roche Pharma Research and Early Development in Basel and leading several Alzheimer's disease programs at Roche. And then I will hand over to Laura.
Thank you. My name is Laura Neisenbaum. It's a pleasure for me to be part of this session. I really appreciate the invitation. I lead the diagnostic pathway group at Biogen and am also responsible for the biomarker strategy for etiquette and map.
Thanks.
Michelle? I'm sorry. Okay. I'm Michelle Gee, and I'm in clinical development in the neurology business group at Eisai, and the clinical lead for the elenbecestat program, which was included the mission AD phase three trials.
And last but not least, Constantinos.
Hello, everyone. My name is Constantinos Aggarinos, and I am an MD. And I have a master's in medical research methodology. And I'm current currently a visiting fellow at the lab of Dimitrios Kapodianis at the National Institute on Aging, located in Baltimore, United States. Thank you.
So I hope we will get a lot of questions, from people about our talks. But for now, I don't see any yet. So we can, I think we can start use this time to ask among ourselves?
Just a little ask for for the audience, so please place your questions in the q and a and add also the name of the presenter that you would like to ask the question. Thanks. Donna?
I have one question for now to you, Luca. Very nice presentation. I was wondering with the levels of antibody that you detect in the brain, did you see any ARIA or any other severe side effects that we would expect from that much antibody in the brain in animal or in a human studies?
Thanks very much, for this very important and also very good question. And and the answer is short. No. We have not seen ARIA so far. However, we need to take into account that the models, that we used for the clinical molecule.
So the nonhuman primates, that we used, they do not have, over, amyloid deposition, at least at the ages, you know, when we when we, tested them. So, in the absence of amyloid deposits and also in the absence of good urine ARIA models, we were not able to to assess, the risk of ARIA in in in our preclinical models. We did not observe any ARIA or ARIA like events in the single ascending dose study in healthy volunteers. However, this study, as you might recall from the presentation, was done in young healthy volunteers. So the age range was 18 to 40 years, and that's on purpose because we wanted to exclude, this potential risk or confounder in in this very first study of r g six one zero two.
And no CAA or microhemorrhages in the mouse model?
No. No. I mean, there are not really, good ARIA models. I mean, increased microhemorrhages have been reported in the literature with antibody treatments, right, monoclonal antibody treatments in mice as well, but we did not really observe any anything like that. And no ARIAE.
Especially ARIAE is is a big problem for for preclinical models. Yeah. Thanks very much. Maybe I can then proceed with the next question, and maybe I will get the question back to you actually, I I really like your presentation on on the single chain variable fragment construct with the collagen domain. And I was wondering about the immune activity of this this collagen domain.
So, I mean, from what I understood from your presentation is that the presence of this collagen domain prolongs the half life of of the molecule in in in central nervous system and in the systemic circulation, and this is kind of the the the main rationale. But what happens then? Like, and and and in terms of the therapeutic, activity, so, is there is this domain recognized by real cells? Does it facilitate phagocytosis? What is your thoughts on that?
So, we actually looked pretty extensively at, mice injected with collagen domain by itself, and we did not see and we looked at the RNA Seq from those mice, and we looked behavior, and we did not see any changes or any kind of, effects from that. On top of that, our main problem with single chains is its short half life and instability. So prolonging the half life would be, we feel more beneficial than, problematic. And I see we have a lot of questions coming in. So we'll start with the first one For, Luca, have you seen any anemia or changes to reticulitis or red blood cells in the patients?
Curious about any potential target tox.
Right. Thank you very much for this question. I mean, it's an important question because, our r g six one zero two construct is a transferring receptor one binder. So this is a potential safety concern, anemia. What I can say is that in the single ascending dose study, we did not observe anemia and also no hematology relate to dose limiting adverse events.
What we did observe, and we will show a little more at upcoming conferences, so I I cannot comment today on the entire safety results of of of this study because this is a topic for upcoming conferences. We did we did observe and also in line with our preclinical observations are transient effects on reticulocytes that were obviously transient in nature and also based on our modeling predictions are not expected to result in anemia upon chronic repeated dosing, especially not in in the ongoing brain shot lady study in 80 patients. But this is, of course, something that we will be monitoring very closely in the in the brain shot lady study. And so especially Maybe I can then proceed with the question. Lots of questions for myself, actually, but we should also include the other presenters.
So I would have actually a question for Michelle and regarding elenbecestat. So you presented the the results from this full dataset analysis on elenbecestat from the MISSION AD study, and I found interesting that you observed this cognitive worsening in six months. So this was the finding that really, remained also, in the in the full dataset analysis. I was wondering, so how does that fit? Is this or relate to the other findings from other base inhibitors?
And, also, an an additional question on that is, with the other base inhibitors, there was this interesting finding that there were there was worsening on cognitive tests that are that are memory related, like ADAS call. But at the same time, there were there were improvements that were reported with these base inhibitors on, I think, verbal fluency tests. And so so I was wondering, yeah, did you observe something similar in with the LMX's thoughts?
So, Luca, thank you for your
for the questions. So starting with the mission AD dataset and the cognitive worsening. So there was subtle and transient worsening speed on the ADAS Cog 11 at six month time point. It was not present twelve month time point or the latest time points, including the the main twenty four month time point, and not seen in in other scales either. In terms then of how that compares to other base inhibitors, I think, as you know, several base inhibitors have now seen some aspects of cognitive worsening, but they are there are slightly different attributes, between them.
So I think then they're they're not necessarily looking the same amongst the different base inhibitors. In terms of what perhaps was driving the ADAS cog worsening that was seen at the six month time points in the mission AD dataset, We have looked into that. And in terms of specific items, it was really being driven by word recall and by word recognition, in in the full mission AD dataset.
Thank you very much.
I'll have here's another question for you, doctor Coolidge. Does any data exist on expression of TFR one in elderly versus young?
That's the so it's I mean, which system? So hematopoietic brain or or general. This is not specified, I guess. I guess. I I think it's a it's a very good question because the target population is, elderly.
I am personally not aware of of of any studies that looked at changes of a transferrin receptor one during aging in, for example, at at brain vasculature. This is something that Timothy is not aware of. But an important question, yeah, because, our patient population is elderly, 80 patients.
And a question from, Fadi Rofa from Uppsala University. He's asking if, you've measured different species of abeta, protofibrils, fibrils, clearance in your in your studies.
This is a question for me?
Yes.
In, which studies exactly? So is this the human study?
Think what they your clearance of abeta if you've confirmed rotofibrils, oligomers, fibrils clearance.
I guess this might
totally better.
But this relates to preclinical experiments in in in mouse models. Okay. We did not specifically look at at oligomeric species. So so the the preclinical experiments I'm aware of and and that I presented in this meeting, there we mainly looked at at essentially ELISA and and also histology. So these were the readouts.
But we did not, to my knowledge, look specifically at certain oligomeric species, like protofibrils or other oligomeric species. Alright. Then so we have a question for Laura. So the CSF LumiPulse assay, has this been approved for screening or diagnosis, and will it be reimbursed by insurance?
Thanks, Luca, and thanks for the question to the audience. In The US, this ask this test, this in vitro diagnostic test, has been submitted to the US FDA, for five ten k five ten k clearance and is currently under review. These assays also are CE marked in other regions, globally. So that's the current status.
Maybe I can follow-up on on on, that question and, as a take home message from your presentation, so it sounds like that the CSF assay and and and the amyloid PET can be used essentially in an exchangeable manner. Is this, do you envision this also for the future if, for example, edoconumab, gets approved that, we could treat patients who only had CSF analysis instead of an amyloid PET imaging?
So in the current status, obviously, the amyloid PET tracers, are approved, in The US, and the CSF tests have undergone review or are undergoing review by the FDA. Certainly, once those are approved, this would provide a mechanism for being able to use CSF as part of the confirmation of amyloid pathology. So certainly in the future, that would be a path by which the amyloid confirmation could occur.
Do you envision, maybe just an additional question on that? Do you envision that also the therapeutic effect, will, to to some extent, have to be monitored by either amyloid PET or or any other markers, maybe CSF biomarkers. So the the pharmacodynamic effect of the treatment, or or is it yeah. What are the discussions there? So do we need to show that that educaramat really reduces amyloid burden also in when it once it gets gets approved?
So, Luke, great question. Thanks so much for that. Really, what we focused, with this dataset was looking at whether the CSF LumiPulse assay would provide, concordance with screening samples. Clearly, any work looking at monitoring, we would need to look at subsequently. Thanks.
Thank you.
Your question probably to Michelle. Does BACE inhibitor have a future in Alzheimer's disease, and what would be primary aspects of improvement?
K. Thank you for that question. I think I think it's fair to say that base inhibitors have a very high hurdle if they are going to progress as a treatment in in AD. And, you know, looking across the base inhibitors, one of the commonalities is that we haven't yet seen demonstration of clinical effectiveness in early AD. So that is an incredibly high level, ahead for this class.
K. Thank you very much. Then a question maybe for Konstantinos. And, so thanks very much for for this very nice, meta analysis of of different, anti amyloid, antibodies and and the randomized controlled trials of these antibodies. So, clearly, there are differences, obviously, between the antibodies, which were assessed in this meta analysis.
So the question which I have for you is, is this reasonable? Is this is this a reasonable approach to combine all these different antibodies in in one meta analysis that assume essentially class effect. Right? Given the fact that the MOA so the mechanism of action may be really different between the antibodies. We know, for example, solanexumab mainly binds monomeric beta, while aducanumab, gantenerumab, the bench four zero one, buying more aggregated data.
So what is what is your thoughts on that?
That is a great question, and thank you for asking this question. So that was exactly the reason that this in addition to the main meta analysis, we performed the subgroup analysis. First of all, we divide we performed the meta subgroup analysis based on the individual drug, but then we performed additional, subgroup analysis based on the mechanism of action. And we also performed the meta analysis, subgroup analysis based on the possibility for amyloid related imaging abnormalities. And in general, these subgroup analyses did not reveal any, substantial differences between the subgroups.
But, what we found was, for the drugs that, were a little nonspecific to the target. These drugs were, vapinezumab and curenesumab, and these drugs, did did not have any clinical effect. The other group was, of course, aducanumab and gatenerumab. These two these two drugs had were targeting oligomers and febrile, and they had some positive effects. And, the other, drug, the other subgroup was solanezumab, which was the only drug to target monomer monomers only and also had some positive effect.
So, the conclusion is that, from the subgroup analysis based on the target, we found that, drugs that have nonspecific targets do not tend to produce effects. So we, we have still to verify that, with future data and future analysis, but, this is what, we found in our subgroup analysis. And that was a great question. Thank you.
Thank you very much.
Question to Laura. If you measured any other biomarkers in the CSF related to inflammation, synaptic plasticity,
Thanks, Yuna, and thank you again to the audience for that question. It's a very interesting question, and, obviously, there are many exploratory biomarkers that have, been identified recently, with recent studies. And what we did, with the aducanumab studies at this point is really prioritize the established biomarkers related to Alzheimer's disease so we could, get an assessment of what was happening within that AAT and framework. And, we will, certainly in the future, explore the additional explore other biomarkers to look to see whether there might be impact in some of these other areas. Thanks.
Laura, from my side, maybe a question. So, I mean, I think there there is a great interest actually in the CSF biomarkers also upon treatment, Right? Especially with such an antibody like aducanumab that really reduces significantly the amyloid burden. My question for you is, like, do you already have any data on that? So what happens to the CSF biomarkers you looked at screening upon treatment?
So how do they change? And, also, in particular, to a beta 42 in CSF, do you know, like I mean, does it normalize over time once flux really gets cleared from the brain? Do we have anything, or are you able to share any information on that?
Sure. Happy to address that question. It's a very important question. And in fact, some of this data has previously been shared at CTAD last year, and, I also direct those interested in further understanding of the efficacy and safety data to the presentations that will be shared on Saturday. In the previous disclosures, we showed that there were some changes longitudinally as you might expect to see for some of these CSF biomarkers.
In particular, there was a reduction in CSF p tau and t tau. And, again, I would encourage you to look at the tune in for the presentations on Saturday for further information.
Go to the presentation.
I have a quick question to you, Luca, and then there is one from the audience. In your impressive preclinical data, is this the only one antibody that you've tested with the conjugation of TFR, or there are many others? Were they similarly improved?
In terms of exposure, I guess, this is the question. So we are exploring I mean, this is a brain shuttle platform. So this is so we are exploring certainly also other mechanisms or other large molecules that could be used as cargoes for for the treatment of of of different indications, actually. And this is essentially the most advanced program that is now in the clinic.
So I meant the other way around. Did you test other antibodies with this?
You you mean, anti amyloid?
Right.
No. The answer is no. So, from the very beginning, this was clear. I mean, it's also a big, opportunity for us because we really have a head to head comparison with our, clinical molecule, gantenerumab, and then can really test, the shuttle version of it. So this is really a a big advantage.
Yeah. I see.
And the question from Tom Coleman. Based on preclinical data and existing clinical data of dantenerumab, do you have sense of how plasma concentration levels translate into levels of amyloid clearance? Because maybe very low dose will be sufficient for clearance.
I think this is a a very good and very valid question. I mean, our preclinical, experiments, for example, the chronic dose study in APP London mice, which I presented, clearly indicates that we can achieve a similar pharmacodynamic effect or similar efficacy with regards to amyloid clearance at a significantly lower dose. So this is something that we have shown preclinically. Whether this will be also the case in humans and eighty patients with amyloid deposit is something that will be now assessed in the brain shuttle AV study, which is has just started essentially. So there, we simply do not have the data to to to to share.
There is some modeling work that has been done. However, this has to be taken with certain with a certain amount of caution. Every model depends, of course, on on the input that you provide into the model, and there are certain uncertainties with regards to the to to the actual effect. So this is but, clearly, r g six one zero two has the potential to result in a faster and also increased and more homogeneous penetration of brain tissue, and our hope is that this will translate into into faster amyloid plaque clearance. And, also, ultimately, this is the the ultimate goal for better clinical efficacy.
But there are different options, and another option could be really that you can achieve essentially a similar efficacy at a significantly lower dose, which is, of course, associated with potentially better safety or or patient convenience, this is also something that that could be beneficial. Thanks for your question. Alright. So we have a few minutes left. And I would have a question actually for Michelle regarding alembicides.
And there, what I found interesting, and and to me, at least, this is new information, was that the cognitive worsening coming back to the to to this finding at six months with elambecestat was also associated with an increase in NFL in plasma from what I recall from your presentation. So what is your take on that? How do you interpret these findings? Does this suggest that the cognitive worsening is also indeed associated with some neuronal damage, or what's your interpretation?
So, yeah, you're you're right that the the nominal, normally significant worsening on the ADAS cog at the six month time point, there was also, changes in plasma and FL at that same six month time point. We actually looked at that relationship post hoc, and there there was no association between those changes. So in plasma, NFL, and the ADAS call.
Okay. Do do we have more clarity, like or I mean, there is, of course, a lot of spec speculation what could be behind this effect. Right? So and any learnings from your program there or any speculation?
Not in terms of speculation, but, you know, in terms of actually analyzing that data, there was no relationship between the changes in plasma NfL and the the ADAS code 11 data at that six month time point.
Thank you.
I see another question here again to Luca. Your your presentation was popular. Infusion time, what biomarkers, will you be monitoring for target engagement and efficacy?
I'm trying to interpret the infusion time part of the question. So what biomarkers will you be monitoring for target engagement and clinical efficacy? So so clearly, in in the ongoing study so that has just started the brain shot lady study study in in patients with Alzheimer's and in the two higher dose groups, which will be evaluated also at three months because we would like also to assess this fast amyloid clearance aspect with this molecule. So this will be the biomarker to assess target engagement and and and pharmacodynamics, essentially. I'm not so sure about the the infusion time.
Think this case, how long, or maybe the treatment period. So this is twenty eight weeks for the brain shot lady study. So this is a study which will essentially I mean, the primary objective is to establish safety and tolerability of r g six one zero two in patients with AD. But as I said, so there are a couple of secondary objectives and and amyloid PET, PK, CSF concentration, and and various other biomarkers in CSF and plasma we will be looking at. Thanks.
I think it is time to wrap up the discussion. I'd like to thank all the participants and the audience for the questions.
Thank you very much.
See you next year in person.
Yes. Thank you very much.
Thank you.