Biogen Inc. (BIIB) Earnings Call Transcript & Summary

Welcome to the live discussion of the -- symposium, Abeta-targeting therapies in AD #1. So my name is Yona Levites. I'm from Center for Translational Research in Neurodegenerative Diseases in University of Florida. And my co-moderator is Dr. Luka Kulic, and he will introduce himself, and then all the members of our discussion will introduce themselves.

Thank you very much, Yona. 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 approach. Then I'll hand over to Laura.

Thank you. My name is Laura Nisenbaum. 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 aducanumab. Thanks.

Michelle? 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 at MISSION AD Phase III trials.

And last but not the least, Konstantinos.

Hello, everyone. My name is Konstantinos Avgerinos, and I am an MD and I have a master's in medical research methodology. And I'm currently a visiting fellow at the lab of Dimitrios Kapogiannis 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 the audience. So please place your questions in the Q&A and add also the name of the presenter that you would like to ask the question. Yona?

So I have one question for now to you, Luka. 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/and human studies?

Thanks very much for this very important and also a very good question. And the answer is short, no. We had not seen ARIA so far. However, we need to take into account that the models that we use for the clinical molecule. So the nonhuman primates that we use, they do not have over amyloid deposition, at least at the ages when we tested them. So in the absence of amyloid deposits and also in the absence of good [ neuron ] ARIA models, we were not able to assess the risk of ARIA in our preclinical models. We did not observe any ARIA or ARIA-like events in the single ascending dose study in healthy volunteers. But 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 on purpose because we wanted to exclude this potential risk or confounder in this very first study of RG6102.

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, on antibody treatments in mice as well, but we did not really observe anything like that and no ARIA-E, especially ARIA-E is a big problem for preclinical models. Thanks very much. Maybe I can then proceed with the next question, and maybe I will get the question back to you actually, Yona. And I really like the presentation on the single-chain variable fragment construct with the collagen domain. And I was wondering about the immune activity of 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 the molecule in central nervous system and the systemic circulation, and this is kind of the main rationale. But what happens then? Like -- and in terms of the therapeutic activity. So is there -- is this domain recognized like real cells? Does it facilitate phagocytosis? What is your thought on that?

No. We actually looked pretty extensively at mice injected with collagen domain by itself. And we do not see -- and we looked at the RNA seq from those mice, and we looked at the behavior, and we did not see any changes or any kind of effects from that. On top of that, our main problem was single chains is it's short half-life and instability. So prolonging the half-life would be -- we feel more beneficial than a problematic. And I see we have a lot of questions coming in. So we'll start with the first one for Luka. Have you seen any anemia or changes to reticulates or red blood cells in patients? Curious about any potential target talks.

All right. Thank you very much for this question. I mean it's an important question because our RG6102 construct is a transferring receptor 1 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-related dose-limiting adverse events. What we did observe, and we will show a little more at upcoming conferences, so I cannot comment today on the entire safety results of this study because this is a topic for upcoming conferences. What we did observe and also in line with our preclinical observations are transient effects on reticular sites 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 the ongoing brain shuttle AD study in AD patients. But this is, of course, something that we will be monitoring very closely in the brain shuttle AD study. Thanks for the question. Maybe I can then proceed with a 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 results from this full data set analysis on elenbecestat from the MISSION AD study. And I found interesting that you observed this cognitive worsening in 6 months. This was the finding that really remained also in the full data set analysis. I was wondering, so how does that fit. Is this related to the other findings from other BACE inhibitors? And also an additional question on that is, with the other BACE inhibitors, there was this interesting finding that they were those worsening on cognitive tests that are memory related like ADAS-Cog. But at the same time, there were improvements that were reported with these BACE inhibitors on, I think, verbal fluency tests. And so I was wondering did you observe something similar in -- with elenbecestat.

So thank you for your -- for the questions. So starting with the MISSION AD data set and the cognitive worsening. So there was subtle and transient worsening seen on the ADAS-Cog 11 at 6-month time point. It was not present at a 12-month time point or the later time points, including the main 24-month time point and not seen in other scales either. In terms then of how that compares to other BACE inhibitors, I think, as we know, several BACE inhibitors have now seen some aspects of cognitive worsening. But there are slightly different attributes between them. So I think they're not necessarily looking the same amongst the different BACE inhibitors. In terms of what perhaps was driving the ADAS-Cog worsening that was seen at 6-month time points in the MISSION AD data set, we have looked into that. And in terms of specific items, it was really being driven by word recall and by word recognition in the full MISSION AD data set.

Here's another question for you, Dr. Kulic. Does any data exist on expression of TfR1 in elderly versus young?

That's a -- so as I mean which system, so hematopoietic brain or general. This is not specified, I guess.

I guess not.

I think it's a very good question because the target population is elderly. I am personally not aware of any studies that look at changes of transferrin receptor 1 during aging in, for example, at brain vasculature. This is something that clinicians are not aware of. But an important question, yes, because our patient population is elderly, 80 patients.

And a question from [ Fadi Rofa ] from [ Upsalla University ]. He is asking if you've measured different species of Abeta protofibril fibrils clearance in your studies.

This is a question for me?

Yes.

In which studies exactly? So is this the human studies?

I think what he -- your clearance of Abeta, if you've confirmed protofibrils oligomers fibrils clearance.

I guess this might...

Almost total...

But this relates to preclinical experiments in most months?

Right.

Okay. We did not specifically look at oligomeric species. So the preclinical experiments I'm aware of and that I presented in this meeting, we mainly look at essentially [ ELISA ] and also histology, so these were the readouts. But we did not -- to my knowledge, looked specifically and certainly oligomeric species like protofibrils or other oligomeric species. All right. 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, Luka. Thanks for the question from the audience. In the U.S., this test, the in-vitro diagnostic test has been submitted to the U.S. FDA for 510(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 that question. And like as a take-home message from your presentation, so it sounds like that this CSF assay and the amyloid PET can be used essentially and in an exchangeable manner. Is this -- do they envision this also for the future, for example if aducanumab 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 U.S. 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 some extent, have to be monitored by either amyloid PET or any other markers, maybe CSF biomarkers, so the pharmacodynamic effect of the treatment? Or is it -- what are the discussions there? So do we need to show that aducanumab really reduces amyloid burden also once it gets approved?

So Luka, great question. Thanks so much for that. Really, what we focus with this data set was looking at whether the CSF Lumipulse assay would provide concordance with screening samples. But clearly, any work looking at monitoring we would need to look at subsequently.

A question probably to Michelle. Does BACE inhibitor have a future in Alzheimer's disease and what would be primary aspects of improvement?

Thank you for that question. I think it's fair to say that BACE inhibitors have a very high hurdle. If they are going to progress as a treatment in AD. And looking across the BACE 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 hurdle ahead for this class.

Okay. Thank you very much. Then a question maybe for Konstantinos. So thanks very much for this very nice meta-analysis of -- a lot of different anti-amyloid antibodies 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 a reasonable approach to combine all these different antibodies in 1 meta-analysis? Let's assume essentially a class effect, right, given the fact that the MOAs or the mechanism of action may be really different between that. But as we know, for example, solanezumab mainly binds on -- beta while aducanumab gantenerumab, the BAN2401, bind more aggregated data. So 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 in addition to the main meta-analysis, we performed the subgroup analysis. First of all, we performed the 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 anomalies. And in general, this subgroup analysis, they do 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 both bapineuzumab and crenezumab. And these drugs did not have any clinical effect. The other group was, of course, aducanumab and gantenerumab. These 2 drugs had -- were targeting oligomers and fibrils, and they had some positive effect. And the other drug, the other subgroup was solanezumab, which was the only drug to target monomeric 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 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.

A question to Laura. If you measure any other biomarkers in the CSF related to the inflammation synaptic plasticity and...

Thanks, Yona. 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 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, 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 abeta-42 in CSF. Do you know like -- I mean does it normalize over time once blocks really get cleared from the brain? Do we have anything here? 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 the 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.

I have a quick question to you, Luka, and then there is one from the audience. In your impressive preclinical data, is this the only 1 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 the treatment of different indications, actually. And this is essentially the most advanced program that is now in the clinic. This is what I can say.

I meant the other way around. Did you test other antibodies with this one?

You mean anti-amyloid?

Right.

No. The answer is no. So from the very beginning, this is clear. I mean it's also a big opportunity for us because we really have had that comparison with our clinical molecule, gantenerumab, and then can really test the shuttle version of it. So this is really a big advantage here.

I see. And a question from [ Tom Coleman ]. Based on preclinical data and existing clinical data of gantenerumab, do you have a sense of how plasma concentration levels translate into levels of amyloid plaque clearance because maybe very low dose will be sufficient for clearance?

I think this is a very good and very valid question. I mean our preclinical experiments, for example, the chronic dose study in APP lung in 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 had shown preclinically. Whether this will be also the case in humans in AD patients with amyloid deposits is something that will be now assessed in the brain shuttle AD study, which has just started essentially. So there, we simply do not have the data to share. There is some modeling work that has been done, but this has to be taken with certain amount of caution. Every model depends, of course, on the input that you provide into the model, and there are certain uncertainties with regards to the actual effect. So this is -- but clearly, RG6102 has the potential to result in faster and it also increase a more homogeneous penetration of brain tissue. And our hope is that this will translate into faster amyloid plaque clearance and also ultimately, it's certainly the ultimate call for to effect clinical efficacy. But there are different options and other options 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 patient convenience. This is also something that could be beneficial. Thanks for the question. All right. So we have a few minutes left. And I would have a question actually for Michelle regarding elenbecestat. And there what I found interesting and to me, at least, this was new information was that the cognitive person coming back to this finding at 6 months with elenbecestat was also associated with an increase in NFL in last month 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 yes, you're right that the nominal, normally significant worsening on the ADAS-Cog at the 6-month time point, there was also changes in plasma NFL at that same 6-month time point. We actually looked at that relationship post hoc, and there was no association between those changes. So -- in plasma NFL and the ADAS-Cog.

Okay. Do we have more clarity, like -- or -- I mean there is, of course, lots of speculation what could be behind this effect, right? So -- and any learnings from your program there or any speculation?

I mean no in terms of speculation, but in terms of actually analyzing that data, there wasn't a relationship between the changes in plasma NFL and the ADAS-Cog 11 data at that 6-month time point.

I see another question here again to Luka. 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 clearly, in the ongoing study, so this has just started, the brain shuttle AD study in patients with Alzheimer's disease. We will be looking at amyloid PET. So change in amyloid PET signal at 6 months and in the 2 higher dose groups, which will be evaluated also in 3 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 pharmacodynamic, essentially. I'm not so sure about what the infusion time means in this case on -- maybe the treatment period. So this is 28 weeks for the brain shuttle AD study. So this is a study which will essentially -- I mean the primary objective is to establish safety and tolerability of RG6102 in patients with AD. But as I said, there are a couple of secondary objectives and amyloid PET, PK CSF concentration 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.

Thank you very much.

Thank you.