Next-Generation CNS Drug Delivery: Brainshuttle Technology and Clinical Implications in Alzheimer Disease

Intro: [00:00:00] Welcome to Neuro Frontiers, a series in which Practical Neurology partners with Reach MD to bring you clinical research and advancements that further clinicians' ability to diagnose and treat neurologic conditions. In this episode, Luka Kulic, MD from Roche, Basel, Switzerland discusses the investigational Brain Shuttle technology.

Host: Dr. Kulic, thank you so much for joining us today. Wondering if you could just start by telling us a little bit about yourself and your role at Roche

Dr. Luka Kulic: My name is Luka Kulic. I am a neurologist by training, a neuroscientist, and have more than 25 years of experience in the field of Alzheimer's disease therapy and research. My role at Roche, so [00:01:00] I'm vice president and global head of early clinical development in neuroscience and rare diseases, and have been the early development lead for trentanumab, a brain shuttle molecule that is currently being investigated in a phase 1B/2A study, and has just transitioned also to phase 3.

Host: Please provide an overview of the brain shuttle technology with an emphasis on its unique method of drug delivery. The brain shuttle technology leverages a physiological mechanism. That is this so-called transfer and receptor-mediated transport mechanism that occurs at the level of the brain capillaries.

Dr. Luka Kulic: This is a physiological mechanism that enables a transport of, in case of the transfer and receptor, of transfer and an iron across the blood-brain barrier. The brain shuttle technology leverages this physiological transport mechanism to smuggle in therapeutic molecules across the blood-brain barrier into the brain to target brain pathologies, in this case amyloid plaques, in case of trentanumab.

Host: Great. [00:02:00] Thanks so much. That's a great overview. And how does this technology, the brain shuttle, compare with other methods of delivering large molecules across the blood-brain barrier?

Dr. Luka Kulic: This is a specific mechanism that leverages a physiological transport mechanism that happens at the level of the brain capillary. It's an active transport mechanism which ensures rapid and enhanced transport of the therapeutic molecule across the blood-brain barrier, and that happens throughout the brain in a very homogenous manner. So that is, I think, an also a very important feature. In one of my previous presentations, I showed, for example, a picture where we looked at the distribution of the, of the brain shuttle molecule as compared to a standard antibody.

So a brain shuttle antibody versus a standard antibody. And what you see is that the access via the brain capillaries, which are everywhere within the brain, results really in this enhanced and homogenous access to the brain. While, for example, a standard antibody is more restricted to certain areas of the brain, so [00:03:00] does not lead to a homogenous penetration of the brain tissue.

Host: And trentanumab uses this brain shuttle technology to improve blood-brain barrier penetration, as you're describing. Mm-hmm. How does this strategy overcome some of the historical delivery limitations that are found with other Alzheimer's disease therapies? 

Dr. Luka Kulic: Trentanumab is our lead brain shuttle program. So, so the first one with, actually, at Roche, with which we have really established a proof of concept for the whole platform. The difference, and, and we have studied trentanumab also, and compared trentanumab also in preclinical experiments with regards to brain penetration. What we've seen is really that we get more over the blood-brain barrier in a more homogenous manner, and that we can target brain pathologies like amyloid plaques more effectively and more broadly throughout the brain.

What is also important to note- is that with this technology, since we can get more over the blood-brain barrier, we can also use a lower dose to achieve the same or even more than we usually achieve with, with standard antibodies, which have a much [00:04:00] harder actually time to cross the blood-brain barrier.

Standard antibody like gantenerumab, the one that we studied years ago at Roche, their brain penetrance is actually quite low. So it's essentially one out of maybe 3,000 molecules that we inject intravenously Gets into the brain tissue. While the, the brain shuttle technology really ensures that it's several fold increased. And not only increased, but then also it's homogeneous throughout the brain. It's really an important differentiation feature.

Host: Sure. In addition, you just mentioned the ability to use a lower dose. How else might the technology impact efficacy and safety of this therapy as well as others? 

Dr. Luka Kulic: We are currently studying the efficacy of troutinumab in the phase 3 program, so TRONTIO 1 and TRONTIO 2, so this is currently ongoing. But in terms of target engagement and clearance of amyloid plaques, what we see is very rapid and robust amyloid plaque clear. This highlights the potential of this technology. But [00:05:00] significantly lower doses than what we usually use with standard antibodies. We know today there is really emerging evidence that rapid and robust plaque clearance is necessary for clinical efficacy, so the more patients we get below a certain threshold of amyloid positivity, the earlier this happens, the more likely will the patients benefit.

There's emerging evidence from the field suggesting that. And troutinumab, and this is what we presented also at this conference, achieves this very rapid and robust amyloid plaque clearance. So as an example, after 28 weeks we saw that 92% of, of the participants in that study were cleared, so fell below the amyloid positivity threshold of, of 24 centiloids, which is very fast.

What is also important to note is that safety d- or profile, the safety and tolerability profile remains favorable. And I think what has been very important for the field is that the amyloid related imaging abnormalities, so this is a common adverse event of these [00:06:00] anti-amyloid therapies, is actually much lower than what we see with, with standard antibody approaches.

And I think this, this combination of very rapid and robust amyloid plaque clearance that is likely associated with better clinical outcomes, coupled with an improved, significantly improved safety profile when it comes to ARIA is something we are very excited about with troutinumab. Yeah, it's fascinating.

Host: Great, thank you so much. And the presentation you mentioned at this year's Clinical Trials on Alzheimer's Disease meeting included results of the phase 12 brain shuttle AD study. Can you briefly describe the key results and the clinical applications of that study? 

Dr. Luka Kulic: Yes. It is a phase 1B2A study that we started in '21. It is a relatively complex study. So it has different parts, and here at CTAD we gave an update on the first parts, or the first two parts of the study. Part one is the so-called dose finding or dose escalation part. Mm-hmm. That's a smaller part with also smaller [00:07:00] number of patients. And then there is a part two.

What we did there, we essentially expanded cohorts that looked promising based on the, the amyloid PET reduction and also the safety profile looked promising in part one. We expanded those cohorts.  And that occurred- With what we call cohort three and cohort four, so 1.8 and 3.6 milligram per kilogram.

And what we presented at SITA was the complete data from part one and part two of cohort three and cohort four. 92% of participants below the amyloid positivity threshold, 70% were actually very deeply cleared. So they reached levels below 11 centiloids, which is kind of another threshold w- which, which suggests very, very also deep clearance of amyloid.

Low ARIA-E incidence. ARIA-E is a form of amyloid-related imaging abnormalities that, that we, people look carefully at in, in these trials. And there we had only one participant in cohort four, so this is active drug and placebo combined in a four to [00:08:00] one ratio, but one out of 75 who developed ARIA-E, which is a very low incidence overall.

Host: Mm. So, so that highlights really this improved safety profile with regards to ARIA. What are the clinical implications of therapies generally that are delivered with Brain Shuttle in terms of AD pathology clearance? 

Dr. Luka Kulic: Yeah. So as I said, I mean, there is emerging evidence in the field that a rapid and robust clearance is necessary for efficacy.So the learnings over the past couple of years from the field have been that those trials in which amyloid was lowered but not, like, to such an extensive or such a great extent, those trials turn out negative. So that's important to note. So only those trials were patients during the double blind treatment period, which is usually 18 to 24, 27 months.

You need to get the levels of amyloid below the threshold of amyloid positivity in most of the people to see a signal. Mm. Those trials that did not [00:09:00] achieve that were negative. Those that achieved clearance in a majority of patients were positive. And we have also done at Roche some research into these relationships, including a meta regression analysis that we actually published two years ago, where we looked at the totality of data, cl- trial data from the field that suggests really that in those trials where early clearance was achieved, so at an early time point.

So for example, in an 18-month trial after six months, if the more people we get at this early time point below the threshold, the larger the, the efficacy signal is at trial endpoint. Mm. So in an 18-month trial, if you see The majority of participants below the threshold at six months, that's a good predictor of the clinical efficacy signal at 18 months.

And based on this meta-regression, we believe that the higher the percentage of people at this early time point that become amyloid negative, the larger the effect size [00:10:00] will be. This is currently based on these meta-regression data. It's not, not proven. It needs to be proven now in the real experiment, and that is ongoing in the TRONTIO studies.

But there is some hope to, to believe that this improved and early deeper clearance may result in a greater efficacy signal. But of course, apart from efficacy, it's really also the safety profile be- because this is a big concern in the field. I think also to, to some skepticism around these therapies and also to access challenges.

Host: That's why I think it's a great advancement that we can essentially clear amyloid with a relatively low ARIA in- incidence. So that's, I think, another kind of key aspect that needs to be highlighted. Okay. Great. And on that topic, you mentioned the low ARIA incidence you've observed and some of the safety considerations and concerns around that. Are there any other specific safety considerations or delivery limitations that are associated with Brain Shuttle?

Dr. Luka Kulic: In our trial, the most relevant or most frequently [00:11:00] reported treatment emergent adverse events are infusion-related reactions. So this is something that is not uncommon with biological therapies.

What is important to note is that these related reactions are generally mild to moderate in severity, and that they are well manageable with premedication. What we do is 30 minutes prior to the infusion, the patients get a steroid injection- One injection and then they get the infusion. What we know is that infusions that were pre-medicated with corticosteroids, they were associated with infusion-related reactions only in 6 to 7% of cases, as compared to more than 30% of infusions that were given without any pre-medications.

Host: That highlights that pre-medication works and that this is a viable and reasonable mitigation strategy. And the results we've talked about and the results you presented at CTAD have focused on the role of Brain Shuttle for delivery of Alzheimer's disease therapies. What are some of the other potential applications for Brain Shuttle in [00:12:00] other fields of neurology?

Dr. Luka Kulic: The Alzheimer's disease is one of the indications we're exploring, and trolandimumab is the most advanced program in a larger indication like Alzheimer's disease, in a sporadic, uh, disease like Alzheimer's disease that we are developing now in phase III. We are excited, generally excited about this technology, and are also in our portfolio at Roche exploring oth- other shuttle molecules and also for other indications.

For example, there is one program that is currently in phase I in multiple sclerosis where we are using the same technology to deliver an antibody that targets B cells, so a CD20 antibody over the blood to essentially, yeah, get this antibody over the blood-brain barrier, leveraging the Brain- Brain Shuttle technology with the idea to target really B cells, which are known to play a pathological role in MS in compartments that are not easily reached by, by standard anti-CD20 antibodies. So this is one of the programs that is currently in the clinic. But of course, in our [00:13:00] earlier pipeline, we are exploring multiple Brain Shuttle molecules for, for multiple different indications.

Host: Thinking through some of the next steps for Brain Shuttle, you mentioned the TRONTIR studies, and can you just give us an idea as to the future directions for the Brain Shuttle technology?

Dr. Luka Kulic: So, as I said, so I think Alzheimer's disease and targeting amyloid is, I think, a great start. The proof of concept that we have established now in the Phase 1b/2a study highlights the potential of this technology for a wide range of indication, neurological indications, where the blood-brain barrier is really essentially limiting.

The blood-brain barrier restricts the access of all kinds of molecules, especially large molecules, to the brain. That opens up new avenues for targeting different pathologies in the brain. As I mentioned, the, the CD20 target in MS, but there are other also misfolded proteins in Parkinson's disease. There are also other proteins than beta amyloid in Alzheimer's disease, like tau.

That really highlights the potential to reach these [00:14:00] brain targets more efficiently and more broadly, which will hopefully result in a much better efficacy than what we see today with our therapies that actually are limited by the fact that there is the blood-brain barrier, which limits the access of the vast majority of these molecules that we inject systemically.

Host: One last question for you. What should physicians tell their patients if a patient comes and asks about the technology after seeing it in the news, for example? It's still an investigational therapy. It's not approved. It's not a marketed product. It is, but it's currently being investigated in Phase 3 in the TRONTIO studies.

Dr. Luka Kulic: There is obviously the possibility, right, to, to participate in clinical trials if patients are interested, and of course, if they are eligible, of course, for these trials. So that is currently the option. This is, I think, a promising therapy, however, still in investigational stage, where we need to really establish properly in a Phase 3 trial the efficacy and safety profile.

Host: Thank you so much for joining us. Really appreciate you sharing this with our listeners.[00:15:00]

Dr. Luka Kulic: You're welcome.

Outro: Thank you to Dr. Kulic for his insights, and thanks to you, our listeners. Neuro Frontiers is brought to you by the editors of Practical Neurology. Please visit practicalneurology.com for more podcasts in the field of neurology.