Latest / Let's Talk Alzheimer's / Trontinemab: A New Brain-Penetrant Alzheimer’s Therapy | Dr. Gil Rabinovici

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Trontinemab: A New Brain-Penetrant Alzheimer’s Therapy | Dr. Gil Rabinovici · Let's Talk Alzheimer's

• Dr. Gil Rabinovici: And what we found at about one third of the dose of other antibodies like Leqembi, amyloid was removed three times as fast. And people who entered the trial had quite a lot of amyloid on their brain as we measured by a PET scan. And by six months, over 90% of those people had completely cleared their plaque by PET. In fact, a significant proportion had already cleared the plaque at three months. Narrator: Welcome to Let's Talk Alzheimer's, your place to go for the most up-to-date conversations with world-renowned research scientists and doctors. And now Let's Talk Alzheimer's with your host, Nancy Keach. Nancy Keach: Welcome to Let's Talk Alzheimer's, a podcast from Bright Focus Foundation's Alzheimer's Disease Research Program. Trontinemab, an amyloid targeting drug being developed by Roche and its subsidiary Genentech is not yet approved for Alzheimer's disease, but it's progressing rapidly through a series of clinical trials. It has a unique mechanism of action referred to as brain shuttle, a technology designed to help the drug cross the blood-brain barrier to remove the sticky proteins that are associated with Alzheimer's from the brain quickly and effectively. Early studies also indicate that trontinemab may have a lower rate of a side effect called ARIA-H. So if it's effective, it may also be safer to take than the current generation of Alzheimer's drugs. To learn more about trontinemab, I spoke in late August 2026 with Dr. Gil Rabinovici, the Edward and Pearl Fine distinguished professor in the departments of neurology and radiology at the University of California, San Francisco. Dr. Rabinovici is on Roche's steering committee for the trontinemab program. Here's our conversation. Welcome, Dr. Robinovich. Dr. Gil Rabinovici: Thank you so much, Nancy. It's really a pleasure to be here. Nancy Keach): So I'm going to jump in. Trontinemab is a drug being developed by Roche and its subsidiary Genentech, and it is not yet approved. It is progressing through a series of clinical trials that are very exciting. And so I believe the first trial, I may be wrong, you can correct me, of TRONT or TRONTI, as people in the industry call it, was the Brain Shuttle AD phase IIA clinical trial, which began in March of 2021 and is ongoing. So to start, can you tell us, Dr. Rabinovici, about what is unique about the way TRONTI works and what we know from the research so far about this therapy? Dr. Gil Rabinovici: Sure. I love the TRONTI shortcut. That'll save me a lot of tongue twisters today. So one of the key challenges in developing treatments for Alzheimer's disease and other brain diseases is something called the blood-brain barrier. Basically, this is the shield that's on blood vessels that protect the brain against all kinds of toxins that are circulating in the blood and prevent those toxins from getting into the brain. So that's great. However, when we're trying to develop drugs specifically to get into the brain, the blood-brain barrier can be a major hindrance. And that's particularly true when you're thinking about large molecules like monoclonal antibodies that are targeting amyloid beta. And so what is unique about TRONTI is that it is a monoclonal antibody that is connected to something that's called a brain shuttle. The brain shuttle is basically a way of getting the drug actively transported into the brain through that blood-brain barrier. The way it works is the brain shuttle actually attaches to a receptor that's present on blood vessels called the transferrin receptor. The receptor recognizes this as, "Oh, this is something I need to bring into the brain." And then like a Trojan horse, it brings that drug actively into the brain across the blood-brain barrier. And that means that we can get much more efficient penetration of the antibody into the brain. Just to put this in perspective, when we're giving antibodies like Leqembi and Kisunla through an IV infusion, we estimate that only about 1% of that antibody that's given IV is actually getting into the brain. So we have to give a lot more drug than the brain actually needs because the penetration is so low. And the goal of Tronti and this brain shuttle technology is really to address that challenge through this Trojan horse mechanism. We've all watched the Odyssey movie, so the Trojan horse is top of mind, and that's exactly what this drug is doing in order to get into the brain. Nancy Keach: And from the first trials, I think they're ongoing, but I know some initial data was released, I believe in 2025. Can you talk about what we know the drug is able to do based on that evidence? Dr. Gil Rabinovici: Absolutely. So just for some context for the viewers, a phase one study is a dose finding study. So it's a study in which a new drug is actually given at increasing doses to volunteers in order to try to understand what is the best dose to actually treat a disease, what is the dose that we need to test in later stages of drug development. And so in this phase 1b study, participants with Alzheimer's disease confirmed through biomarkers PET or CSF were recruited and they were given increasing doses of this antibody. About 150 people were recruited and most of them got the higher doses, so either 1.8 or 3.6 milligram per kilogram, about 120 of those 150 got those higher doses. And what we found I think can be summarized really simply in that at about one third of the dose of other antibodies like Leqembi, amyloid was removed three times as fast. And so just to put that in perspective, people who entered the trial had quite a lot of amyloid on their brain as we measured by a PET scan. And by six months, over 90% of those people had completely cleared their plaque by PET. In fact, a significant proportion had already cleared the plaque at three months. So we're talking about potentially a really short duration of induction treatment in order to clear those plaques. And what we've learned from other studies so far in the field is that it does seem to be beneficial. The more completely and faster you can remove detectable plaque from the brain, the higher the likelihood of getting a clinical benefit. That's what we've learned both from positive and negative trials of amyloid targeting antibodies. And so because we're getting probably so much more antibody into the brain, that antibody is able to engage, to get the brain's immune system to gobble up the plaques and the plaques can be cleared very fast. That is the main finding so far in the dose escalation or phase one study. Of course, another really important point is ARIA. Just to refresh people's memory, this is a side effect that we worry about very much with all the different anti-amyloid antibodies. What ARIA is, shifts in brain fluid that can lead to swelling or bleeding in the brain as a result of these treatments. And in most cases, ARIA is actually asymptomatic. It doesn't cause any symptoms or causes very mild symptoms that are completely reversible if you pause the treatment. However, there can be really severe cases of ARIA that present with stroke-like episodes, seizures, and even there have been some fatalities associated with really severe ARIA. So ARIA is a side effect that we worry about. So how does this brain shuttle mechanism, what is Tronti's record vis-a-vis ARIA? So far, it seems like the rates of ARIA in that phase one study, they're not zero, but they're really low. So for example, the rate of ARIA-E, which is the ARIA that's associated with swelling in the phase one study, was about at 6%. And just to put that in perspective, the rates of ARIA-E with Leqembi and Kisunla are more like 12 to 15%. So it may be not only that this antibody is more potent, that it can clear amyloid faster and more completely, but also it may be safer in terms of the risks of ARIA, not risk-free, but safer. And that is a really important learning. Nancy Keach: This sounds incredibly hopeful. Is that correct? Dr. Gil Rabinovici: It is really hopeful. I'm just amazed, just to put this in perspective, a little over three years ago, we had no disease modifying therapies available for patients with early stage Alzheimer's disease. Now we have two approved therapies and we're also seeing a rapid improvement in these drugs in terms of their potency and in terms of their hopefully safety profile. It's really important to note, and as I'm sure we'll discuss, the Tronti program is now moving towards larger clinical trials with more patients involved, also to evaluate for the clinical benefit. Is there a greater clinical benefit than with the current antibodies if we can clear the plaques more completely and faster? So that's still an open question. I think many of us are hopeful that the answer will be yes, but even if the clinical benefit is similar, but the safety profile is improved and the treatment duration is shorter, those are already some significant advantages, and it just shows you how fast our field is moving in terms of getting better therapies. Nancy Keach: Thank you so much. It is very helpful. Ana Luisa from El Paso, Texas had written, "If trontinemab can cross the blood-brain barrier more effectively and remove amyloid plaques quickly, what evidence shows that it can also slow memory decline and improve patient's quality of life?" And so you're using the phrase clinical benefit. Can you talk about what the phrase means and what we know from the early studies? Dr. Gil Rabinovici: Right. So what we really want to know isn't is this drug great at removing amyloid, but is it good at slowing memory decline? And the answer is that is still to be determined. So the way drug development works is in the early phases, you figure out the right dose, and often you use a biomarker to help you understand what the right dose is. For example, you're looking for a dose that can completely clear plaque, and you're also looking at safety profiles. How well do patients tolerate different doses? The question of slowing memory decline requires more participants in a clinical trial. And so that is where the program is right now. The two clinical trials have launched that are called phase three clinical trials. Phase three clinical trials are the trials that are actually designed to test for a benefit in terms of slowing memory decline and functional decline. Those trials are called Trontier one and Trontier two. They're global trials that were just recently launched, and those will answer the question of does this drug also slow memory decline compared to a placebo? The way the phase three trials work is that people who enter the trial are randomized to get either drug or placebo, so it's really important to control for that placebo effect. Everyone is blinded, so the patients, the doctors, everyone doing the assessments doesn't actually know who's on drug or who's on placebo to eliminate any bias. And then at the end of the trial, we unblind and evaluate memory decline, functional decline, and figure out did people who got the drug do better than people who are on placebo? So that actually requires a larger trial, more patients, and that's where the program is right now, just starting the phase three trials. Nancy Keach: DeLore in San Diego, California and Bruce Rivera on the chat are asking, is the new medication anti-amyloid only or does it address tau as well? Dr. Gil Rabinovici: This is an anti-amyloid antibody. So it recognizes accumulated forms of the amyloid peptide that eventually form plaques. The antibody is actually almost identical to gantenerumab, which is another antibody that Roche Genentech tested in Alzheimer's. It had some effects on amyloid, quite a good effect on amyloid, but maybe not enough to see a clinical benefit. But by adding the brain shuttle, changing it now into Tronti and having a much more potent antibody penetration into the brain, we see a much more potent response in terms of amyloid removal. And again, we're going to see, but the hope is that we will see a really potent clinical response as well in terms of slowing memory decline. That said, this brain shuttle technology can be used in the future for other drugs, maybe antibodies that are targeting tau or other elements of Alzheimer's disease biology. And so there's two exciting things. One is this might be a really good anti-amyloid antibody, but I think the bigger picture reason that so many people are excited is the technology which might facilitate much better delivery of drugs into the brain, and that can be generalized to other mechanisms, other drug targets as well. Nancy Keach: So technically this is not an anti-tau mechanism drug, but the technology of bringing drug more effectively across the blood-brain barrier means that in the future, if there are anti-tau type tau targeting drugs available, this may help that come into being. Dr. Gil Rabinovici: Correct. And I just want to also add that we think that targeting amyloid does have effects on tau. So even though if the antibody is targeting amyloid, from a lot of different streams of data, we think that amyloid really potentiates the spread of tau tangles, and then the spread of tau tangles is what is most closely associated with dysfunction of brain areas, brain networks, and ultimately with memory loss and dementia. And so we think that by removing plaques, the hope is that we are also slowing that progression of tau, and that in that way we're modifying or slowing the progression of the disease. So what is the evidence that this drug is hitting other elements of Alzheimer's disease? So for that, we use biomarkers. We measure tau. We can measure tau in the spinal fluid, and now increasingly, as I'm sure you've covered, we can measure tau in the blood. And what we've seen in the phase one, so the early phases of TRONTI, is that there is a very significant reduction of phosphorylated Tau-217 in the blood. This is a biomarker that we're using to track the effects of amyloid on tau. Other antibodies like Leqembi and Kisunla have also shown a reduction in phosphorylated tau in the blood, but not to the degree that we see it with TRONTI. It's about a 50% reduction in P-tau-217 in these early phase trials, which is, I would say, about double or more the effect that we've seen with the other antibodies. We also see effects on tau in the spinal fluid, and we see the effects of tau on another biomarker called GFAP, which is a biomarker that's measuring inflammation, can also be measured in the blood and in the spinal fluid, and there are also reductions that we see in GFAP. So beyond just clearing the plaque, which we're measuring with PET scans, there is some evidence at this point that the drug is affecting what we call the downstream elements of Alzheimer's biology. By removing plaque, you're also potentially affecting tau, inflammation, and other processes that we know are really important for the evolution of Alzheimer's disease. So far, so good in terms of seeing those broader effects that we are in fact expecting when we're targeting amyloid. Nancy Keach: I'm going to go into a bit of a lightning round with you because there's so many great questions. Jean from Alameda, is the medication potentially effective for people with early onset Alzheimer's due to blast trauma such as with veterans? I know there was just an article, I think, in the Times about CTE and football also. And then also, could this therapy potentially benefit patients with other types of dementia, non-Alzheimer's like FTD, Lewy body vascular, or possibly Parkinson's disease? Dr. Gil Rabinovici: We're thinking of this drug as particularly a drug to treat Alzheimer's disease because it is targeting the amyloid plaques, which are that core feature of Alzheimer's disease biology. So unfortunately, this drug is unlikely to be beneficial in other neurological conditions. That's maybe an oversimplification because amyloid plaques are potentially an important part also of dementia with Lewy bodies, and there is actually a clinical trial right now to assess the benefit of one of the anti-amyloid therapies in Lewy body dementia. So it's possible that some other diseases, in particular Lewy body disease, may have a benefit from targeting amyloid. We have to still evaluate that in clinical trials, but this drug as it is right now is being developed specifically for Alzheimer's. That said, the brain shuttle technology, which brings any drug into the brain more effectively, could be useful for developing drugs for a broad array of neurological diseases, including frontotemporal dementia, LATE disease, a lot of other neurological diseases, Lewy body and other diseases of the brain. Nancy Keach: Lots and lots and lots of questions about APOE4 and ARIA. And so just a couple. Nancy from Charlottesville, Virginia. Is the company hoping to recruit a target percentage of APOE4 homozygote carriers? It means two copies of the APOE4 allele. And Michael from Thiensville, Wisconsin, I think is the risk of ARIA with this drug, and you already addressed this, but you can put this together with the APOE4 questions, expected to be lower than with the other monoclonal antibodies in a patient with genotype APOE34. Can you try to address that in one go? Dr. Gil Rabinovici: Sure. So let's just start with the background, which is that APOE4 is the major risk factor for developing ARIA with anti-amyloid antibodies, including Leqembi and Kisunla. People who have one copy are at higher risk than people who have zero copies of APOE4, and in particular, people who have two copies of APOE4 are at the highest risk of developing ARIA. And for that reason, some US sites, but specifically some countries around the world are not allowing treatment of people who have two copies or homozygotes. Regarding the design of the clinical trials, the APOE4 genotype is allowed, so there is no exclusion of E4 homozygotes. There aren't any particular targets in terms of the percentage of people, but my guess is we're going to see at least what we see in other Alzheimer's trials, which is at least 15% of people getting into the trial are going to be E4 homozygotes. My guess is that might end up being higher because for some people, they might enter the trial because either they are not able to access the existing antibodies or those antibodies are not approved for E4 homozygotes, and those individuals might have a higher incentive of enrolling in a randomized trial right now. They recognize they may get placebo, but they're not able to get the other antibodies right now, so this might be their best option. So my guess is we will see at least 15% E4 homozygotes, probably a much higher number than that in these trials. In terms of the risk of ARIA, so as I stated in the phase 1b study, the rates of ARIA-E, the ARIA with inflammation, which is the most directly attributable to the antibody was about 6%. So it wasn't zero, but it was about half or even more or less than half the rates that we've seen with the other antibodies. That said, ARIA still occurred. In most cases, it was mild radiographically, clinically. However, there was one fatality in the phase one study. This was an individual who had severe ARIA and actually passed away from ARIA. And so while we think the risk will be lower with this drug, it's not going to be zero. We know that. So we still have to be very thoughtful about assessing people's risk and informing individuals about that potential risk as they enter the clinical trial or maybe in the future thinking about this drug for their care. We don't yet. The numbers are just too small of people who have been treated with a drug to have estimates of the rates of ARIA in E4 homozygous specifically, but we will get those numbers from the phase three trials. Nancy Keach: And I'm going to go into the phase three trials that are current and then also into the prevention trials. But before that, we had several questions about, here's one from Gary. Can trontinemab be administered to someone who has had more than four microhemorrhages? We had somebody else ask five to seven micro hemorrhages. And so are they potential candidates for this therapy? Dr. Gil Rabinovici: Right now, the clinical trials are excluding people who have more than four micro hemorrhages or tiny bleeds in the brain. They're excluding people who have something called superficial siderosis, which is bleeding at the surface of the brain. The person who had the fatal case of ARIA in phase one actually did have that siderosis before treatment. So that was actually adjusted to say, let's be really safe. It's plausible that this drug will be safer in the future for people who have microbleeds, but right now the clinical trials are using very similar exclusion criteria to the trials for Kisunla/Leqembi and excluding people who have evidence of previous bleeds with a concern that they would be at higher risk for having brain bleeds from the treatment itself. Nancy Keach: Thank you. And I real quickly want to say, because we are talking about ARIA and brain bleeds, that while there was that one fatality and ARIA has to be monitored very carefully, can you comment as ecumenically as possible on ARIA and monoclonal antibodies and the risk-benefit kind of ratio of, or I guess I would put it more broadly, are the side effects generally manageable and monitorable because it sounds so scary, brain bleeds. Dr. Gil Rabinovici: It does. It does sound scary. I think the reality is a lot less scary, and I think the narrative around these drugs has used words like swelling and bleeding and to catastrophize this a bit. I don't want to minimize either because there can be severe cases, but let me just give you some numbers. So we think the rates of ARIA-E, which is the swelling, are about 12 to 15% with the currently approved antibodies. Those are the ones we know more about, so those are the ones I'm going to discuss. Out of those, about 80%, 75 to 80% of people who have ARIA don't actually have any symptoms. They don't know there's anything going on. But what we do is we do MRI scans as we start these drugs very frequently to monitor for ARIA, and that's where we catch most of the cases of ARIA is just by doing the MRI monitoring. And the bleeding, again, we say bleeds in the brain, but often these are tiny little one or two little tiny dots that we can detect on an MRI but are not causing any symptoms or a tiny little area of signal change on the MRI that's indicating a shift in the fluid. When people have symptoms, they tend to be pretty mild and non-specific. So people have complained of headache, a little bit of visual change, a little bit of dizziness, and those symptoms almost always resolve. And in fact, the swelling on the MRI scan resolves if you pause the treatment and continue to monitor people. So ARIA is usually mild. It's usually asymptomatic or mildly symptomatic. That said, in less than 1% of people, ARIA can be severe. It can cause major swelling in the brain that we see on an MRI that definitely causes symptoms. It can cause a larger bleed in the brain and in just a handful of cases, but these are tragic, every case is tragic, people have died of severe ARIA. And so it is really important also to be, this is a rare side effect, but it can occur, it can be severe, and it's really important just that everyone, patients, families understand that potential risk. The specific risk depends on APOE. So people who have one or two copies of E4 are at higher risk, not just of having ARIA, but of having symptomatic or more severe ARIA. And so it really is an individual discussion with every patient. That said, a lot of drugs that we use to treat really severe illnesses like cancer, autoimmune conditions, those drugs also can rarely have really significant side effects. And yet people who are living with these diseases may say, "Okay, I understand. I'm assuming some risk with the treatment, but I am really motivated to do anything I can to slow this down, to continue to stay where I am at the, for example, the MCI stage where I'm still able to do a lot of things independently and have a lot of meaningful interactions with family, friends, hobbies." And so some patients are willing to assume those risks. For other people, they may be more risk averse, maybe they're higher risk based on their MRI profile, the genetic profile. After we have that conversation, they say, "You know what? These drugs aren't for me. There's too much risk involved." Or actually the treatment is too burdensome. That's another issue. Coming in every two weeks or every four weeks for IV infusions, that's a really serious commitment, getting all those safety MRIs. And some people just find that too burdensome. So it really is an individual decision about whether the drug is right for someone who may be eligible for this class of medications. Nancy Keach: And the last question before we actually talk about Trontier one and two and PrevenTRON and the trials is Heather asks on YouTube, "If a person has received Leqembi, Kisunla, or an anti-amyloid drug, are they eligible to potentially participate in a TRONTI trial? Might they receive a benefit?" Dr. Gil Rabinovici: Unfortunately, people who have previously been on other anti-amyloid drugs are currently excluded from the trials, even if they're no longer on those drugs. The reason for that is that at least in these initial clinical trials, we really want to understand what is the benefit and risk associated with TRONTI specifically. And if you enroll people who have been on other drugs, it becomes a little bit difficult to disentangle if they do show a benefit. Is that due to the Leqembi they received previously? Is it due to the TRONTI right now? And so for that reason, these trials are kept relatively clean in terms of these are the first anti-amyloid drugs that these individuals are exposed to. So people who have been on those drugs unfortunately are not eligible for the current clinical trials. That may change in the future, but in terms of these trials, they are an exclusion criteria. Nancy Keach: Let's talk about the trials that are running for trontinemab currently and in the relatively near future. Can you talk to us about TRONTIER one and two? And then trials upcoming? Dr. Gil Rabinovici: Sure. So the first two trials that are currently open for trontinemab are trials for people with early clinical stages of Alzheimer's disease. So these are individuals between ages 50 to 90 who have either mild cognitive impairment or mild dementia. And have confirmation of amyloid pathology by PET scan or CSF, and also have specific cognitive scores. So the mini mental state exam has to be over 22, and they actually have to be below a threshold on a memory test. The exclusion criteria are evidence of previous brain bleeds or really significant vascular changes in the brain if people have unstable medical conditions or other neurologic conditions that could be contributing to their cognitive decline. And then actually people who are on anticoagulants, so not aspirin, but the more aggressive blood thinners are currently excluded from the trial. These are two trials that are happening in parallel. They're identical in their design. Each study is recruiting about 800 people with early stage Alzheimer's at about 150 sites. These are global studies. So they involve sites in North America, in Europe, the UK, Australia, China, Japan, truly global studies. And these individuals are going to be randomized to receive either that 3.6 milligram per kilogram dose IV every month, which is the dose that was most potent for removing plaque for seven doses. So we really are talking about just a six-month treatment. And then individuals are converted to maintenance therapy, meaning they get another infusion every three months just to keep those amyloid levels down or to placebo. And these trials go on in their blinded stage for 72 weeks of treatment. And then at the end, when everyone has had 72 weeks of either drug or placebo, there will be an unblinding. It's estimated that that will occur in about two years, so sometime in the middle of 2028. And then we will assess whether these trials hit their primary endpoints. And the primary endpoint for these trials is very similar to the endpoints that were used for the approval of Leqembi and Kisunla. These are changes on the scale called the clinical dementia rating sum of boxes or CDRSB, which is a scale that is measuring cognition and function, how patients are doing cognitively and how they're functioning in their daily lives. So that's the primary outcome. And what we're hoping to see is a significant reduction in progression on that scale in people who are randomized to receive drug versus those who are randomized to receive placebo. So the trials are ongoing. And again, we're estimating that they will be completed by the middle of 2028, which means that recruitment must be going really well. Nancy Keach: Before I go onto the next trial and prevention trials in general, I just want to address this. We're talking about best case scenario, Trontier one and two keep going gangbusters, they get fully enrolled, and potentially the first data that will be looked at would be released around 2028. Now in science terms, that's fantastic. That's pretty quick and it's exciting, but in human being terms, it's incredibly painful and frustrating that we have something today that sounds so promising and potentially the data will not be available until 2028. Okay, that's how science works. We have to have evidence and evidence takes quite a while to responsibly collect. If the data in 2028 was beautiful, if it really showed quick amyloid clearance, lower incidence of ARIA and a good cognitive benefit, approximately how long would you estimate it would take before it is available to patients? I know that puts you in a bad spot, Doctor, but approximately based on what we know today. Dr. Gil Rabinovici: Yeah, I can't really answer that. This really depends on FDA and other regulatory agencies around the world. It's hard to put a timeline on it. I'll speak just for the US where I'm more familiar with the regulatory environment, so I apologize to our international viewers, but I would be shocked if the FDA didn't expedite this and take a very quick look at it as fast as possible while still maintaining the rigor that we need in our drug approval process. So it won't be instantaneous, but hopefully it will be as fast as possible once the trials are completed and reported publicly. I would just say that one of the concerns around approval globally has been the concern of the risk of ARIA. I've said I think that is catastrophized and overstated, but it is a risk. So I think that an improved safety profile would go a long way. We're hoping, of course, the clinical benefit would be even greater than the about 30% slowing that we're seeing with the other antibodies. But even if it's about the same, but the safety profile is better, I'm optimistic that that will help push regulators and payers to cover it. Nancy Keach: Let's talk about the next study and prevention studies in general. There's another trial called PrevenTRON. But Dr. Rabinovici, can you tell us about that trial and how it will differ from Trontier one and two? Dr. Gil Rabinovici: So Trontier one and two are recruiting people who have cognitive impairment already, people who have MCI or mild dementia due to Alzheimer's disease. Of course, we've learned, and I'm sure you've covered here, that the changes of Alzheimer's disease in the brain, the accumulation of plaques and tangles starts to occur many years before people have even the earliest symptoms of memory loss. And we know that people who are accumulating amyloid as they get older, even if they don't have symptoms at the moment, they're at higher risk of developing cognitive decline, developing MCI or dementia over the next few years. And I think many of us are excited about the possibility that if we go even earlier and treat people when they already have plaque, but they don't yet have symptoms, that they may be a greater benefit to these treatments than when we're already treating established disease. And in fact, that these treatments might be very helpful in delaying or even preventing the onset of memory loss. And so this is a hypothesis that exists in the field. There are currently two clinical trials with the approved drugs with Leqembi and Kisunla. These trials are called AHEAD 345, that's a trial of Leqembi. And TRAILBLAZER ALZ3, that's a trial of Kisunla in cognitively normal older adults who have evidence of amyloid. And hopefully in the next couple year or two years, we're going to start to get results from some of these trials. Trontinemab may be a very attractive treatment for people who have amyloid but no symptoms, especially if you can treat for a shorter time and there's less risk of side effects. Even people who don't have symptoms might be more interested in trying that treatment if it can in fact prevent or delay cognitive decline. And that is what PrevenTRON is designed to test. So PrevenTRON will be enrolling older adults ages 55 to 80 who have no cognitive or functional problems, have a study partner and have evidence of amyloid pathology based on the PTAU-217 blood test. And in fact, the threshold for enrollment is set at a higher level for people who not only have elevated PTAU-217, but have a level that puts them at higher risk of developing cognitive problems in the next few years. About 1600 individuals will be recruited and randomized to receive either trontinemab induction over six months and then maintenance or placebo. Again, these will be global trials. And the primary outcome there is actually an event which is the development of cognitive impairment, a moment when someone goes from being cognitively normal with amyloid to having clinically significant memory loss. And the trial will be testing whether treating people with TRONTI will reduce the risk that they will develop MCI or dementia over the next few years compared to placebo. So that is the design of PrevenTRON. It's quite similar to the design of the Trailblazer ALZ3 study, which is also enrolling people based on the plasma P-tau-217 blood test and also using this time to event as a primary endpoint rather than just following people for a set amount of time and then seeing what happened to the drug versus placebo. So these trials are a little unpredictable in their timeline because you actually need to have enough events of people developing cognitive impairment before the trial is unblinded and you can test the results. Nancy Keach: And is there sort of a pre-trial screener called TRAVELER? Am I correct about that? Can you talk about TRAVELER if that is relevant? Dr. Gil Rabinovici: Yeah, so TRAVELER is a registry that Roche has developed basically to have a trial-ready cohort, to have information about people who are really interested in participating in clinical trials. It's all done remotely, so it doesn't require in-person visits. Individuals are pre-screened, they get a memory test. I won't say which one, so people won't practice, but they get a memory test and they also get a blood draw for P-tau-217. And then based on those two things, they are actually referred for potential clinical trials. So people who had an abnormal or a high level of PTAU-217 and had impairment on their memory test, for example, could be referred to the Trontier one and two studies. Individuals who have a high PTAU-217 but perform normally on their memory test, they may be great candidates and will be referred for PrevenTRON. So it's basically a way of people saying I'm interested in trials for Roche to have some indication of their biomarker status and their memory performance and then get people involved in trials. What's been really great about Traveler is A, it's been very successful in registering large numbers of people. So I think there's over 10,000 people already registered. But the other really important thing is that people who have registered for Traveler tend to have much more racial and ethnic diversity than we've often seen in these clinical trials. So about 20% of people in traveler self-identify as Black, about 20% as Latino. This is much more representative of our US racial and ethnic demographics. 5% self-identify as Asian. So it's really important, of course, to have access to trials for people of all backgrounds and to also test drugs in samples that are representative of people who are at risk for the disease. And that's where a lot of trials have fallen short in the past. There has been under-representation of certain communities in these trials. And so the goal of Traveler, and it's been successful so far, is actually to have a more diverse pool of potential clinical trial participants and enable access to communities that in the past have been underrepresented in research. Nancy Keach: We don't talk about that a lot here, but it is extremely important scientifically. And so I want to remind people that having diverse participation in clinical trials is not a social construct necessarily in and of itself. This is science and you have to have a good representation of types of people in a trial to make it what they call generalizable, but to apply it to people with different genetic backgrounds. So I want to ask two broader questions, and the first is about this idea of prevention trials, right? What would you say are the ethical considerations of taking a drug before somebody has symptoms? Taking drug, trying a drug based on the fact that they have amyloid in their brain based on a blood test or a PET scan or a lumbar puncture? Dr. Gil Rabinovici: Well, I think the science is very clear that people who have amyloid in their brain are at higher risk of developing cognitive impairment. That doesn't mean everyone will develop MCI or dementia, but there is a significantly higher risk and if people live long enough, it is actually likely, I think, more likely than not that they will develop some level of impairment. And so I think that there is a huge need, not just to treat people once they're symptomatic, but actually to think about prevention. Dementia is such an incredible public health crisis for us as the population is aging. And if we had a treatment that could even delay the onset of dementia by five years, that would reduce people's risk by over 50% of getting dementia in their lifetime. It would reduce the economic cost on families and on healthcare systems. And so I really think prevention is important. And of course in medicine, we have many precedents. High blood pressure, unless it's really extreme, doesn't cause symptoms. High cholesterol, unless it's really extreme, doesn't cause symptoms. Even early stage diabetes may not cause symptoms, but we know that treating high blood pressure, treating cholesterol, treating early diabetes prevents heart attacks, strokes, potentially even dementia. And so in the same frame, if we know that amyloid in the brain is a significant risk factor and we have drugs that can be given to try to ameliorate that risk, that is something we do in medicine all the time. Of course, for any individual, a decision is going to be based on their risks, their perceived benefits. The hope is, of course, that we'll have a drug like a statin that we use for high cholesterol, just a pill that people could take that would keep their amyloid levels at bay, and we wouldn't be talking about infusions or ARIA or other things. I think we'll get there someday, but at the moment, the class of drugs that we have for prevention that we're looking at in terms of pharmacological prevention, at least we're looking at this class of anti-amyloid antibodies. Nancy Keach: And you mentioned controlling blood pressure, and my understanding is in terms of modifiable risk factors, that is the most important thing you can do is take care of your heart health. So I'm just going to mention it again because it's something you can do today when we're talking about these drugs maybe not being available for a while. And in the last couple of minutes, I'm going to ask another broad question that we discussed before we started the program, and that is about clinical meaningfulness. So we talked about ethics of taking a drug before you have symptoms, and that's one question. But as we're developing these drugs that are actually working for the first time in history, to some degree, there's a lot of pushback. There's a lot of naysayers out in the community who are writing, "Oh, these monoclonal antibodies, the effect barely matters. It's not worth the risks." So there's this debate that can be really confusing to people. So when we talk about clinical meaningfulness, the monoclonal antibodies that are on the market, Leqembi and Kisunla, hopefully trontinemab, if it gets approved in the next several years, can you talk about what we know about clinical meaningfulness so that people can make educated choices about whether this is meaningful to them without being confused by the noise? Dr. Gil Rabinovici: Yeah, that's a great question, Nancy, and it's really tough, right? So these drugs, even when they're working, they don't make people's memory better, they don't stop memory from declining. So you're asking, well, what is the point? What is the clinical benefit that someone might get from the drugs? One analysis that was done both for Leqembi and Kisunla that I found very useful and that I use in my discussions with patients about risks and benefits is an analysis where they looked at progression to the next disease stage. So for example, that means that if people entered the trial at the MCI stage where they had memory loss but were still independent, what was the risk that they would develop dementia during the trial, that they would start to need some help with some of those more complicated daily tasks? And in both trials, they found that being on drug reduced the risk of progressing in disease stage by about 35 to 40% compared to placebo. So that is something that is obviously, I think, clinically meaningful to most people, which is, can I stay independent or am I going to start to need some help in my daily tasks? And so that is an analysis that I present to patients. I say, this drug at a group level, we saw that it reduces the risk of progression in that disease stage by about 35 to 40%. That's one way of framing clinical benefit. And then of course we go on and discuss the risks of ARIA and other side effects based on their APOE status and other potential risk factors. Nancy Keach: And you talked about time to progression to the next stage and a percentage, 35 to 40%, and this is where I think people get confused, and I know that this isn't an exact science at this point, but I think we were talking about that roughly translating, and this is say a course of 18 months with a monoclonal antibody that's already been approved, Leqembi or Kisunla, statistically speaking, slow your time to progressing to the next stage of development by about five months. And that's over a shorter 18-month course. So as the time stretches out longer, that could mean a little bit of a longer delay. Dr. Gil Rabinovici: There was a paper led by Giovanni Frazoni at the University of Geneva where he compared the benefit and the risk of these new Alzheimer's drugs to drugs that are approved and used to treat other diseases like cancer, MS, rheumatoid arthritis, multiple sclerosis. And what he found was that the Alzheimer's disease drugs stacked up pretty well against drugs that we use for cancer, for autoimmune conditions in terms of their benefits and also in terms of their risk profile. So why do we think about Alzheimer's and dementing disorders in a different way? It's hard for me not to think that some of these regulatory agencies are biased in how they're thinking about older adults, how they're thinking about mental health, because they're clearly using a higher bar than they're using for other devastating diseases. And even though Alzheimer's can be invisible in terms of its physical impact until very late stages, it is a devastating disease. It is actually as feared, if not more feared by older adults in comparison to cancer, in comparison to heart disease. And so we're not asking for any special treatment, but just use the same bar that you use for other drugs when you're thinking about this disorder. Nancy Keach: So as our time today comes to a close, I want to thank you, Dr. Rabinovici, for your time, for sharing your information, for your amazing dedication to this field. There's obviously tremendous interest in trontinemab. There's tremendous interest in participating in trials, in prevention trials, in disease modifying trials, in lifestyle modification trials. So thank you. Thank you for joining us today. Please come back. Dr. Gil Rabinovici: Absolutely. It was really my pleasure. Thank you so much. Nancy Keach: Thanks for listening to Let's Talk Alzheimer's. Initial reports on trontinemab�s brain shuttle technology and low side effect profile make it one of the most exciting drugs currently in clinical trials for Alzheimer's disease. Over the next several years, we'll know much more about how well it works and also about whether the brain shuttle technology's ability to courier drug across the blood-brain barrier could also be used for other drugs that are not brain penetrant. If you are interested in finding out whether you qualify to participate in a clinical trial using trontinemab, please call Genentech's trial information support line, 1-888-662-6728. And if you'd like to learn more about Alzheimer's clinical trials or find studies recruiting in your area, visit the Alzheimer's Disease Research Program at brightfocus.org/clinical-trials. Remember, life is very short. Tell everyone you love how much you love them, give them a hug and hold them close to you. Have a great day and be well. Narrator: Thanks for listening to Let's Talk Alzheimer's. If this episode help you better understand Alzheimer's disease, please hit like and subscribe to stay informed. And if this podcast would be helpful to people you know, please share it with them. For trusted information on Alzheimer's and the latest research towards a cure, visit brightfocus.org. Get the latest information on new medications, lifestyle changes, active clinical trials, and breakthrough technologies. Thank you to our sponsors, Lilly, Biogen, Eisai, and Genentech for making this program possible. And thank you so much for spending this time with us.