Rx for Alzheimer's

[00:00:12] Speaker A: Welcome to the Age of Aging, a show about living well with an aging brain. Produced by the Penn Memory center in the Michael Nadoff Communications hub. I'm Terence Casey. Our next full season is coming together and will be in your feed in about a month. In the meantime, we're excited to share a special episode featuring Penn Memory center co directors, Dr. David Wolk and Dr. Jason Karlewish, who also serves as the show's executive producer. Last month, they attended the Clinical Trials on Alzheimer's Disease conference, and today they'll share what stood out to them, what they're watching closely for 2026 and beyond, and how the field is thinking about the present and future use of anti amyloid therapies. They also discussed the highly anticipated GLP1 trial results for Alzheimer's disease. But spoiler alert, the results were negative. I'll be back after their conversation. Jason, take it away. [00:01:16] Speaker B: Hi, Dave. Happy New Year. [00:01:18] Speaker C: Hello. Happy New Year. [00:01:20] Speaker B: Did you have a good New Year's, Dave? Good holiday? [00:01:23] Speaker C: Yes. Did you have a good holiday, Jason? [00:01:25] Speaker B: I had a great holiday. I worked on the syllabus for my class this coming semester. The Alzheimer's crisis had a great time, so I'm teaching that. What about you? What did you do? [00:01:36] Speaker C: I worked on my syllabus. No, we went to Montreal. [00:01:40] Speaker B: Oh, someplace warm over the holiday. Great idea. [00:01:43] Speaker C: Yeah. [00:01:44] Speaker B: Well, we were in someplace warm, though, in early December. San Diego. [00:01:49] Speaker C: That's right. [00:01:50] Speaker B: Yeah. Clinical trial and also CTAD, clinical trials and Alzheimer's disease, 2025. Did you get to stay at the meeting hotel? [00:01:57] Speaker C: I did not. I stayed at the Hard Rock Cafe across the ways. [00:02:02] Speaker B: Wow. Did you get any sleep? [00:02:06] Speaker C: It doesn't live up to its name. It's not. [00:02:09] Speaker B: I was sent to what amounted to kind of a. Kind of a distant, let's just say, step count in. I got my step count in. [00:02:17] Speaker C: Yeah, that's pretty close. [00:02:18] Speaker B: Yeah, I was like, very far away. Anyway, we were in sunny San Diego for CTEC clinical trials on Alzheimer's disease, and I thought we could chat a bit about, like, what we. What were our takeaways from this? Once upon a time, it was kind of a boring meeting because the clinical trials were kind of not very successful. And then things started to change. Although that was the famous location and the same ballroom, I believe, where the famous Aducanumab results were released. But we won't talk about that. What impressed you about the findings that were presented about our current treatments? Lecanemab and Donanemab. We certainly had some presentations there about those two drugs. Yeah. [00:02:56] Speaker C: I think, I mean, I will say just to step back, that there was a time at this meeting where you basically had to squint to believe any of the trials should move on from earlier phase studies to later phase studies. And I think just the breadth of different interventions and the ability to move the biology of the disease with all these wonderful kinds of measures that we now have seems to be a much more consistent theme across the board. So that in of itself adds excitement to the meeting. In terms of lecanemab and donanemab, I think there were sort of two big themes in my mind and I think, you know, from talking to you, you agree as well. One is that there's was more emergence of some of the real world data, the implementation of replarapies in practice or in, you know, actually across the world in different countries, including the United States, that seem to support the idea that these drugs can be administered fairly safely, that they basically have similar safety profiles. Not actually a little bit better than what we saw in the clinical trials themselves, which is comforting. There are probably some caveats to that in terms of which institutions are reporting and how widespread it is, but I think that that was very, very encouraging. [00:04:26] Speaker B: Yeah, no, I think what we're seeing is in some sense the drug's complexity might be their savior because, you know, you can't just be a lone rogue prescriber of these drugs. You really need a very, you know, established infrastructure, as we've learned at the memory center, to get these drugs going. And so in some sense it kind of assures kind of rational prescribing and such. Yeah, no, I agree. It was very impressive. What about the efficacy data though? So we have a very interesting situation here. We have one drug, Donanemad, that says take it until you clear amyloid, roughly 18 months. Once amyloid's clear, stop it. You have another drug that says take it forever. That's the Kmabat. Granted the after 18 month period of at one dose, you go to a lower dose, the quote, maintenance dose, et cetera. So we've got one drug that says take me until you clear amyloid and you're done. The another one that says take me for kind of ever. So what did we take away about which drug is sort of the drug to take if you want to get the benefit for as long as you can. What was your takeaway? [00:05:26] Speaker C: I think the takeaway is that we don't know. [00:05:31] Speaker B: Yeah, that's exactly what I care. I think we didn't make friends there with either company on that one. [00:05:38] Speaker C: I mean, I think there was and they've now been presented at several meetings more and more long term data, open label data from both drugs. One of the issues with after the placebo controlled randomized portion of a trial ends is everyone is on drug after that point, after the 18 months of the trial, so you don't really have a placebo group to compare to. But both drugs are compared to other matched populations with regard to disease severity and other features. And both drugs seem to show a similar widening of the benefit of the drug over time. So that that 25 to 35% slowing of disease seems to continue when you compare to these matched control groups. And I think what was telling about that, again with all the sort of caveats of historical control groups where again, they're not as matched as in a blinded trial, but they both drugs look very similar in the relationship to that historical control group over time, which suggests to me that both drugs have pretty similar efficacy over a longer period of time, despite the fact with one you're not continuing treatment and then the other you're continuing maintenance therapy. So, yeah, yeah. So I don't feel like there's really compelling reason to say that, you know, maintenance therapy is better with lecanemab and the strategy that's used with Donanemab, they do target different aspects of amyloid in the brain and so it could very well be the case. Lecanemab, you need to continue to take it over time and Donanemab, you don't, I think, when I suspect you have a similar feeling based on our conversations within the memory center. But right now it comes down to convenience with the cost and convenience. [00:07:33] Speaker B: Yeah, yeah, no, it's fascinating actually. So I think we're in a very interesting period because I, I sensed lecanemab has now sub Q prep, which is available for that, for the extension phase. But they're pretty keen, I bet, to get that sub Q prep approved for the initiation phase. Because I think what we're in for is a very interesting period where let's fast forward, let's suppose that, suppose that approval happens. Okay, well, I can take an intravenous drug, you know, monthly for 18 months or I can take a sub Q drug kind of for a long time. Which one do I want to do? I think it'd be a very interesting question of convenience. But I have the hunch we're going to see cost march in. And I would predict actually it'll be very interesting, almost battle of price. And this is where the insurers will become Very interesting too because there'll be a lot of negotiations going on about what's available or not. So I think we're in for an interesting ride in the next 12, 24 months with the existing therapies as to which one is the preferred therapy and why. And I have the hutch. Certain opinion leaders will line up on various sides with various slide decks. It could be, get, could be a kind of amusing, but we won't go there. [00:08:41] Speaker C: Yeah, I, again I, I, I, I think it, the, the only way to really know is to do like a head to head trial. Yeah. [00:08:48] Speaker B: Do you think that's going to happen? [00:08:49] Speaker C: Never going to happen. [00:08:50] Speaker B: So yeah, never, never say never. But I think the odds on that one are yeah, we won't give it comparative odds, but yeah, yeah. So, but let's look to the future and I think that's what I, I think you and I had the same. There was a great presentation by Ronald Dimados of, of, of Lilly about the, the next generation of anti amyloid therapy shuttling past the ARIA risk. So he's getting at the, you know, these microscopic bleeds and edema otherwise known by that quirky name Aria. We actually have therapies in the works that might significantly reduce that risk. What was your takeaway from that? [00:09:25] Speaker C: Yeah, so I think there's this brain shuttle technology that Roche has developed related to their drug Gantaneer mab, which failed actually in clinical trials and actually had somewhat less ability to clear amyloid than the current approved drugs. But that attaching this sort of shuttle to the antibody allows it to pass into the brain in a, a more direct way than currently how these drugs are administered. So one of the things about these drugs is there's very little brain penetration of these antibodies and so you're giving people doses like a thousand times or more in the periphery that then gets into the brain. And the way it gets into the brain is through the fluid that surrounds the brain and sort of into the surface of the brain. And there's a fair bit of data with these kind of brain shuttles that allow you to cross the blood brain barrier more easily, that there's sort of more even distribution and a lower dose that's required of these drugs and better targeting of them. And importantly, because of the way they get into the brain there may be less likelihood of this ARIA side effect because the antibodies don't necessarily have to travel along the blood vessels themselves which seems to contribute to what causes the inflammation and the bleeding associated with aria. [00:10:53] Speaker B: It was an excellent, it was a really Compelling presentation because it really kind of delved into the mechanism, which I don't pretend to be able to fully recite here at all. But my walk away was, you know, once drugs that use the shuttle mechanism are shown to also be effective, I think we're going to see a whole new generation of these drugs available, don't you? [00:11:14] Speaker C: Yeah, I mean I, I think they presented data that I think one, you know, and not much of this they have presented before, but includes the sort of full data from their phase two trial. I believe this is Roche. Yeah, for Trontinumab, which is the sort of souped up version of Gansmarabab that really shows very impressive clearance of amyloid from the brain in a shorter period of time than we would expect for the current drugs and also much lower rates of aria, which will likely make them a lot safer, I think. You know, the thing that is interesting to me also though is that these shuttles, Roche has one of them, but there are other shuttles that other companies are working on. Implications not just for anti amyloid therapy, but for actually a lot of CNS based therapies. Because one of the challenges in treating central nervous system disorders is getting things into the brain, into the brain. So I think very exciting that they've been able to, you know, show this to work in now in a, in a very applied practical way in the context of anti amyloid therapies. But I think it's going to have implications for other Alzheimer's related therapies, but also potentially for under brain disease diseases. [00:12:38] Speaker B: You know, in some sense it's interesting, the blood brain barrier has been thoroughly breached. We're able to measure the diseases now with various biomarker measures that we would never have thought we could have done at some, you know, in blood, et cetera. And now we're also seemingly able to get the drugs into the brain much easier. So we really have breached that, that barrier to the brain? Yeah, no, I think in a few years we'll look back on the existing therapies as historical and we'll be using these new generation therapies that'll be much less dosing, less frequency of dosing and a better safety profile. I think that's something to look forward to in the future. [00:13:15] Speaker C: I'm curious to ask you, what do you feel about the ethics of trials around tretinumab since they're designed to be placebo controlled? Yep, it's a good question. [00:13:26] Speaker B: I think as long as there are people saying no to the existing drugs, I think a Placebo control makes sense. I don't think we've arrived at the point where to not be on one of these drugs is. Of course patients can refuse even the safest and most efficacious treatments for a disease. But I think the rates of uptake and whatnot still show us that there's a spectrum of tolerance for the risk and benefit of these drugs. So I think with a decent informed consent process, the placebo controlled trial for now is still viable. But that door may close. I mean, if we start to see these shuttle drugs being more efficacious, safer, et cetera, it's going to be hard to sort of continue doing placebo controlled trials in this space. It's going to be really hard. Which in the history of other drugs means you go abroad to India or Russia or given our political geopolitical order, God knows where you'll go. But anyway, we'll set that aside, listeners. We just invaded Venezuela earlier tonight of recording this. Anyway, so there were some other results that were presented that were. That were rather evocative. I'm joking here. But of course the Evoke Evoke plus results that namely the Novo Nordisk's presentation of their GLP1 inhibitor wasn't Ozempic, but it was, it's, it's an Ozempic like compound that they tested in persons with mild cognitive impairment or mild stage dementia of the Alzheimer's type based on biomarkers of amyloid over a reasonably long period of exploding 18 months of drug versus placebo. [00:14:58] Speaker C: Two years. [00:14:59] Speaker B: Yeah. 24 months. Yeah. Two trials. Two adequate, well designed placebo controlled trials which was a bold. Didn't have a lot of phase two data going into it, which may be one of the many reasons why Monday Morning Quarterbacks unfortunately operate for this truck is what the results were, of course. Dave. [00:15:16] Speaker C: Negative. [00:15:17] Speaker B: Yeah, negative. I mean, yeah. Really? Yeah. There wasn't even a smidge of difference between drug and placebo over 24 months. [00:15:26] Speaker C: I mean it, you know, it, it there they provided a rationale for why they moved forward. My these drugs have been very successful for a variety of health related outcomes and so I think they felt very sort of ambitious about wanting to apply this in the context of Alzheimer's disease without as much of the kind of preliminary data as we expect before you get to two parallel phase three trials. Maybe because of the success of these drugs they had the sort of financial backing to do this where other companies couldn't necessarily move this forward. But yeah, there has been a tendency. [00:16:05] Speaker B: In the field though to skip phase Two and be a little frisky. I do think issues of patent life enter into this. Namely, if you do a phase two, you're chipping away at your. Your exclusivity. And I think. I think their drug semaglutide is coming to its end soon. So there may have been a little urgency there, but, you know, we'll. That was not presented as I. Yeah, so. [00:16:26] Speaker C: Well, I mean, you know, so I think a couple things about the trial. So they provided their motivation and there was some data. Most of it was historical data, but there is some data in specific groups around potential benefits for cognition like type 2 diabetics, which I think doesn't necessarily apply to the population that they studied here. I think, you know, to me, it also was an example of where the biology was very unclear. You know, they presented, I think, four or five different mechanisms as to how. [00:16:57] Speaker B: I'm interrupting, but to me, the ultimate was at the end of it. There was a question to the Novo Nordisk presenter about getting it at mechanism of action. And the Novo presenter said, well, it depends on what mechanism you want, or something like that. I mean, there's about four or five possible mechanisms. But I think the issue. The clinical endpoints were completely negative, but there was this provocative finding on Alzheimer's biomarkers. It was subtle, but it was there. And it led some of us to say, well, maybe there is something there. They just didn't give the right dose. Granted, the game oral. [00:17:34] Speaker C: Which biomarker are you referring to? [00:17:36] Speaker B: I knew you'd call me out on. [00:17:37] Speaker A: Which biomarker, because I don't think they're. [00:17:39] Speaker C: The traditional AD biomarkers where there was some data in, I think, CSF but not in blood. And so I. I think there. It was pretty limited. Any kind of. [00:17:49] Speaker B: Let me get my. Let me get my notes here. Let me get my notes. I got my biomarker response on P. [00:17:55] Speaker C: Tau181,217 in blood, there was not any. [00:18:01] Speaker B: But in CSF there was. Yeah. [00:18:03] Speaker C: And in a much smaller sample in csf. I. I was not particularly moved by the. By the biomarker results for this trial. [00:18:12] Speaker B: I. I'm not moved to prescribe it, but I just to be tempted, you know, one could say again, dosing that. Have they given injection, et cetera. One might have thought we get more into the brain, you might see more there. Again, I, you know, I'm not. [00:18:25] Speaker C: I might, you know, given the sensitivity of plasma biomarkers, not showing plasma efficacy is sort of in that big of a trial over that Long of a period of time, I think is a bit hard to think that targeting AD itself during symptomatic phases, at least is. [00:18:46] Speaker B: And yet they did present data from one of the trials that got them the cardiovascular indication that was a proteomic signature for dementia risk. That was a very compelling reduction of the, of proteomic signature, the dementia risk. In a study though, that we don't have data yet about incident dementia, et cetera. That adequate. So there are these signals going on here. [00:19:09] Speaker A: Yeah, there. [00:19:09] Speaker C: I don't, I, I don't think that there might not be signals of systemic, metabolic and other salutary processes that might protect your brain to some extent. I think the argument about directly, at least in the context of active Alzheimer's pathology, that you're altering that biology is probably a little harder to make that argument at this point. I do suspect that GLP1s are going to have a significant effect on dementia risk because they're going to reduce obesity and cardiovascular disease. And so I think at a public health level they'll have a significant impact. I'm just less convinced of the direct. [00:19:50] Speaker B: Effect which could lead to do the study again for the most provocative label FDA could ever grant for the reduction of the risk of all cause dementia. That would be quite a drug to prescribe. So let's pivot though, actually, I think this conversation is pointing our way to Pointer. So there was more data from the famous Poynter study. I can't remember what the acronym is for, but it's a study of intensive lifestyle intervention in people at a elevated risk of developing dementia based on a host of factors like body weight, blood pressure, et cetera. They don't have dementia, but they're at risk of it. And Pointer, of course, the top line results were presented at AAIC in Canada this summer in Toronto, which showed an effect of this structured intervention greater than the unstructured intervention on an overall measure of cognition. True, the group that didn't get the unstructured measure also got better on the cognitive measure, but not by as much as the other group. We could debate effect sizes there, but they presented some more data at ctad, data around the effect of the structured intervention on other cardiovascular risk factors. And guess what? What did we see with sleep? Apnea was reduced, if I'm not mistaken. Blood pressure and cerebral blood flow were also improved. So a host of findings there, but there was also some rather disappointing findings. What stood out for you? [00:21:15] Speaker C: Yeah, so, you know, I feel like the, you know, the Pointer study seemed to suggest that these kinds of interventions have general health benefits. And I fully believe in the notion that a healthier body and a sort of healthier vascular system protects your brain from or allows you to be more resilient to things that occur to your brain as. As you age. And one of those things can be Alzheimer's disease. And so I think, you know, this. The study showed some evidence of benefit in people who had higher risk related to some of these risk factors. And that living a healthier lifestyle, as we tell all of our patients all the time and I think try to live by ourselves to varying degrees, I think is clearly a benefit. I think what, you know, we're sort of left with is a lot of a sort of lack of clarity and if anything, more negative data with regard to. Does this move the biology of. [00:22:20] Speaker B: Because what were the points or findings on the biology of. [00:22:23] Speaker C: Yeah, that there was very little change on our sort of traditional, you know, biomarkers of Alzheimer's disease. [00:22:29] Speaker B: So there's almost two parallel conversations going on. There's mechanism interventions that we think are targeting the disease and therefore changing disease markers. And we're beginning to see a story of interventions that target other things that don't change the markers of the disease but still seem to do good things for the brain. I'm not trying to raise a controversy here, but the latter, I think, has a less clear biological way to measure what's going on. In other words, you know, measure neuron health. I mean, we don't have a neuron health measure, really. You know, it says how healthy your neurons are, not, et cetera, although maybe, you know, microstructural measures on MRI or something might become a new way to talk about how healthy your neurons are. [00:23:14] Speaker C: We'll see. [00:23:15] Speaker B: But it was. It was an interesting finding there. No effect on Alzheimer's markers, but certainly effects on a host of risk factors. And again, this overall cognitive measure, we don't know yet that that pointer study reduces the risk of developing dementia. They don't measure incident dementia in that study. So we don't know that that translates into reducing getting dementia. So that's a. That's a. That's an unknown. [00:23:37] Speaker C: One thing, sort of stepping back to the Evoke trial, that I think is important, and the Evoke plus trial is that the trial was. This was stated multiple times. Well designed in that, you know, both the treated and untreated groups showed really no difference in their clinical outcomes. And the reason why I think that's important is there were more adverse events, more weight loss, more nausea. So both positive Health things and maybe some negative ones in the treated group versus the untreated group. And I point that out because I think there's been at least some thought as to the degree to which our blinding and the anti amyloid therapy trials might influence outcomes. And I think it's interesting that in a trial where there was a fair bit of what we call functional unblinding because individuals got sick and stopped the drug early for a variety of different reasons, that we didn't see any impact on outcomes. Now obviously there's a lot of psychology to these types of things and so who knows about how people view a side effect in one drug versus the other. But I did find that to be a kind of interesting result, partly because I was just so amazed at how much those curves overlapped with each other in the treated and untreated group, which in and of itself is. Usually there's a little bit of noise more so between the curves. [00:25:04] Speaker B: Yeah. My takeaway on evoke and whatnot. The meeting in general with evoke on my mind, no pun intended. There was, I thought I've been still chuckling at what Eli Lilly did, which was host a dessert reception for all the attendants there. I thought that was. They seem to be endlessly clever, the Lily folks there. So we were all gorged our disappointment over the evoke results by having big piles of dessert at the beating. Next year's meeting I think is in Boston. Am I wrong on that? [00:25:37] Speaker C: I think that's right. I think that's right. [00:25:39] Speaker B: Yeah. So we stay in the US and I guess next time, Dave, you and I'll gather after London, which is when AAIC will be in London this coming year. We'll things between now and then maybe we may hear the results of the Trailblazer 3 study. We're perpetually reminded Dan Skavansky and STAT was yet again reminding everyone that it's a time to event trial. So the moment they hit the pre specified number of incident cases of transition to CDR 0.5 or 1, the machine will analyze the data. So tomorrow even we might hear the results of that study of Donanemab in persons who are at risk of developing MCI or dementia caused by Alzheimer's that may read out this coming year will be very exciting if it does. So we'll see. Always good to chat, Dave. [00:26:31] Speaker C: Yeah, nice to chat. Nice talking to you. [00:26:33] Speaker B: Yeah. [00:26:34] Speaker C: Maybe we'll actually run into each other at the next. [00:26:37] Speaker B: Yeah, we never. It's as small as the meeting is. I think I thought that maybe you had skipped it, or you were spending all your time at the bar, because I didn't. I didn't see you. [00:26:45] Speaker C: Yeah, that's at the dessert bar. [00:26:51] Speaker A: Hi. Terence here. Again, thanks for listening to this special episode of the Age of Aging. Our new season will be here in just a few weeks, but in the meantime, it would mean a lot if you rated and reviewed the show on your favorite podcast platform and shared this episode, or any episode that you love with someone who might enjoy it. Those small actions make a big difference in helping new listeners find the show. A big thank you to Dr. David Wolk and Dr. Jason Karlewish for their time and insight today. We'll see you all soon for season five. [00:27:22] Speaker B: Sam.