Lecanemab, Clinical Trials, and the Importance of Clinical Meaningfulness

Transcript

Intro: I'm Dr. Nathaniel Chin, and you're listening to Dementia Matters, a podcast about Alzheimer's disease. Dementia Matters is a production of the Wisconsin Alzheimer's Disease Research Center. Our goal is to educate listeners on the latest news in Alzheimer's disease research and caregiver strategies. Thanks for joining us.

Dr. Nathaniel Chin: Welcome back to Dementia Matters. The Clinical Trials for Alzheimer's Disease meeting, also known as CTAD, is an annual event bringing together experts from academic and industry research to discuss the latest developments in the field of Alzheimer's disease diagnostics and therapeutics. Held between November 29 and December 2 in San Francisco, California, the CTAD 2022 meeting highlighted numerous key trials and their findings, including results from the Clarity AD trial for lecanemab, which we discussed earlier this year. Over the next few episodes, we'll be joined by some of the conference's key speakers to discuss the latest developments and interventions presented at CTAD. Your returning guest, Dr. Paul Aisen, is joining me today to talk about the annual conference. Dr. Aisen has been a leading figure in Alzheimer's disease research for three decades, serving as founding director of the Alzheimer's Therapeutic Research Institute, known as ATRI, and the University of Southern California, Keck School of Medicine, which coordinates the NIH-funded Alzheimer's Clinical Trials Consortium and the Alzheimer's Disease Neural Imaging Initiative. As well as leading the ATRI, Dr. Aisen is a member of CTAD's organizing committee, a co-chair for the annual EU-US Task Force on AD Trial Methods, and is co-editor-in-chief of the Journal for the Prevention of Alzheimer's Disease. Dr. Aisen, welcome back to Dementia Matters.

Dr. Paul Aisen: Thanks, I'm happy to be here.

Chin: I would like to start with some history. Can you share with us how and why this conference was developed?

Aisen: Sure. Well, CTAD started 15 years ago, and the idea was to bring together clinical trialists, the people working on clinical trial methods, trial designs, and conducting therapeutic trials in Alzheimer's disease. So other meetings in the field had covered broader topics such as bench research, epidemiology, and many other aspects of Alzheimer's research. This meeting was set up to focus on clinical trials and clinical trialists. It started with under 100 participants. This year's meeting had about 2,000 in person and many more online, so it has grown quite a bit.

Chin: Yeah, it's a pretty significant increase over time, and of course, the field is very exciting, which I'm going to ask you questions about in the next few minutes. But now that the conference is over, what were some of the highlights for you?

Aisen: Well, certainly the highlight would be the presentation on the first evening of the lecanemab Clarity results. I think this is a milestone in AD therapeutic research. It was very exciting, I think, for all attendees to see a detailed scientific presentation and discussion of the results of the lecanemab program, so I would say that was the highlight.

Chin: You have a lot of knowledge and experience in clinical trials. Were there some presentations or findings that perhaps caught you off guard? Did anything surprise you that was presented this year?

Aisen: I wouldn't say that anything was surprising. There are many presentations, many oral presentations, many posters covering drug development programs from their earliest stages to late stages, and there's always a great deal to learn. Many people are presenting results and not everyone agrees on ideal optimal methods, so there are areas of discussion and even disagreement. But I wouldn't say there were any major surprises. Yeah, I would not say there were major surprises at the meeting.

Chin: For our listeners, when we think about therapeutics, most people, of course, jump to these monoclonal antibodies, and those that listen to this podcast are very aware of that. But the presentations at CTAD are quite diverse. They're looking at behavioral symptoms. They're looking at other cognitive enrichment strategies. They're looking at the methods themselves, so it's a pretty diverse group of people. Now, for the next question, I do want to focus on what you've already mentioned with lecanemab, but there were two significant phase 3 clinical trials presented at CTAD. Lecanemab was one, and then gantenerumab was the other. Could you share with us some of your takeaways from each of those presentations?

Aisen: Sure. Well, they're both major phase three programs, large clinical trials, testing a monoclonal antibody that targets amyloid deposits in the brain, and the idea behind both is that if you can remove amyloid to a significant extent, that should slow the clinical progression of the disease since amyloid is a key driver of the disease process. With lecanemab, the therapy resulted in a major reduction in amyloid. The lecanemab was administered intravenously and as expected, on average, the reduction in amyloid level came down to normal. With gantenerumab, the antibody was administered subcutaneously rather than intravenously. The dose schedule involved a long titration phase, and the hope was, again, that amyloid levels would drop to normal in the majority of participants. The finding that was disappointing was that while there was a significant reduction in amyloid levels as indicated by amyloid PET scans, but the result was less than anticipated, and the majority of participants did not have their amyloid levels reduced to the normal range. I think that is key to understanding the differences in the results between lecanemab and gantenerumab. Lecanemab, as expected, slowed clinical progression. Gantenerumab seemed to be having a mild favorable effect, but a very small effect on clinical progression. It had a favorable effect on biomarkers. But overall, the results suggest that you really have to have that traumatic reduction in amyloid or clinical progression may not respond in the anticipated way.

Chin: I appreciate that insight, and one of the things I appreciated at the conference was really avoiding the use of the phrase failed trial, because in this regard, while gantenerumab didn't reach its ultimate goal, it's been very helpful in understanding success and why certain things are successful in lecanemab versus gantenerumab, and really the importance of the things you just said. So instead, we should be using the phrasing negative result. Is that right, Dr. Aisen?

Aisen: Yeah, I think that's certainly true. It's a trial that is highly informative. The gantenerumab trial is highly informative. We learned about, again, the subcutaneous administration and dosing considerations and changes in many biomarkers as well as clinical assessments, and this now joins the results we've already seen with lecanemab and donanemab to give us a fuller understanding of anti-amyloid immunotherapy and how best to move forward. So we've now seen results from those three antibodies as well as, of course, aducanumab, and putting everything together, we're getting a consistent picture that can guide future therapy.

Chin: Given the findings from lecanemab and the other presentations, where do you think the clinical trial field is moving? In essence, what do you predict the next five years will look like?

Aisen: Well, first of all, the results of the lecanemab trial are clearly positive, not just in the primary outcome measure, the CDR sum of boxes, a clinical rating scale, but in all of the key secondary outcome measures as well. So it is a clearly positive trial with results, as expected, a significant though somewhat modest reduction in clinical progression by 27% when administered in the stage of disease that we call early AD. As I mentioned, I think that is a major milestone. It is a clear indication that targeting amyloid is beneficial. It has therapeutic potential to slow disease progression. But the slowing, 27% – while I think very important and meaningful – is not the final goal. We want to find a bigger effect on disease progression and ultimately halt disease progression and prevent the disease, and I think we can build on all that we've learned from these trials to see where the path towards greater success lies, and I think there are two principal directions that we need to explore. One is to treat earlier in the disease. If we can slow progression by 27% at the early symptomatic stage, we expect that we will have a bigger effect on slowing, a more dramatic slowing of clinical progression if we start therapy before symptoms appear. That is a major approach that is now being tested in the field, both with lecanemab in the AHEAD program, and with donanemab in the Trailblazer 3 program. So earlier targeting of amyloid is a key next step and it'll be about five years before those early intervention trials which require four years of treatment, about five years before we have results of those trials. The other major lesson I think is that once you reach the symptomatic stage of AD, even the early symptomatic stage, that for a dramatic slowing, we may need to target more than one aspect of the disease. The disease becomes quite complicated as it progresses. There are a number of copathologies. First and foremost, the tauopathy, the development of tangles, which we think is accelerated by the accumulation of amyloid. The development of tangles is present in people with symptomatic AD, and we think we should add therapy targeting tau and tangles to anti-amyloid antibodies to increase the benefit. But the tauopathy is just one of the complicating comorbidities. We want to also add on therapies that target vascular components, inflammatory components, endocrine components, and others. We think that with a complex disease, we're going to need complex treatment, combining multiple approaches to get the optimal result.

Chin: For our listeners, when Dr. Aisen is saying early AD, you're referring to mild cognitive impairment (MCI) that we believe is due to Alzheimer's disease and then mild stage dementia that is due to Alzheimer's disease. Is that right?

Aisen: That's correct. Early AD is MCI, as you say and early dementia, that are part of the Alzheimer's spectrum as confirmed by the presence of amyloid deposits in brain indicated by amyloid PET scans or evaluation of cerebrospinal fluid.

Chin: So then with each clinical trial that leads to a negative result, or as we've discussed, a lack of clinical benefit or meeting your primary outcome, the amyloid hypothesis is inevitably challenged. I know that you've discussed this as well, so the success of leucanumab may be questioning that trend, but I'd still like to know your thoughts on where amyloid tau neurodegeneration, this idea of the ATN framework, where does that fit in clinical research, specifically in clinical trials?

Aisen: Well, just to step back for a minute, our understanding of this disease has grown enormously, particularly in recent years, as we've been able to better visualize or assess all of the components of the disease. We've known from the first description of Alzheimer's that there were plaques and dangles, so that's amyloid and tau abnormalities. But until the last 20 years we were unable to measure those changes and only could be sure of the presence of plaques and tangles at autopsy, and in 2004, the first amyloid PET imaging technique was developed with a tool called PiB PET. In 2016, tau PET was developed as a way to image tangles. So with these new PET scanning methods, we could finally see, in living people with scanning techniques, amyloid plaques and tau tangles. Now, those still, as I said, are not all of the biological underpinnings of the disease. There's also neurodegeneration, loss of brain cells, loss of brain connections, synapses, and inflammatory changes, vascular changes, and other changes, and increasingly, we can measure many of those abnormalities. Over the last few years, we've started to use advances in blood testing to give us an eye on multiple aspects of the disease, and we now have accurate blood tests that reflect amyloid accumulation in brain, tangle formation in brain, neurodegeneration in brain and inflammation in brain. That allows us to identify people who clearly have Alzheimer's disease and monitor disease progression in multiple aspects. Our current approach to identifying people for trials and following people in trials is to use a panel of measurements that tell us how much amyloid, how much tauopathy, tau tangles, how much neurodegeneration and how much glial change or inflammatory reaction in brain is present in people and how they respond to different types of treatment. The ATN approach formalizes this multi-dimensional approach to identifying and monitoring changes in Alzheimer's disease, where the A is presence or absence of amyloid as indicated by amyloid PET or cerebrospinal fluid or now blood tests, and the T plus or minus is an indication of whether there's significant accumulation of tangles of tau changes in brain, again, by tau PET or blood tests that indicate tau or cerebrospinal fluid, and the N is an indication of extent of brain volume loss and loss of brain cells or neurodegeneration. Here we have imaging methods with MRI and blood tests as well that give us a quantitative assessment of neurodegeneration. So now we often talk about Alzheimer's disease studies in terms of the ATN characteristics of the population, assessments of amyloid, of tau and nerve degeneration abnormalities.

Chin: Well, along those lines, on day one of CTAD, Dr. Reisa Sperling and Dr. Suzanne Craft gave wonderful presentations and they emphasized at some point in their talks the need for multimodal therapies. This idea of combining more than one treatment method to treat Alzheimer's disease, because as you said, it becomes more and more complicated as the disease progresses. Currently, and I don't want to say primarily studies are looking at amyloid and tau, but many studies look at amyloid and tau. Do you agree that the ultimately effective treatment is going to target the multiple pathways, many of which you've already mentioned? But if you do, why aren't these trials happening right now?

Aisen: Well, I do agree that particularly at the symptomatic stage, we're going to need multiple therapies to get the optimal benefit. I hope that at the very earliest stages, even at a primary prevention approach, eliminating amyloid may be sufficient. But clearly, as the disease progresses, there are multiple abnormalities that need to be addressed, so I would agree that we need multiple therapies. Now, all trials in Alzheimer's disease are complicated, as you mentioned, and this was, of course, the reason for starting the CTAD meetings. The methods are very difficult. We're talking about a brain disease that is complex, is not readily accessible by physical examination or interview and requires multiple procedures to accurately characterize the disease, and to measure benefits of treatment, we need accurate assessments. We need to have standardized approaches that allow us to compare results of different trials, and there's a huge complexity when we move from monotherapy trials, testing one intervention, to trials that test two or more interventions. In fact, whereas in a monotherapy trial, you might have two arms to the trial, active treatment or placebo treatment. Once you're assessing more than one therapy, you have multiple arms and the simplest multi-therapeutic trial would have four arms: a placebo arm, an anti-amyloid arm, an anti-tau arm, and a combination arm, to fully understand how the two therapies you're testing anti-amyloid and anti-tau work by themselves and work in combination. When you start to think about even more arms, it's vastly more complex. So prior to having any consensus about how to administer anti-amyloid therapy, thinking about combination therapy was a daunting prospect. Now we have a good understanding of anti-amyloid therapy, and it's much more feasible to envision adding on additional therapies such as anti-tau therapies and other approaches to what we've learned with anti-amyloid approaches. So it hasn't happened yet because it's so complicated, but the recent advances in anti-amyloid therapy are enabling us now to design combination trials.

Chin: Thank you for that explanation, and I'm excited to see then what CTAD in the future looks like, because I would imagine that these combination therapies would be presented at this conference.

Aisen: Sure.

Chin: You alluded to the idea of multiple etiology and the complexity of other diseases in the brain, so I want to ask the following question, and I'll preface it by saying at the end of November of 2022, Dementia Matters did this great podcast with Dr. Roderick Corriveau, the program director of the National Institute of Neurological Disorders and Stroke. In that episode, we discussed multiple etiology dementia or mixed dementia, where multiple different things are happening in the brain that are leading to the symptoms that people think of as dementia. So knowing that mixed dementia is more common than we thought, and clinical trials in general focus on one disease at a time, will we inevitably miss other important factors contributing to brain diseases in the current framework of clinical trials? Do you ever envision clinical trials that are in one study looking at multiple different causes of dementia?

Aisen: Well, again, there are certainly multiple different causes, and some have no relationship to Alzheimer's disease. There are infectious causes, traumatic causes, vascular causes, congenital causes. There are many causes of dementia. Dementia just means brain failure. In the case of Alzheimer's disease, the disease itself is complicated, as we've been discussing, and in fact, it includes aspects of the other most common causes of age-related dementia. So the two most common causes of age-related dementia would probably be vascular dementia and Lewy body dementia. Lewy bodies are lesions in the brain caused by accumulation of a different protein, α-Synuclein, and vascular dementia is caused by strokes, large strokes or tiny strokes. We now know that roughly half of the people with Alzheimer's disease have concomitant Lewy body disease, and the majority of people with Alzheimer's disease have significant vascular disease. So it's not just that we're targeting multiple etiologies at the same time. To treat Alzheimer's disease, we have to treat multiple dementias because of the complexity of the disease. Now, there are studies moving forward that look at other dementias primarily, for example, dementias that don't have amyloid, but perhaps only have tau abnormalities, the so-called primary tauopathies, and they are being studied with anti-tau therapies on their own. But as we've said, Alzheimer's disease needs to be moving towards combination anti-amyloid, anti-tau therapies, and we will be moving towards adding on vascular approaches as well. So it's not simply looking for treatments for all of the causes of dementia, which of course we need to do, but we need to evaluate all of the dimensions of Alzheimer's disease.

Chin: That's fascinating. Thank you for framing it that way, because that's not something that I had considered, but that overlap and how it relates to Alzheimer's disease is important for us to consider too. Now, I won't be ending our podcast today with an easy question. In fact, on the contrary, I'd like to ask you one that continues to be a challenge in clinical trial work, and that is of clinical meaningfulness. So drugs like lecanemab can show a 27% reduced decline in research participants based on validated survey instruments, but is the percentage itself meaningful to a person? I know that question is asked a lot, but I'm wondering too, in addition to that, are we using the right tools to measure it? So in your opinion, how do you define clinical meaningfulness and what research tools do you think best capture that and should be used in clinical trials?

Aisen: Well, you're right that it's a difficult question, and it's one that's getting a lot of attention appropriately these days. Clinical meaningfulness is critically important. Our treatments have to be beneficial from the perspective of the people that we're treating and their families, and how do we define when something is clinically meaningful? There's no simple answer to that question. I would start by saying slowing disease progression itself would be accepted as clinically meaningful by many, many people. Without putting a number like 27% on it, many people affected by this disease would say, what we really want to do is to be able to slow the disease down. In that sense, disease slowing or disease modifying therapies are clinically meaningful, and yet we would all agree that, say, a 1% slowing of decline is too small to be important to people, and we always have to balance the benefit in terms of clinical slowing against the risks. All therapies have risks, and anti-amyloid therapies have clear risks that we need to monitor and consider. So at what point to do the benefits outweigh the risks and justify the treatment? We need to understand this from the perspective of people with the disease and their families, and we need to involve them in the discussions. We need to use broad assessments that look at different aspects of the disease, including from the perspective of individuals with the disease and their families. Not just memory testing, but assessments that measure the impact of the disease on people so that we can assess the impact of treatment overall on individuals' lives and of their quality of life, and we need further studies into such assessments. There's general agreement in the field that a slowing of progression by 20% or more would be clinically important, and when you think about a disease that lasts multiple years, a slowing of 20% or 30% can have a major effect in delaying clearly important milestones like the loss of one or another functions or even the loss of independence by not just months but by years, so slowing of disease progression is a powerful clinically meaningful benefit but we do need to work harder on fully understanding and achieving consensus on when we have reached a clinically meaningful benefit.

Chin: Well, with that, thank you for your time today, Dr. Aisen, and your work on CTAD. It was an excellent conference, and I look forward to sharing my interviews with some of the keynote speakers who presented there in the ensuing weeks, and thank you again for your time.

Aisen: Thank you very much for having me.

Outro: Thank you for listening to Dementia Matters. Follow us on Apple Podcasts, Spotify, Google Podcasts, or wherever you listen or tell your smart speaker to play the Dementia Matters podcast. Please rate us on your favorite podcast app -- it helps other people find our show and lets us know how we are doing. Dementia Matters is brought to you by the Wisconsin Alzheimer's Disease Research Center at the University of Wisconsin--Madison. It receives funding from private, university, state, and national sources, including a grant from the National Institutes of Health for Alzheimer's Disease Centers. This episode of Dementia Matters was produced by Amy Lambright Murphy and Caoilfhinn Rauwerdink and edited by Taylor Eberhardt. Our musical jingle is "Cases to Rest" by Blue Dot Sessions. To learn more about the Wisconsin Alzheimer's Disease Research Center and Dementia Matters, check out our website at adrc.wisc.edu, and follow us on Facebook and Twitter. If you have any questions or comments, email us at dementiamatters@medicine.wisc.edu. Thanks for listening.