Lecanemab for Treatment of Alzheimer’s Disease


Drs Cohen, Atri, and Sabbagh share data on lecanemab, an anti-amyloid beta antibody, that was presented at CTAD 2022.

Marwan Sabbagh, MD: Dr Cohen, Dr Atri did a great job setting up the discussion on where we’re moving now, which is more focused on lecanemab [Leqembi], the Clarity study, and then we’ll talk a bit about donanemab right after that. Can you give us your thoughts about Clarity AD [Alzheimer’s disease]? Can you comment about the study design, population, efficacy? Can you generally give us your impression on the data?

Sharon Cohen, MD, FRCPC: Sure. This was a big attraction of CTAD 2022 [Clinical Trials on Alzheimer’s Disease Conference].

Alireza Atri, MD, PhD: That’s why a lot of you were in the room.

Sharon Cohen, MD, FRCPC: And a well-attended session. People were holding their breath. What are we going to learn? We had topline results through a press release at the end of September that told us that we had highly significant primary outcome measures CDR [Clinical Dementia Rating] Sum of Boxes for the Clarity AD study with a P value of .00005. And all of the secondary outcome measures showed positive and highly significant outcomes. But what we learned in the session, we saw the baseline characteristics revealed. This is an early AD population in Clarity AD, a large study. Almost 1800 patients with either mild cognitive impairment or mild dementia, and either CSF [cerebrospinal fluid] or PET [positron emission tomography] imaging finding of amyloid pathology. Early AD, randomized 1:1 to lecanemab 10 mg/kg IV biweekly or placebo and treated for 18 months. And there is an open label extension which didn’t read out yet. It’s not concluded. We learned more about the outcome measures. What we learned about the primary outcome measure, the CDR Sum of Boxes is, yes indeed, 27% slowing of disease for mild cognitive impairment and mild dementia due to Alzheimer’s disease at 18 months. And there was an item level analysis for the CDR Sum of Boxes showing that each of the 6 sub-domains that make up that scale were all showing benefit from lecanemab. There wasn’t any inconsistency there. On the secondary outcome measures we learned beyond what we heard in the press release. The actual percentage slowing of disease for the clinical outcome measures. We learned that on the ADAS-Cog [Alzheimer’s Disease Assessment Scale-Cognitive Subscale] there was 26% slowing and for the functional scale, the ADCS-MCI ADL [Alzheimer’s Disease Cooperative Study-mild cooperative impairment activities of daily living], there was 37% slowing. A large degree of slowing compared to what we’ve seen in other trials. I mean we are seeing for the first time all of the measures, all of the clinical outcome measures showing slowing of disease. As far as amyloid lowering, it was very substantial, and this was a key secondary outcome measure. The first in the lineup of analysis. And amyloid was robustly lowered. I should say for the clinical measures, we saw the benefit starting, the separation from placebo and lecanemab treated patients at 6 months and the benefit increased over time to the 18-month mark and with some modeling, looking at if that continues to separate then we’re going to get even more benefit the longer you treat. With amyloid lowering, we saw a significant lowering of amyloid as early as 3 months and quite profound lowering, this is on PET measured by the centiloid scale, so that most patients were amyloid-negative by the end of the trial or by PET centiloid value you could not detect amyloid anymore. These are exciting results. It’s the first time we’ve had clear consistent results in an anti-amyloid trial. And what makes this different from aducanumab [Aduhelm], donanemab, gantenerumab? There’s a lot of buzz about trying to figure this out. But we know lecanemab has a predilection for targeting protofilbrillar amyloid. And tenfold greater than plaque bound amyloid, which is different from donanemab, and a thousandfold greater than monomeric amyloid. It’s these large aggregates that are still soluble, which many feel are a particularly toxic species of amyloid that lecanemab is getting at. I won’t go on further. There were a lot of other interesting outcomes to do with quality of life and to do with biomarkers, other biomarkers, not just amyloid. But all pointing consistently in the direction of benefit with lecanemab treatment.

Marwan Sabbagh, MD: You wanted to add something Ali?

Alireza Atri, MD, PhD: I completely agree. This is the first time in our field where you had a phase 3 study of a monoclonal that was designed, powered well, implemented, executed in all ways as it was supposed to be and it was a slam dunk. It’s very consistent. The primary outcome measure’s consistent, secondary is consistent, biomarkers, for the most part, all going down the right path. There was target engagement. By the end, about two-thirds of individuals, not all, were amyloid negative, about two-thirds were. The safety was nothing unexpected. It was similar to the phase 2, and the RA [rheumatoid arthritis] rates were on the lower side consistent with phase 2 and manageable, mostly asymptomatic again. But the data that was patient-related health outcomes was consistent about quality of life. Again, this is double-blinded data, the patients don’t know whether they’re on drug or not and the family members don’t know. And yet their burden was lower, their quality of life was better relative to the placebo group, and that’s important. And then the type of analysis, multiple different kinds of sensitivity analyses looking at whether you censor for RA or not? What type of population? All go the same direction. Not to over blow it, this is not a cure, again. But when you have somewhere between 25% and maybe 35% slowing now, imagine as we learn about this more, we’re going to hopefully be able to target even more with biomarkers over the next 5, 7, 10 years to make that benefit maybe 60% or 80%. That’s an important foundational step for our field. That can’t be minimized. There was overall a good mood because this is a meaningful treatment that has shown in a big study, safety and efficacy.

Marwan Sabbagh, MD: I have to say, finally. That’s all I can say is finally. We’ve been waiting for this one for a long time in our field. And you did extrapolation in your presentation, going well past then. You showed that the delta gets bigger. Can you comment on that?

Sharon Cohen, MD, FRCPC: That’s right. If you look at the slope of decline, because the difference between placebo-treated and lecanemab-treated increases from the first dose to, or the first-time measurement on clinical outcomes, to the 18 months. And with a slope calculation, it’s 32% slowing per year. If you go out to 2 years, the difference is not, on CDR Sum of Boxes, .48. It’s .68 at 2 years. And I’m not mis-quoting .48 as by slope analysis, a .45 is by the least square mean. But if that difference keeps extending, and there has been modeling that’s been published with the phase 2 data, you end up spending more time in mild stages of disease, less time in later stages. Because when people are impaired and dependent, that’s not an ideal time for many to make that disease longer. But early on, yes. And the modeling from the 201 lecanemab study shows we’re saving years, 2.5 to 3.5 years. And that same simulation modeling has been done and will be published for Clarity AD. So that will be interesting. And that health prediction modeling is necessary for all of us, for the health care system to plan ahead.

Eric McDade, DO: It is important, though, those are models and those are estimates. So we’ll need long-term follow-up to see if it’s truly disease-modifying, then we should still see that effect continue to grow over time. We just need to see if that holds up to what the models predict.

Sharon Cohen, MD, FRCPC: Yes, and maybe I could make a separate comment that, as we’ve said, all of these anti-amyloid monoclonal antibodies are a bit different. And the dose and titration, etc., amount of amyloid-lowering, time to amyloid-lowering differ. But the baseline characteristics were a bit different in the lecanemab study. The age range was broader. The allowance of people with comorbidities in the study was much greater than what is usually allowed in these kinds of trials. And there was a greater diversity also, especially Hispanics. And so that gives a clinician confidence that this drug, tested in a controlled trial, may be more likely to benefit my patient in the real world than if we had these very idealized populations that are not inclusive of the usual medications. I didn’t mention anticoagulants. They’re allowed to be on anticoagulants, which is an atypical in monoclonal anti-A-Beta, amyloid trial. So we’re seeing more of a real-world snapshot with lecanemab and people are excited about that, too. The generalizability of results.

Marwan Sabbagh, MD: Because most trials have a very ideal population, which is hard to represent in the real world.

Alireza Atri, MD, PhD: But there will be. I mean this is not going to be for every patient with Alzheimer’s disease. This clinical effect if you’re in the severe stages or the moderate stages, we don’t have data for that. Even individuals who are in the MCI [mild cognitive impairment] or mild dementia stages, there has to be a translation of what happened in the confines of a laboratory, the RCT [randomized controlled trial], to the real world. And that’s where appropriate use recommendations will come in, to suggest where that funnel is. And that funnel isn’t going to be everybody with MCI. Some people are going to be more appropriate for that because they’re going to have to meet some appropriate inclusion criteria. Then individuals have to then be able to weigh their risks and benefits themselves and decide what they want to do. Hopefully being able to provide that choice for patients and families, that autonomy for them, is going to be important when you’re facing a condition that is still incurable and decreases your life expectancy and quality of life.


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