Yale Psychiatry Grand Rounds: February 17, 2023

February 17, 2023

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Lecanemab: The First Disease-Modifying Therapy for Alzheimer's Disease

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00:00Very kind introduction. By the way,
00:04you didn't hold me back in residency,
00:07except for maybe the the raucous
00:09Halloween party. So I think that's
00:12a topic for another. OK. Number.
00:23So just get this reset.
00:43OK, and you can see the.
00:48See. OK everyone OK, great.
00:51Well you all I I think have varying
00:55degrees of familiarity with with
00:58what I'm going to talk about.
01:02You know in particular the the recent
01:05controversy in the news about the
01:07first so-called disease modifying
01:09therapies for Alzheimer's disease.
01:12Back in 2021, you know,
01:14they came to the news I'd you can't
01:16approved the first disease modifying
01:18therapy for Alzheimer's disease.
01:20But then immediately, well wait,
01:22it wasn't full approval.
01:24It was accelerated approval based on a
01:27biomarker and that's plaque clearance.
01:29And immediately there was,
01:31you know, a huge controversy.
01:34Culminating about 10 months later in the
01:37decision by CMS not to pay for the drug.
01:41And then as the dust settled for that,
01:44we started to hear about lacanada
01:46different drug that actually appeared
01:48to meet the bar for full approval in
01:51in a in a more straightforward manner,
01:54although as we're going to see the
01:56Kanab has its own uncertainties
01:58and some of its own controversies.
02:00But all of that is what I'm going
02:02to be talking about today.
02:04Now this is my disclosure,
02:06I'm going to be talking mainly about
02:08the drugs aducanumab and lichen,
02:10amab,
02:10Yale and I received grant support
02:13for the conductive conduct of
02:15trials with these drugs.
02:16And I'm also a paid consultant
02:18to Asahi who makes like canaman.
02:20I don't have any any financial stake
02:23in the in the success of these drugs.
02:26And almost all of what I'm going to show
02:28you is from peer reviewed publication,
02:30mainly that the New England Journal
02:32article there about 2 exceptions to that.
02:34And I'll try to show you mention
02:37when I'm showing you something
02:39that is not peer reviewed.
02:41Well, so in in talking about like Canada,
02:44I think we need to go back to the the whole
02:48controversy with the earlier drug aducanumab.
02:52So there it was,
02:55June 7, 2021,
02:57a day that would live.
02:58You know,
02:59in something I'm almost concerned that
03:02they waited a day so they didn't try
03:05to eclipse the anniversary of D-Day,
03:08but it was, it was huge news,
03:11but then almost.
03:12Instantaneously came the backlash,
03:15the controversy.
03:16You know, that this was only,
03:19you know, approval based on biomarker,
03:21not full approval.
03:24And I'm going to go into more of
03:25what the controversy was about.
03:27But I think to do that I need to do a
03:31little background on the pathogenesis
03:33and mechanisms that underlie these drugs,
03:37and then more detail about the
03:39actual evidence for and against.
03:42You can't,
03:44amab.
03:45So by way of background you know
03:47these these are anti amyloid
03:49drugs and we need to look at the
03:52mechanism of amyloid production.
03:55So what we're looking at here is the
03:58production of the toxic abeta peptide.
04:01I think you can see my cursor
04:04from the the amyloid precursor
04:06protein over here on the left.
04:10So this AP spans the the cell membrane then.
04:15The neuronal membrane in this case.
04:18And it is cleaved by the
04:20enzymes beta and gamma
04:22secretase to form the toxic a beta fragment.
04:26And exactly where where it's
04:29cleave makes a difference,
04:31where it's clear by gamma secretase.
04:34And the main major forms as
04:37we'll see are in a beta 42,
04:39a little longer form.
04:40And 40 it's a beta 42 that's
04:44particularly malignant, amyloidogenic,
04:45prone to aggregate into the.
04:48Into the more toxic species
04:50and what are those?
04:52Well, a lot of evidence is that those
04:56toxic species are soluble aggregated
04:59species oligomers and and larger
05:03oligomers referred to as proto fibrils.
05:07And all of these forms you know do
05:10also aggregate further into plaques.
05:13And overall,
05:14the goal of these therapies though
05:17is to alter the balance between
05:21production and clearance so the
05:25antibodies aim to clear amyloid
05:28and alter the balance favorably.
05:31And what what are these antibodies?
05:34Such as Lacan Amab and and I do cannab.
05:38Well,
05:38that's that's shown here in in a
05:41somewhat busy table that I that I do
05:44really want to simplify a great deal.
05:46So these are in the case of aducanumab,
05:51this is a an actual human antibody
05:54was donated by 100 year old
05:57Swiss woman a few years back.
05:59Been cloned and mass produced.
06:03And now it's administered every four
06:05weeks intravenously as a treatment.
06:08Of note is that it's what we call an
06:11n-terminal antibody and the a beta
06:1642 is shown down here in purple.
06:19You know the 42 amino acid structure and
06:22the end terminal is on the left side.
06:25And so how'd you can't remember
06:28by buying certain amino acids
06:303 through 6 on the left side?
06:32What's important about that is that even
06:35when amyloid is aggregated as oligomers,
06:38proto fibrils,
06:39plaques.
06:40This portion of the of the
06:43peptide is visible to antibodies,
06:45so they will still they will
06:47still target it and clear it.
06:51And over on the in the right
06:53columns you can see the big red,
06:55yes for all of them are in fibral.
06:58So if it's an end terminal antibody,
07:00that's why it targets
07:02these aggregated species.
07:03It actually doesn't target
07:05target monomers to speak of.
07:08And we can't. Amap is similar.
07:10It's different but similar.
07:11So it's a humanized antibody.
07:13It's, you know,
07:14derived from a mouse antibody but
07:17fully humanized and structure.
07:19It's also end terminal binding
07:21amino acids one through 16,
07:24and so it also binds oligomers
07:26and proto fibrils in particular,
07:28and to some extent fibrils.
07:34Now moving back to Umm aducanumab
07:39and the aducanumab story.
07:42So this drug, you know, was, you know,
07:45developed over the last several years.
07:47These are data from the original,
07:50one of the original phase one studies,
07:53a Phase 1B study.
07:54And what we're looking at actually are
07:57individual PET scans from individual
08:01participants who received you know either
08:04placebo or progressively higher doses of
08:07aducanumab over the over a one year trial.
08:11And these images are horizontal transaxial
08:14through the brain and and high amyloid
08:17binding is shown in red followed by yellow.
08:20So for example this person on the
08:23top row was in the placebo group.
08:25And you can see that their baseline and
08:28one year scans look pretty similar,
08:30not much change being on placebo,
08:34but with progressively higher
08:36doses of aducanumab,
08:383 megs per keg, 6 megs per keg,
08:4010 megs per keg administered again as as
08:44in infusions every four weeks you see
08:47progressively more clearance of amyloid
08:50signal and in fact in the bottom row,
08:53the 10 milligram per kilogram dose which.
08:56Is the clinically relevant
08:58dose when all of sudden done,
09:00this person scan is actually
09:02normal at the end of the study.
09:04The bit of yellow you see here is
09:06in the white matter and it's what
09:08we would call nonspecific binding.
09:10But if if they entered the study
09:12with the scan,
09:13they would have not been allowed because
09:15they didn't have evidence, you know,
09:17of of amyloid on their pet scan.
09:20So very dramatic plaque clearance.
09:22So this is something that we
09:24had never ever seen before,
09:25you know,
09:26until this study.
09:29And and you know Biogen was
09:32understandably very excited.
09:33They actually skipped phase two.
09:35They went right from
09:36phase one to phase three,
09:38but maybe a mistake as we'll see later.
09:41Now these now flash forward are
09:43data from one of the two pivotal
09:46phase three trials called emerge.
09:49Um and. What we're looking at here
09:52again is amyloid plaque clearance,
09:55but now we're looking at it quantitatively
09:57and this is now over a year and a
10:00half instead of a year 78 week trial.
10:02You can see that the placebo group
10:04doesn't have much change in the
10:06amyloid binding over the 18 months,
10:08but the relevant high dose group,
10:11mostly 10 megs per kig in purple
10:14has dramatic plaque clearance.
10:16And again without going into
10:18the quantitation in detail,
10:20suffice it to say that most of
10:22these people had normal appearing.
10:24Pet scans visually,
10:26quantitatively at the end of the study.
10:29But the question then is,
10:30is that associated with clinical benefit,
10:33so at least in the case of the?
10:39Emerged study, the answer was yes.
10:42So here we're looking at the the primary
10:45outcome of this study called the Cdr SB,
10:48the clinical Dementia Rating scale some
10:51of boxes and for for the many of you
10:54who aren't familiar with that what that
10:56is is it's very commonly used now as
10:59the primary outcome in in these trials.
11:02It's based on an interview with a partner
11:06caregiver as well as the patient participant.
11:09Themselves, and it generates
11:11scores in each of 6 domains.
11:14Three of them are cognitive,
11:16three of them have to do
11:17with daily functioning.
11:18They're all scored zero to three.
11:21So the overall Cdr SB score is 0 to 18,
11:25with higher scores being worse.
11:28A 0 is a perfect score.
11:32And people in this early AD group
11:34that tend to be bunched with
11:37scores between 0.5 and about 6.
11:39What you can see in this
11:41in this study though,
11:42is that the placebo group worsens
11:45over the course of a year and a half,
11:47to the tune of about 1.75.
11:50And the at height, the high dose side,
11:54you can't imagine group,
11:55which is the relevant group, worsens as well,
11:58but about .39 less than the placebo.
12:03So that's the delta and that that is,
12:05you know, statistically significant.
12:09And Umm and this, this is a positive study.
12:13Now the problem is,
12:15is that the FDA requires two such studies
12:18and Biogen had skipped phase two.
12:19They might have gotten an opportunity there,
12:22but they were required to have a
12:24sister study in phase three and
12:26that was that was called engage
12:29and here are the data for engage.
12:33These are the data with the Cdr.
12:36By the way engage also showed very robust.
12:39The amyloid plaque clearance on PET scan,
12:42when it came to the clinical measure,
12:45the primary outcome, it was a total bust.
12:48You know, there's nothing here.
12:51The the worst line in purple
12:53is the high dose side.
12:55You can't amab group,
12:56although it's trivially different
12:58from the placebo group.
13:00So you know one positive and
13:03one very negative study.
13:05Now, what to make of that,
13:07you know,
13:07how could that possibly be?
13:11So. This is before I really go into
13:15this very scary looking figure,
13:17let me give you just a little background
13:20that these studies emerge in again and
13:23engage really went through quite an ordeal.
13:26One that many of you know is that
13:29they were actually halted prematurely
13:31for a futility analysis which is
13:34done commonly in our field where an
13:37interim analysis looks at the data
13:39fully up to a certain point and and
13:41a judgment has made us about whether
13:43there's any chance chance of success.
13:45And the futility analysis indicated that
13:48that they were in fact futile and the
13:52studies were stopped and and all the
13:55participants were brought in termination.
13:57Visits and so on and and it was a it
14:00was a complete mistake, you know,
14:02the futility analysis because
14:04when all the data came in,
14:06and particularly there,
14:08there were three more months that had
14:10elapsed from the data cut point to the
14:13time all the data stopped being gathered.
14:15And and and obviously emerge will
14:18emerge emerged as a positive study.
14:21So and and without going into all of
14:24the the reasons why the BIOSTATISTICIANS
14:27messed up which they which they did.
14:31There is yet another thing that
14:33happened to these studies that was very
14:35unfortunate and that is that Biogen
14:37determined that the dosing they were
14:40using for the studies was really not
14:43not optimal and actually did a midstream.
14:46Changing of dose.
14:47And with that involved is originally
14:49they had not felt everybody could
14:52safely tolerate the high relevant
14:54dose of 10 megs per kig.
14:56That's the dark blue in this figure.
14:59So,
14:59so a lot of people who carry the APOE 4
15:02gene were only going up to six megs per keg,
15:05which is, you know,
15:06ultimately determined to be,
15:07you know,
15:08subtherapeutic.
15:09So they made a midstream adjustment and
15:13now what you would want now what what
15:16these with this figure is showing you is.
15:19Individual level dosing for the high
15:21dose arm of the study and only those
15:24people assigned to active treatment,
15:27not placebo.
15:28So what you really wanna see here
15:31is that from 24 weeks onward,
15:34they should just be all dark blue.
15:37That would be the ideal.
15:38Apart from early discontinuations,
15:39it should just be a sea of dark blue.
15:43But it's not.
15:45The yellow, you know,
15:46a lot of people who who,
15:48you know were early terminated for
15:50futility and all of these lighter
15:52shades are people who were still,
15:54you know,
15:54mucking around with subtherapeutic
15:56doses for a long time.
15:58And the argument Biogen made
16:00to the FTA is that, Umm,
16:03you know,
16:04is,
16:05is that this differentially impacted
16:08the two studies because in emerge
16:1129% of people receive the full
16:13complement of the 10 milligram.
16:15Kilogram doses and engage only 22%.
16:19Did you know is that a big difference
16:21this had to do with the fact that
16:23that engage was an earlier timeline
16:25study and so it didn't benefit
16:27as much from the modifications.
16:29But in any case the argument
16:31Biogen really tried to make
16:33to the FDA and the FDA,
16:35you know to some extent you know,
16:37agreed was that if you just looked
16:39at people who received the full
16:41complement of doses both both
16:43studies you know should benefit.
16:46Unfortunately that's not how it works.
16:47When you talk about a phase three
16:49registration trial with the FDA,
16:50you don't get to do these
16:52you know post doc things.
16:53You've got to, you've got to,
16:55you've got to pre specify and
16:57you've got to meet your aims and and
17:00clearly you know one study did not.
17:02So then just to summarize the aducanumab
17:06controversy here in this slide,
17:08you know we had FDA approval
17:11June of 21 via the accelerated
17:13pathway based on the biomarker.
17:16That was unvalidated.
17:17You know to that point this was completely
17:20against the recommendation of the FDA
17:23Advisory Committee who voted 8 to one
17:26against many of them resigned you know,
17:28in protest after the approval and then you
17:32go ten months later and and CMS does a,
17:35you know a fairly unusual makes a
17:38fairly unusual decision not to pay
17:40for the drug despite FDA approval
17:42and they indicate they're only
17:44going to even consider.
17:46Traditional,
17:46full traditional approval
17:48based on clinical measures,
17:49not biomarkers and only under in
17:52in in a research context coverage
17:55with evidence development.
17:57So that's where that stood.
17:59And you know Biogen then subsequently
18:02you know launched yet another study
18:04which you know which they they
18:07really needed to call Envision and
18:09this is the attempt to have a second
18:12positive study that's done under the
18:15accelerated pathway as a confirmatory study.
18:17Although practically in this case
18:19it's really you know and I think an
18:21attempt to have a redo on on full
18:23approval and so they're they're
18:25trying to do this you know fairly
18:28launch it fairly rapidly.
18:30And then at the end of this past year,
18:32many of you may have seen that
18:34there was a congressional report.
18:36That found the whole process
18:39was rife with irregularities.
18:41I mean the FDA and Biogen,
18:43you know,
18:44we're really investigated including
18:46that there was this unusual
18:48collaborative work stream where FDA
18:50officials met repeatedly with Biogen,
18:53you know, to analyze trial data,
18:55you know,
18:56mutually.
18:59All right. Well, and so it was
19:01in the wake of all of this that
19:04along came the news last fall,
19:07you know, initially kind of quietly.
19:09That a similar drug lacanau
19:12amab appeared actually to meet
19:14the bar for for full approval.
19:16You know, based on on results those
19:19press released in late September,
19:20fully presented at the end of November
19:23and appeared online in the New England
19:26Journal at around that time at the
19:29print publication just January 5.
19:31And for the rest of this talk I'm
19:33really going to focus on you know,
19:35this publication you know and
19:37and the data in it.
19:40So the Kanab, you know one more time,
19:43this is a a busy slide.
19:45I'm really just focusing on the
19:47lower right and the red font that
19:50lichen amab you know again is a
19:52humanized IG1 monoclonal antibody.
19:55It's selectively binds to
19:58soluble aggregated species,
20:00you know oligomers and proto fibrils.
20:02It's got 1000 fold selectivity for those
20:06species over monomers and it even has
20:08a tenfold selectivity over fibrils.
20:10That are in plaque so that we know it.
20:13It binds plaques because as you'll see it,
20:15it clears amyloid plaque on a PET scan.
20:19Here's the Clarity AD study design
20:21and and by the way I one thing I
20:26should I should probably provide
20:28clarity on which is that I'm only
20:30going to show you one study,
20:32I'm not going to show you
20:34two studies right now.
20:35Why is that?
20:36And it's because in this case you
20:39know the Canada went through very
20:41extensive phase two testing and their
20:44phase two study done in you know 850
20:47people which was actually a positive study.
20:50Still not a registration trial and so it
20:53was accepted as as a first positive study.
20:56So in this case the cannonade
20:57really needed to confirm that with
20:59with a single large phase three
21:01trial and that that's the reason.
21:03So in this study you can see that
21:07there were 1795 people who were
21:10randomized with early Alzheimer's
21:13and that means MC I you know or
21:18prodromal Alzheimer's or mild.
21:20Alzheimer's dementia but the but the
21:22they had to be confirmed for Alzheimer's
21:26pathogenesis by any amyloid PET scan.
21:29They were randomized 1 to one
21:32to either like cannab or placebo
21:34like cannab dosed as 10 milligram
21:37per kilogram every two weeks.
21:39So this is administered twice
21:41as often as that you can amount.
21:45And that was an 18 month trial and
21:47that at the end of that you know there
21:50is an open extension trial which
21:52is very much ongoing and that means
21:55everybody in in this phase is on active drug,
21:58no more placebo and I'm not going to
22:01the New England Journal paper doesn't
22:03cover the extension phase at all.
22:06I'm only going to mention it when
22:07it comes to some of the you know
22:10publicized you know safety issues that
22:12have come up in the extension phase.
22:14And on the far right,
22:16the outcome measures and so on,
22:19I'm not going to,
22:20I'm going to go into these
22:22individually over the next few slides.
22:27But before that, the this shows the subject
22:32disposition and analysis populations.
22:35So meaning that before we got to the 17195
22:39people who were randomized and treated,
22:42there were nearly 6000 who were screened.
22:45Most of them were not eligible for the
22:48reasons shown in the screen failure box.
22:50You know, usually it's that they didn't have,
22:54you know, amyloid positivity on
22:55pat or even more commonly that they
22:58weren't quite in the right cognitive
23:00range for this early ad study.
23:03But in any case.
23:05The 1795 who are randomized and treated
23:08were then evenly divided between
23:10the placebo and the lucama groups.
23:12And in the placebo group 84.4 completed
23:16the full 18 month study but they
23:19can't amount Group A little less
23:2181.2 that's typical and the reason
23:23is because of more side effects,
23:26more adverse events you know as
23:28shown in in these boxes and the the
23:32populations of analysis are are
23:35worth you know just mentioning for
23:37for all efficacy measures we looked
23:41at what's called the modified.
23:43Intent to treat population.
23:45And all that means is you have to have
23:49somebody who was randomized actually
23:51got at least a dose of the drug and
23:54actually had one follow-up assessment
23:56that you could you could analyze because
23:59not everybody gets dosed gets there.
24:01They might have had to terminate early,
24:03you know for a side effect and
24:05never had a follow-up assessment.
24:07So that's the population used
24:09for efficacy measures.
24:10The safety population is everybody,
24:13everybody who you know was
24:15randomized and dosed.
24:19Now here are the baseline
24:22characteristics of the 1795 people.
24:25As you can see, this was a global study,
24:29although a majority of them were in the
24:31far right column in the United States.
24:34And just a couple of things to touch on.
24:36It was a broad age range about,
24:39I think 20% were underage 65
24:43and close to 15% were over 80.
24:49The other thing of note here I want
24:52to call attention to is race and
24:55ethnicity and and that's because in
24:58our field we've done really a bad
25:00job of including populations that
25:03represent the United States population.
25:07It's a it's a really, really important thing.
25:10This trial actually did the best of any of
25:14any such similar trial that I'm aware of,
25:17but still inadequate.
25:19So as an example, you know,
25:22in the United States 4.5%
25:24of participants were black.
25:27That's good for us,
25:28but it's it's woefully inadequate.
25:30This should be, you know,
25:319 or 10% if you go by black
25:34seniors in the United States with.
25:38Hispanic ethnicity,
25:39we actually did well, this is,
25:43this is really good 22.5% because that
25:46actually over represents Hispanics who,
25:49who in the senior senior age groups
25:52would again be in the order of 10%.
25:54But we still need to do better
25:57and it's an important issue.
25:59With regard to other
26:01clinical characteristics,
26:02I won't go into all of these.
26:05You know,
26:06most of these folks are really early,
26:08you know,
26:09more MCI prodromal than they are dementia.
26:12Most of these people are are functionally
26:14independent at the start of the study,
26:16you know, people who drive a car,
26:17who do their own finances,
26:20who do cooking, manage their meds,
26:22that's the majority of people.
26:24This is really quite,
26:25you know, early stage,
26:26although it includes some with
26:29you know very mild dementia.
26:31What we for status is another
26:33important thing.
26:34For those of you not familiar,
26:35April 4 is the major genetic risk
26:38factor for Alzheimer's disease.
26:39You know, late onset Alzheimer's and.
26:44And typically about 69% of all the
26:48participants carried the April 4 at
26:51least one copy apply 4 allele that
26:53that compares to about maybe 15
26:55to 20% in the general population.
26:57This is a very typical sample in this
27:00regard and we see that percent for you know,
27:02people who carry one copy versus.
27:062 copies of the homozygotes,
27:07homozygotes for about
27:0915.5% of the population.
27:12And this is important,
27:13you know,
27:14as we'll see,
27:15particularly as it relates
27:16to some of the safety issues,
27:19about a little more than half of people
27:22were on an approved Alzheimer's drug
27:25like a cholinesterase inhibitor or memantine.
27:29So now I'm gonna jump into the.
27:32The top line efficacy
27:34endpoints for the study.
27:36So again the primary endpoint is
27:38just what it was for aducanumab,
27:41it's the change from baseline
27:44at 18 months in the Cdr SB.
27:47I'm also going to show you most
27:49of the key secondary endpoints
27:51shown on the right,
27:52one of biomarker which is
27:55clearance of amyloid on PET
27:57scan and then clinical measures.
27:59I'm, I'm only going to show you,
28:01I'm not going to show you the
28:02adcoms for the sake of time.
28:04I'm going to show you the pure cognitive
28:06and functional measures though.
28:10So, so this is perhaps you know really
28:12the key slide you know of of the whole
28:15presentation regarding we can't amab,
28:17you know these are the results for the the,
28:20the primary outcome, the primary endpoint.
28:23This is what makes it a positive study.
28:26The CD RSB and you know this is
28:30this is similar to what we saw for
28:33aducanumab in emerge and engage except
28:36you'll remember that that you know
28:39the the directionality was different
28:41instead of you know up being bad now
28:44down is being bad and we we did that
28:47because that way you could look at
28:49all the slides I looked at all the
28:51figures in the study and down was
28:53always bad but in any case that's how
28:55it's graphed and what you can see.
28:57Is that the placebo group worsens
29:00by 1.66 points over 18 months.
29:03Not quite as much as in the end you
29:05can't map studies and the treated group.
29:111.22 with a difference of 0.45 and
29:15which is highly highly statistically
29:17significant and it represents a 27%
29:20slowing of decline at 18 months.
29:23Drug placebo differences are evident
29:25as early as six months and they at
29:29least numerically widen. Thereafter.
29:34Now this is the,
29:35this is a non peer reviewed slide,
29:38but I wanted to to show this in
29:40relation to these Cdr data because
29:43a lot of the controversy you know
29:46about these kind of results is
29:48are they clinically meaningful,
29:50they're highly, highly,
29:53statistically significant,
29:54but are they meaningful.
29:55And I'm going to mention you
29:57know as I go two or three ways
29:59that at least I think about the
30:02meaningfulness of the results.
30:04And one way that I would commonly
30:06explain to A to a patient or participant
30:09is what's shown here and it has to
30:12do with kind of a time savings.
30:14So that is that in the placebo group
30:17the amount of deterioration that
30:20occurs at end of study at 18 months.
30:23If the rates of decline continued
30:26after 18 months as they as they are
30:29to that point and that's that's an
30:31if that's a that's a big assumption.
30:34The actively treated groups
30:35will get to the same point,
30:37but they will get there about
30:407 1/2 months later.
30:41So in that sense it's like a 7 1/2
30:44month time saving of a certain level of,
30:46you know,
30:48cognitive daily functioning.
30:50A more conservative way by the way
30:53than extrapolating is to interpolate.
30:55And that's what shown in the other
30:57kind of blue line where you where
31:00you asked the question at what
31:02point did the placebo people already
31:04get to the point where the lucama
31:06people did at 18 months and that and
31:08then you go backwards 5.3 months.
31:10So that would be a more conservative,
31:12you know estimate and probably maybe
31:14the truth is somewhere in between one.
31:16One thing that's very clear though
31:18is that this kind of.
31:20Measure is very much related to how
31:23long you're on the drug, right.
31:25So and as we'll see at the very
31:27end of this presentation,
31:29you know we start to think about
31:31treating people earlier and for many
31:33years we may be able to think about
31:35much bigger effects than any of these.
31:38But you know this is this is a
31:41speculation now we're back to real data.
31:45And now I'm moving on to the
31:47key secondary outcome,
31:48starting with the the biomarker amyloid pet.
31:52So just as we saw with aducanumab,
31:55you know,
31:56which dramatically clears
31:57fibrillar amyloid on a PET scan,
32:00the same is true with lacanada here
32:03in the 18 month study you can see
32:07that people in the placebo group
32:09had you know at least a little
32:13numerical increase in amyloid binding,
32:15whereas those on the kinomap,
32:18you know steadily decreased.
32:21There is the scale that I'm not
32:23going to explain to you called a
32:25centroid scale that is being used.
32:27This is a way of standardizing you
32:29know Emily PET data across studies,
32:31across scanners, across radiopharmaceuticals.
32:34But suffice it to say that you
32:38know the drug placebo difference
32:41here was 59 centroids again highly
32:44significant but but to make to
32:46to talk a little bit about what
32:48what center Lloyd's you know.
32:50Represent.
32:51Note that at the start of the study,
32:55people averaged about 76 centroids.
32:59Note also that to get into the study,
33:02the threshold of positivity was
33:05probably about $0.30 Lloyds.
33:07And then note finally that at the
33:10end of the study those in the active
33:13group were at around 23 centroids.
33:16Most of them had normal scans,
33:18you know, visually and quantitatively
33:20at the end of the study.
33:22And these these differences
33:23appeared very early,
33:24as early as the very first
33:26pet scan at three months.
33:30Now moving on,
33:31you know to other key secondaries,
33:33this is the pure cognitive measure,
33:35the 8 US cog which is scored zero to 90.
33:39Higher scores are worse.
33:42And what you can see here is that at
33:45the end of the 18 months the drug
33:50placebo difference was 1.44 points
33:52between drug and placebo, again highly,
33:56highly significant representing a 26%.
33:59Slowing of decline and and significant
34:02differences were evident again as
34:04early as the six month time point.
34:07And finally, this is the pure functional
34:10measure relates to activities
34:12of daily living, the ACS MCIDL.
34:15This is, excuse me,
34:17squared zero to 53.
34:21In this case lower scores are better.
34:25But we graph it,
34:26you know the same direction for ease
34:29of understanding and and what you can
34:32see is that the placebo group worsens
34:35to the tune of about 5 1/2 points.
34:38The actively treated about two points
34:42less than that highly significant in
34:45this case representing a 37% slowing of
34:49decline with the treatment differences
34:52again evident as early as six months.
34:55And with regard to clinical meaningfulness,
34:57I would just I find at least in
35:00in when people see these data,
35:03this is a measure that is more
35:06easily seen as meaningful.
35:08Because of what it is, right?
35:10Again,
35:10these are people who mostly start the study,
35:12able to drive a car, do finances,
35:15you know, Cook, manage their medications.
35:18And they have, you know, a 37% slowing,
35:23you know, in the loss of such abilities.
35:25So, you know,
35:27it's hard not to think of such such
35:30kinds of effects as as meaningful,
35:32you know, in real life.
35:37But with regard to clinical meaningfulness, I
35:39want to go on to yet another kind of measure.
35:42Now what I've shown you up until now
35:43are the top line, you know, results,
35:45you know, the primary and the secondary,
35:49but there are other, you know,
35:50more exploratory measures that were done
35:53and one of them pertains to quality of life.
35:57Quality of life which may not be.
36:00Fully measured with cognition and function,
36:04so in this case.
36:05We're looking at four different
36:07scales that were administered.
36:09The two in the top row are both
36:12assessed quality of life for the
36:15patient participant themselves.
36:17The two in the bottom row of for the,
36:20you know the caregiver partner.
36:22And without going into these in detail
36:25you know what you can see is that
36:27all four of them show statistically
36:30significant benefit you know slowing of
36:33decline and and just as a poster child
36:35of these I will cherry pick the QOLA.
36:38Be subject because.
36:39Here is a a a questionnaire that asked
36:44questions like how happy are you?
36:47How are your relationships with your family,
36:49with your friends?
36:50How do you feel about where you're living?
36:52You're you know, your your overall health.
36:54And on this measure,
36:56the Kanab is associated with
36:58a 56% lower decline.
37:00And comparison to the placebo
37:02group at the end of the study.
37:05So again for those who think no clinical
37:07meaningfulness in these kind of effects,
37:09I mean I I would I would just ask to to
37:12look at these these kinds of results.
37:18Now we're going to talk
37:20about safety of like Hannah.
37:22And to do that I need to introduce
37:26this funny term amyloid related
37:31imaging abnormalities shortcut Aria.
37:34So it's a cute acronym.
37:37I personally don't really like it
37:38a whole lot because it implies that
37:40these are only imaging abnormalities,
37:44you know, whereas they're real pathology.
37:45So I actually like to use the terms,
37:47you know, amyloid related,
37:49you know, edema and hemosiderin.
37:52And I'll slip into those, I'm sure.
37:54But in any case, you know,
37:57Aria, there are two types.
38:00There's the RE which refused to,
38:04which refers to effusions or edema,
38:09and then there's the RH,
38:11which refers to the deposition of
38:14the blood product hemosiderin.
38:16Aria you seen typically on T2
38:19flare sequences on MRI and Aria H
38:22on the heme sensitive sequences.
38:24Sequences such as, you know, grading, ECHO.
38:28Umm or aswi, the so and by the way,
38:33why do these occur at all?
38:36It's not fully known but the leading
38:38view is that monoclonal antibodies,
38:41anti antibodies by clearing amyloid
38:43deposits in the blood vessels you
38:46know that are in the endothelial wall
38:48will cause increased permeability
38:50of the blood brain barrier,
38:52which can cause,
38:53you know,
38:54leakage of molecules that wouldn't
38:57normally pass.
38:58Drawing fluid osmotically that
39:00that's the explanation for edema and
39:03then for hemosiderin you get actual
39:05breakage of of small vessels you know
39:07with with small bleeds for example.
39:10But this slide shows what these
39:12things look like on MRI scan.
39:14So Aria E for edema effusion
39:18is shown in a C&amp;D and in a you
39:22know we're looking at you know
39:25the most robust maybe maybe.
39:28Obvious example of you know a parenchymal
39:33signal abnormality here in the right
39:37occipital lobe with some gyral swelling.
39:43In C,
39:44we're looking at a more pure sulcal effusion,
39:48which is another way that this can present
39:50not so much parenchymal as you know,
39:53a sulcal effusion.
39:54And then in D we're looking at
39:56A at A at a very subtle case,
39:58which we do see where just a wee bit of,
40:02you know,
40:03gyral swelling is evident and a little
40:05bit of a circle effusion is evidence.
40:07So that would be a very subtle case
40:10with regard to Aria H as we'll see.
40:13This can come in different forms.
40:15The one shown here is microhemorrhages
40:18and that's in panel B in the red
40:21circle you see these three dots.
40:23Micro hemorrhages are defined
40:24as less than a centimeter.
40:26These are much smaller than that,
40:27you know, maybe 3 millimeters.
40:28So they tend to occur where edema
40:32has also occurred by the way.
40:35And we'll talk more about that.
40:37The the other forms of RH not shown
40:40here are superficial siderosis and
40:43macro hemorrhage, which is you know,
40:46to find us more than a centimeter
40:48and we'll talk more about that.
40:50So now going back to the safety
40:53data for Liquin amab in light of
40:56in light of that first of all
40:59here we're looking at.
41:01The. We're looking at the the most
41:05serious adverse events that occur.
41:07So for example, you know deaths,
41:10deaths were fairly balanced 7 on placebo,
41:146 on the Kanab.
41:15Next we look at serious adverse events,
41:18things that require for example
41:20hospitalization and and what I
41:22want you to see here is that the,
41:25it's really only three kinds
41:26of events that are occurring
41:28more on the Kanab than placebo,
41:30it's those that are associated
41:32with these RERH.
41:34And then the third category would
41:36be infusion related reactions,
41:38you know mild hypersensitivity reactions.
41:41All other SME's are actually you
41:44know quite balanced between drug and
41:47placebo and and again as much as
41:49these essays are more common on drug,
41:52they're they're still not very common.
41:54I mean they're all in the order
41:56of 1% frequency.
41:59This slide shows you know common adverse
42:03events now including non serious adverse
42:06events and and again I think the the
42:09real take home message is that it's the
42:13it's the ones in these three categories
42:15even for non serious AE that are more
42:19more common on lecanu amab infusion
42:21related reactions RER AH everything
42:23else down at the bottom of the slide is
42:26is not is really not more common on Lebanon.
42:29So want to just take a moment to
42:31focus on infusion related reactions
42:33because I won't talk about these again.
42:36So 26.4% with like Kanab,
42:407.4% with placebo.
42:42These tend to be almost always
42:46mild to moderate,
42:47you know 96% of them are they tend to
42:49occur with the very first infusion,
42:51most commonly the only occur once.
42:56And RE&amp;RHM going to talk about
42:59in the next slide, next slides.
43:01So, so Ari E you know many of
43:05us think this is really the most
43:08important toxicity of of these
43:10drugs because it is not rare,
43:13it is sometimes symptomatic and
43:16and necessitates you know pausing
43:18infusions until it resolves. Um.
43:22So the the key statistic here that you
43:26can see is 12.6% frequency on LEINAD,
43:301.7 on placebo.
43:31You know why does it occur on placebo?
43:34Well it it does occur spontaneously
43:37in related to amyloid angiopathy.
43:40You know CIA people with a lot of of
43:42amyloid angiopathy are disqualified
43:44from the study in the 1st place.
43:47You know if they have more than
43:48four microhemorrhages at the
43:50start they they don't enroll in
43:51the study for safety reasons.
43:53But there can be spontaneous cases of this.
43:57And. Symptomatic cases are only 2.8%,
44:01you know, of, of the total.
44:04When they're symptomatic,
44:05what are the symptoms usually,
44:07you know, headache, visual blurring,
44:09confusion, things like that.
44:10And and you know and in general
44:13working with a lot of these antibodies,
44:16I mean, you know,
44:17I view these as very manageable numbers.
44:19I mean I will tell you that
44:21they're 1/2 to 1/3 of the rate of
44:24what other trials have reported,
44:25you know, with other antibodies
44:27without going into detail,
44:28not head-to-head comparisons.
44:30Or just, you know, just lower,
44:32these are substantially lower
44:34numbers than the other trials report.
44:42Now a little more detail on Aria H
44:45Again refers to hemosiderin deposition.
44:50Hemosiderin, you know,
44:51a blood product that shows up on the.
44:54Team sensitive sequences on MRI.
44:58So just to review again, Aria,
45:01Ah, you know is generally
45:03comes in three categories,
45:04microhemorrhages that we
45:05saw on the on the image,
45:07they're less than a centimeter.
45:10Superficial siderosis is a you know is
45:13a thin deposition of hemosiderin on the
45:17brain surface actually in the sub peel space.
45:22And um, cerebral macro hemorrhage
45:24is you know is a micro hemorrhage.
45:28Well it's more than a centimeter you know
45:30it's it's the delineation between the two.
45:33So what you can see overall here is
45:35that the the key statistic is that 17.3
45:38frequency for RH with Lacan Amab 9.0 placebo.
45:43Of real note though is that the increase
45:48in like cannab is really area and the.
45:52Actually micro hemorrhages that
45:54are associated with edema.
45:56So if you take cases where there's no edema,
45:59these actually aren't more common
46:01on drug than placebo.
46:03And again they have for a lot of
46:05these occurred spontaneously again
46:07in relation to you know mild CAA,
46:10you know in these subjects.
46:14And RH is almost always asymptomatic.
46:18It when it's symptomatic,
46:21it's usually because it's with RE,
46:23and it also is some, you know,
46:26a boy for genotype is a risk for RH.
46:30Now I wanna spend a little bit
46:32of time on macro hemorrhages,
46:34which have caught a lot of press,
46:37especially, you know,
46:39large low bar and fatal hemorrhages.
46:43And I think that they,
46:45as important as they are,
46:46I think they've gotten a real inordinate
46:49and very imbalanced coverage in the press.
46:52So, so just to be clear.
46:56In the double-blind study,
46:58there was one fatal lobar hemorrhage,
47:01and it occurred in the placebo group.
47:04The two that have been reported in the
47:07press are in the open label extension.
47:09You know,
47:10one of these was a 65 year old
47:13woman E4 homozygote who had a
47:16left MCA stroke occlusion and was
47:21administered TPA emergently in the ER.
47:25And those of you familiar know that
47:27there's a there's a substantial risk
47:29of major hemorrhage with with TPA and
47:32that's what happened and and she died.
47:34The second case is of a A a
47:38fairly frail 87 year old man.
47:40He's actually older than would
47:41have been allowed in the study.
47:42At the start of the study E4 non
47:45carrier who was on the anticoagulant
47:47pick Saban for atrial fibrillation,
47:50he had a lobar hemorrhage and and
47:52thus the apixaban was stopped.
47:54But then now with untreated
47:56atrial fibrillation,
47:57he had an MRI and which is
47:59probably what he died from.
48:01So you know,
48:02are these cases related to the kanima?
48:05You know, I would say possibly they are.
48:07On the other hand,
48:09as a blinded site investigator,
48:10I would have said that the case on
48:13placebo was also possibly related.
48:16So you know, we really don't know.
48:19And if you look at the overall
48:22frequency of these cases, it's,
48:24it's about one in 1000, right,
48:26it's 0.1% for people taking placebo.
48:29It's about 0.1% for people taking
48:31like canama when you consider
48:33the greater exposure to lucama.
48:36On the open label extension.
48:38So I think we need to balance
48:39you know what we hear in the
48:41press with some of these numbers.
48:43And I especially think we need to
48:45balance this issue which is that there
48:48can be catastrophic events like this,
48:51balance that against the untreated
48:53state of Alzheimer's disease,
48:54which is uniformly progressive
48:57and uniformly fatal.
49:00And in fact when we talk to patients
49:02and their families about these
49:03risks in relation to these drugs,
49:06people who are interested in
49:07these drugs to begin with.
49:08Which are the people I talked to?
49:10It's you really don't hear
49:13people being deterred by these,
49:15you know, this degree of risk.
49:19Now I want to finish with biomarkers
49:23because I think the biomarker
49:25results are are probably every
49:27bit as interesting as the as
49:29the you know clinical effects.
49:31By way of background when we talk about
49:34biomarkers and Alzheimer's disease,
49:36I want to introduce the the
49:39current notion of of of Alzheimer's
49:41you know biologically which is
49:44this a TN classification, a for amyloid,
49:47T for tile and for neurodegeneration.
49:51So most people with Alzheimer's disease,
49:53you know, start out in the yellow
49:56circle that is amyloid doesn't.
49:58And what that means is the amyloid
50:00pathogenesis tends to be detected first.
50:03From there, if they have Alzheimer's,
50:06eventually Tau pathology
50:08will also be detectable.
50:10It may be there earlier,
50:11but the ways it's detected,
50:12you know, tend to to follow.
50:14And important thing is that Alzheimer's
50:17just defined by this intersection, A plus.
50:21Key is equals Alzheimer's disease.
50:24These people also will will progress
50:27to have neurodegeneration the blue
50:30circle and then there's the green
50:32circle which is cognitive impairment.
50:35And important to point out that people
50:37kind of can have all of these pathologies
50:41and still remain cognitively normal.
50:43And it's the people are cognitively normal
50:45who may may represent the best target
50:48for treatment as well sake at the end.
50:51So what does lecanu mob do for amyloid?
50:54First of all?
50:55Well, we saw what it did for amyloid pet.
50:59What about soluble amyloid,
51:01such as a curse in super spinal
51:04fluid and plasma?
51:05And that's what's shown here.
51:09On the left,
51:10we're looking at lacanada effects on CSF,
51:13Abeta 40 and 42.
51:15Remember, 42 is the more important one,
51:17the malignant one.
51:18In the upper right,
51:20we're looking at the ratio of 42 to 40
51:23and in the lower right we're looking at
51:26the corresponding ratio in blood plasma.
51:29Overall, one thing to note is
51:31that in in Alzheimer's disease,
51:33actually these all go down,
51:36not up because,
51:37and that's thought to occur because they're
51:40being aggregated and deposited in the brain,
51:43you know, as plaques.
51:45So up is good, you know,
51:47in these cases.
51:48And what you can see is that although
51:50there's no effective lukianov on EBITDA 40,
51:53the more important a beta 42, you know,
51:56there's a definite normalizing of the A beta.
51:59Aggregation process and that's
52:01also shown in the ratio of abeta
52:0442 to 40 and it's even shown
52:07in the same ratio in plasma.
52:11What about Tau?
52:14Well, with Tau there are are two main.
52:18Things that are being measured,
52:20there's the phosphorylation of
52:21soluble Tau which is thought to be
52:25an early marker of Tau pathogenesis,
52:27and that's what's shown here.
52:29What we can see is that for phospho
52:32Tau 181 steady increases in people
52:36on placebo and decreases relative
52:39to that and people taking liking
52:42amab in both CSF and plasma.
52:48Tao pet on the other hand is measuring the.
52:53The is looking at the aggregation
52:55you know of Tau into.
53:00Uh deposited as neurofibrillary
53:02tangles or dystrophic neurites in
53:05brain can be measured on a PET scan.
53:08In this case we're looking at pet
53:11data from multiple brain regions.
53:13Although I should point out that the
53:15ones of pre specified interest were
53:17in the temporal lobe you know which
53:19are represent earlier Brock stages.
53:21And what we can see here is that for
53:26three different temporal lobe regions
53:28and medial temporal lobe so-called.
53:30Meta temporal and a whole temporal.
53:33In all cases,
53:34there was a statistically significant
53:37blunting bilican amab compared
53:39to the placebo group.
53:41You know, with increasing,
53:42you know,
53:43Tau deposition on PET scan.
53:49One measure of end of neurodegeneration
53:52would be volumetric MRI and
53:54that's shown shown here.
53:56First of all in the top row
53:58we're looking at the effects of
54:00lecan amab on whole brain volume,
54:02cortical thickness and
54:03lateral ventricular volume.
54:05And maybe paradoxically Kanab is
54:08associated with greater atrophy
54:10and all of these measures.
54:12Now this is something that's
54:14been seen many times before now
54:16with anti amyloid therapies and
54:17and one simple explanation.
54:19Maybe simply that it represents plaque
54:22clearance which which reduces volume.
54:25The bottom row shows hippocampal
54:27volumes and in this case that effect
54:30is not seen and in fact like Kanab
54:33is associated with less atrophy in
54:37hippocampal volumes at end of study.
54:40So where do we go next from here?
54:44You know we can't amab may be ready for
54:46the clinic you know remains remains
54:48to be seen by you know FDA and and CMS.
54:51It did receive the accelerated approval
54:54based on plaque clearance January 6th.
54:58Umm, and it was submitted.
54:59They submitted for traditional approval on
55:02January 6th with a decision likely to occur,
55:05you know,
55:06probably late spring.
55:07And then the question will be,
55:08will CMS revisit coverage decision?
55:11I just want to highlight here in the
55:13middle though that this whole issue
55:16of accelerated approval based on
55:18biomarker is really controversial.
55:20And for anyone interested,
55:21we're going to have a webinar
55:24debate next Thursday.
55:25Dennis Selkoe's going to
55:26take the affirmative.
55:28That this is a ready,
55:29we're ready for this,
55:30so I'm going to take the negative.
55:32Here's the link.
55:33We can put it in the chat and
55:35if anyone has any trouble you
55:37can just e-mail me and I'll make
55:39sure that you get registered.
55:41The other where to next is is
55:43where we go scientifically.
55:45And I think these results really beg the
55:48question about earlier intervention,
55:50you know then clarity AD which
55:52was in early symptomatic disease,
55:55I think we need to go to pre
55:57symptomatic disease which is what
55:59the ahead study does and this
56:01study was started already about
56:03almost three years ago.
56:05And we fortunately chose the cannabis
56:07the drug before we knew these results.
56:10But there are two parts of.
56:13The head study people in the
56:15so-called a 4-5 arm have elevated
56:17and clearly elevated brain amyloid.
56:20In the A3 portion they have
56:23sub threshold elevation,
56:25you don't it's it looks visually normal
56:27but we know these folks are destined
56:29for further you know accumulation.
56:31So maybe even a better point
56:34of of intervention.
56:35Your head study design is shown
56:38here to four year long trial 5050
56:42randomization people in the A45
56:45arm with clearly elevated amyloid.
56:47Start out every two week infusions for
56:49two years and then go to every four weeks.
56:52Those with the intermediate
56:53levels can just be on every four
56:56weeks for the entire duration.
56:57Maybe a three study.
57:00So in summary of what I've shown you,
57:04the cannab treatment met all primary
57:07and secondary endpoints versus
57:09placebo at 18 months with highly
57:11significant differences starting at
57:13six months. And I think one of
57:15the most compelling things is how
57:17consistent the results are across a
57:19broad range of endpoints and subgroups.
57:21The safety profile of LA Canada I
57:25would consider acceptable with lower
57:27rates of Aria E compared to other
57:29published studies with other antibodies.
57:32Biomarker studies revealed that we cannot
57:34have improved both of the essential
57:37biological features of Alzheimer's,
57:39both amyloid and Tau and they did it by Pat,
57:42CSF and blood plasma.
57:45And this indicates biological
57:48disease modification.
57:50The brain MRI volumetric analysis
57:51indicated that like Canada was associated
57:54with reduced hippocampal atrophy,
57:56but greater global and cortical atrophy
57:59possibly related to amyloid removal like
58:03Kanab has received accelerated approval
58:05with the decision on full approval
58:08pending and it's uncertain whether CMS,
58:11you know,
58:12Medicare will revise coverage
58:14decision and last you.
58:16Had to study is investigating were earlier.
58:19Whether early or pre,
58:21symptomatic intervention may be
58:23associated with greater effect sizes.
58:26So I I thank you for your attention
58:29and I'll take questions.