Yale Psychiatry Grand Rounds: February 17, 2023

Transcript

• 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• 02:39that is not peer reviewed.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&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&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.