[HN Gopher] A Positive Amyloid Trial, Finally?
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A Positive Amyloid Trial, Finally?
Author : kens
Score : 25 points
Date : 2022-09-28 16:45 UTC (1 days ago)
(HTM) web link (www.science.org)
(TXT) w3m dump (www.science.org)
| pessimizer wrote:
| Helpful article. The headlines and editorial coverage of this
| made it look fantastic, except for any of the concrete
| information in the story I read, which made it look most likely
| completely worthless.
|
| https://www.theguardian.com/society/2022/sep/28/alzheimers-d...
|
| _> Success of experimental Alzheimer's drug hailed as 'historic
| moment': Study shows cognition in early-stage patients on
| lecanemab declines by 27% less than those on placebo_
|
| Wow, something's happening!
|
| _> The cognition of Alzheimer's patients given the drug,
| developed by Eisai and Biogen, declined by 27% less than those on
| a placebo treatment after 18 months. This is a modest change in
| clinical outcome but it is the first time any drug has been
| clearly shown to alter the disease's trajectory._
|
| We've gone from "historic" to "modest" in two paragraphs.
|
| _> On a 14-point scale used to assess Alzheimer's progression,
| patients on the drug scored 0.45 higher than those on the placebo
| treatment, with an Alzheimer's patient being expected to decline
| by about 1 point a year._
|
| That is very modest. And it's a questionnaire, not memory
| testing?
|
| _> Howard said: "The accepted minimum worthwhile difference
| ranges from 0.5 to 1.0 points, [meaning] that there are going to
| be some very difficult conversations and decisions in the next
| weeks and months."_
|
| So it's not even clinically significant? They have a metric that
| they decided to call the "accepted minimum worthwhile
| difference," and this is less than that. Doesn't that mean it's
| not worthwhile? I'm guessing based on the name.
|
| Is this just the first of a series of press releases to start
| building up public sentiment that can be eventually used to avoid
| the controversy generated when the FDA approved the last
| Alzheimer's drug that definitely didn't work?
| mmastrac wrote:
| I don't necessarily disagree with your premise, but something
| _can_ be both historic and modest. The first, tiny steps can
| show that there's something we can do about it and that's
| historic.
|
| Whether these benefits actually exist... well I'm on the same
| page as you with skepticism.
| pessimizer wrote:
| > something _can_ be both historic and modest.
|
| Totally agreed. But can something be both "historic" and not
| even "minim[ally] worthwhile"?
| ekianjo wrote:
| If you read Biogen you already know thete is nothing but fluff
| at this stage.
| adamredwoods wrote:
| doh! /removed obvious link
| [deleted]
| qqqwerty wrote:
| It sounds like the question they still need to answer is if
| this effect continues indefinitely, or if it is a one time
| effect. Across a 10 year disease progression this could slow it
| down by 2.5 years. I might make that trade off, at least in the
| early stages of the disease. Not sure I would want to slow
| things down in the later stages though. At that point just get
| it over with.
|
| It is also not clear from the press release what the response
| distribution looks like. If some people respond really well and
| others do not (but it averages out to 27%), maybe Alzheimers
| treatment starts to look a bit more like cancer. Where you try
| a few things and hope something sticks. My hunch is that is
| probably where we are headed, but I am not an expert in this
| stuff.
| pessimizer wrote:
| > Across a 10 year disease progression this could slow it
| down by 2.5 years. I might make that trade off, at least in
| the early stages of the disease. Not sure I would want to
| slow things down in the later stages though. At that point
| just get it over with.
|
| Especially since it seems like there might be some pretty
| brutal side effects.
| SrslyJosh wrote:
| > As I write, Biogen stock (BIIB) is up about $70/share, a sudden
| 35% jump that adds billions of dollars to their market
| captitalization, so there's definitely a lot of optimism out
| there.
|
| Who cares if it's reproducible? =)
| gizmondo wrote:
| You can short it if you think it definitely won't reproduce.
| Otherwise it's not clear why adding billions to the market cap
| is unwarranted.
| resoluteteeth wrote:
| I feel like this should probably be assumed to be a
| methodological problem or a statistical fluke until proven
| otherwise at this point.
| bilsbie wrote:
| It's sad we're at this point where we can't trust anything
| published. We have to think about funding, politics, peer
| pressure, publication bias.
| [deleted]
| gizmondo wrote:
| With p=0.00005 it's very unlikely to be a statistical fluke.
| arolihas wrote:
| Phase 3 trials are highly regulated and basically designed to
| not be statistical flukes.
| joelthelion wrote:
| This is not your regular quick scientific paper, though. It's
| the result of a very large phase three trial, involving
| hundreds of very qualified people, and a budget of around a
| billion dollars. It's as serious as it can be. Of course, we
| should probably wait to see what the outcome of the FDA review
| will be.
| jcranmer wrote:
| It's the press release of the initial analysis of a readout
| of a clinical trial. Mining the results for good news is a
| distinct possibility.
| keeptrying wrote:
| A bit too many brain bleeds in the sideffects for my liking. :-/
| llamaLord wrote:
| Hasn't the entire amyloid theory been coming under a huge amount
| of scrutiny recently for being almost a mafia-like cabal of
| somewhat questionable science?
| jcranmer wrote:
| > Hasn't the entire amyloid theory been coming under a huge
| amount of scrutiny
|
| Yes.
|
| > recently
|
| I'm using Derek Lowe as my litmus test for how the field
| reacts, and he's been leaning against it since around 2015-ish.
| So "recently" might not be all that recent.
|
| > for being almost a mafia-like cabal of somewhat questionable
| science?
|
| Uh, what?
|
| It recently came out that one of the papers in Alzheimer's
| research was faked. However, the importance of that faking on
| the field is actually relatively little: what it purported to
| establish was a direct causative link between a single amyloid
| precursor and memory decline--which was already the prevailing
| theory. As Derek Lowe describes it
| (https://www.science.org/content/blog-post/faked-beta-
| amyloid...):
|
| > I could be wrong about this, but from this vantage point the
| original Lesne paper and its numerous follow-ups have largely
| just given people in the field something to point at when asked
| about the evidence for amyloid oligomers directly affecting
| memory. I'm not sure how many groups tried to replicate the
| findings, although (as just mentioned) when people did it looks
| like they indeed couldn't find the _56 oligomer. And judging
| from the number of faked Westerns, that's probably because it
| doesn't exist in the first place. But my impression is that a
| lot of labs that were interested in the general idea of beta-
| amyloid oligomers just took the earlier papers as validation
| for that interest, and kept on doing their own research into
| the area without really jumping directly onto the_ 56 story
| itself. The bewildering nature of the amyloid-oligomer
| situation in live cells has given everyone plenty of
| opportunities for that! The expressions in the literature about
| the failure to find _56 (as in the Selkoe lab's papers) did not
| de-validate the general idea for anyone - indeed, Selkoe's lab
| has been working on amyloid oligomers the whole time and
| continues to do so. Just not Lesne's oligomer.
|
| In other words, amyloid hypothesis was prevailing before the
| paper anyways, it would have remained prevailing without the
| paper, and the paper itself never appears to have directly
| inspired actual clinical work on any of the failing drugs. It's
| hard to believe that the field would have abandoned amyloid
| hypothesis without the failure: there are many other reasons to
| believe the amyloid hypothesis, and the main reason to not
| believe it is only because _clearing amyloid hasn't improved
| Alzheimer's in actual drug candidates*.
| JamesBarney wrote:
| This is an exaggeration for clicks. We've since discovered that
| amyloid beta is probably not the cause. At least isn't very
| casual, or has sophisticated causality by the time we start
| treating people. It's also true there were people in control of
| Alzheimer's spending who had blinders on.
|
| But! There was a lot of reasons to think it was amyloid-beta,
| everyone with Alzheimer's has amyloid beta, early onset
| Alzheimer's is related to amyloid beta processing, mice that
| produce lots of amyloid beta or are injected with amyloid beta
| have Alzheimer's like symptoms.
| ncmncm wrote:
| Certainly about every paper nowadays is about stuff going on in
| a breed of mice engineered to produce lots of amyloid plaques.
| Hardly nobody knows or cares what happens in actual patients.
|
| The best methods we know of to protect real people against
| dementia are:
|
| 1. Get vaccinations. It doesn't seem to matter so much which
| ones. But Tdap and flu are seen to do the job.
|
| 2. Eat plenty of cheese.
|
| 3. Get treatment for herpes. I think valacyclovir is the
| mainstay.
|
| 4. Keep your gums healthy.
|
| There is no rigorous information to indicate why these seem to
| make a difference. Precious few people are looking. Certainly
| the people in charge of grants for Alzheimer's research are not
| awarding them for any such effort.
|
| When the whole house of amyloid cards finally collapses, what
| will amyloid specialists do with the rest of their careers?
| Maybe it would be smart to get a jump on that now...
| canadiantim wrote:
| Where are you getting your information on the methods to
| protect against dementia? That seems like a very dubious list
| tbh
| bilsbie wrote:
| How much of that is the healthy user bias though. Those are
| all things healthy people generally do.
| macrolime wrote:
| Healthy people generally eats lots of cheese and
| valacyclovir?
| jrussino wrote:
| You don't serve Emmenthaltrex at your cocktail parties?
| ;-)
| UncleOxidant wrote:
| Cheese? Where is that coming from?
| mmastrac wrote:
| Most studies are done on mice... /s
|
| But seriously,
| https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073537/
|
| > Oleamide and dehydroergosterol identified from Camembert
| cheese induce microglia into the M2 anti-inflammatory
| phenotype, leading to neuroprotection. The mechanisms that
| regulate microglial activation and inflammation in
| Alzheimer's disease are important targets for disease
| prevention. The regulation of microglia via daily lifestyle
| habits has been receiving increasing attention. The intake
| of neuroprotective and anti-inflammatory compounds
| including oleamide and dehydroergosterol in meals is safe
| and easy, so nutritional approaches are promising for the
| prevention of neurodegenerative disorders.
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