A Positive Amyloid Trial, Finally?

https://www.science.org/content/blog-post/positive-amyloid-trial-finally

by kens • 4 years ago

37 49 4 years ago

I feel like this should probably be assumed to be a methodological problem or a statistical fluke until proven otherwise at this point.

bilsbie2• 4 years ago

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.

joelthelion2• 4 years ago

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.

jcranmer2• 4 years ago

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.

ekianjo7• 4 years ago

Oh like none of those has ever been hacked before. Either you have short memory or you are naive.

arolihas• 4 years ago

Phase 3 trials are highly regulated and basically designed to not be statistical flukes.

ekianjo7• 4 years ago

of course not. you need several phase 3 studies to know if your result is not a fluke. you can always get lucky.

gizmondo2• 4 years ago

With p=0.00005 it's very unlikely to be a statistical fluke.

ekianjo7• 4 years ago

Thats not what the p value says at all.

llamaLord• 4 years ago

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?

ncmncm4• 4 years ago

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...

bilsbie2• 4 years ago

How much of that is the healthy user bias though. Those are all things healthy people generally do.

UncleOxidant• 4 years ago

Cheese? Where is that coming from?

canadiantim• 4 years ago

Where are you getting your information on the methods to protect against dementia? That seems like a very dubious list tbh

JamesBarney• 4 years ago

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.

AlbertCory3• 4 years ago

I don't think I would call it clickbait. As you said, "there were people in control of Alzheimer's spending who had blinders on."

If something sounds good (as everyone admits) but it's failed over and over, and certain people with power shut down any alternatives, then "mafia" is maybe pejorative but not unfair.

jcranmer2• 4 years ago

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 Lesné 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 Lesné’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*.

zosima3• 4 years ago

There is a huge amount of genetic evidence that amyloid-beta or its precursor APP is involved and causal in Alzheimer's. That's not in question.

But since there's been so many trial failures trying to get rid of amyloid-beta, it has become clear that there's something missing to the story.

I think talking of mafia or cabals is a bit exaggerated, but perhaps there has been a bit too much focus on the easy-to-see and study plaques and aggregates of amyloid-beta and to little on what happens before the plaques develop. (Something that is much harder)

SrslyJosh• 4 years ago

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? =)

gizmondo2• 4 years ago

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.

ekianjo7• 4 years ago

Biogen was already caught corrupting the FDA to approve their last fake drugs even though it did not meet any endpoints. Massive systemic failure of institutions.

pessimizer4• 4 years ago

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?

mmastrac2• 4 years ago

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.

pessimizer4• 4 years ago

something _can_ be both historic and modest.

Totally agreed. But can something be both "historic" and not even "minim[ally] worthwhile"?

adamredwoods• 4 years ago

doh! /removed obvious link

qqqwerty• 4 years ago

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.

pessimizer4• 4 years ago

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.

ekianjo7• 4 years ago

If you read Biogen you already know thete is nothing but fluff at this stage.

keeptrying• 4 years ago

A bit too many brain bleeds in the sideffects for my liking. :-/

A Positive Amyloid Trial, Finally?

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