Celebration Thread! Biogen is going to the FDA with Aducan.

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J11
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

Very big day tomorrow!

Tomorrow is the day that Lecanemab is finally available (for those who can afford it out of pocket).
This will be another Alzheimer's Liberation Day!

Actually having a disease modifying treatment on the shelf for AD is a massive step forward.
Clearly the possibility now of going off label offers the potential of never entering into the endless
cognitive decline stage. In our experience this cognitive decline was noticeably present decades before
an official dementia diagnosis. For example, simple memory impairment without dementia can be
present years and years before symptoms of dementia. Having an opportunity to actually do something
in this pre-AD stage will be such a blessing.

Of course, we would really like to have subq dosing and some clinical research for safety. Efficacy has already been
demonstrated in the later stages, what is now of greater interest is to know what a really safe preventative dose might be.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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J11 wrote:I would think that the pre-MCI microdosing that I am suggesting would decrease on label risk by an order of magnitude. It already does not seem to demonstrate sound clinical judgment to wait and wait and then treat with the maximal clinically tolerated dose.
I hope there is efficacy with pre-MCI treatment. It is so sad to see graphs like the one below from the CLARITY trial. The curve of decline flattens, but only for a limited time. Then the disease relentlessly progresses again. We will have to wait and see what the results are from the AHEAD trial.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by NF52 »

J11 wrote:
karelena wrote: Mon Jan 23, 2023 3:34 am I hope there is efficacy with pre-MCI treatment. It is so sad to see graphs like the one below from the CLARITY trial. The curve of decline flattens, but only for a limited time. Then the disease relentlessly progresses again. We will have to wait and see what the results are from the AHEAD trial.
That graph is from the Phase 2 trial, (aka 201 CORE and OLE); you can see the different doses which were used to determine the most effective. A few other differences between 201 CORE and CLARITY:
  • 201 removed people if they were identified as having ARIA-E or ARIA-H. CLARITY did not; either "dosing through" MRI-confirmed, neurologically "mild" ARIA or "pausing" dosing for one or more doses if symptoms and/or MRI imaging showed moderate ARIA. They also added unscheduled MRIs for participants who developed symptoms suggestive of mild ARIA(beyond an isolated headache or episode of nausea) as an added safety measure.
  • ApoE4 carriers on the 10mg/kg (of weight) biweekly dose in European sites in the 201 Study were moved down to 5 mg/kg by outside European monitors; ApoE4 carriers were all on the 10 mg/kg dose in CLARITY.
The results is that all participants in CLARITY got the 10mg/kg dose and most completed the full trial (and are in the OLE now). Here's the graph of results from CTAD. The first graph shows a definite increase on the Activities of Daily Living Scale over 18 months, which most participants and family members rate as far more important to them than cognitive skills. The second screen shot shows the CDR-SB.

Presenters noted that a divergence in scores occurred at the 3 month period (the first arrow), even before a significant amount of amyloid beta would have been removed, and continued to increase in the divergence from placebo for 18 months (second arrow). Based on the trend, several presenters, including some NOT in the Lecanemab presentation, noted the relative benefit may increase during the 18-month Open Label Extension, when original CLARITY participants on lecanemab to a full 18 months on the drug.
Image 1-7-23 at 1.43 PM.jpeg
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

Karalena, thank you for reposting the figure from my post. This gives me a chance to tighten this one up. I think it is worthwhile to do so because this could be an especially important perspective for those considering Lecanemab treatment.

Firstly, the data is derived from this article.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9768996/
Specifically, from the supplemental file and figure S2 on the top right.
The figure on the top left is labeled in centiloids though it seems clearly to actually be SUVR. The figure on the top right uses centiloids and the dots are spaced out more so I used that one because it is easier to data grab the dots.


So, to be clear this is the phase 2 result and I derived the result in the figure that you posted. I was able to grab 68 placebo dots and 29 10 mg/kg every two weeks dots. What I then did was sorted each of these two groups and plotted their CDR-sb change from baseline versus the percentile rank.

So, I'll run through the bottom figure which you posted, but this time to make it clearer I'll only include the high dose 10 mg/kg every two weeks (blue line) and the placebo (black line). What does this percentile figure actually mean? Look at the blue line where it intersects the green line near 0.4. This point shows that the 40% of patients on 10 mg/kg every two weeks who had the best response to Lecanemab on the phase 2 were cognitively unchanged or better. That is actually fairly impressive. 40% of treated patients did not actually get worse? I like; I like a lot.

Now look to the right where the black hatched line intersects the blue line. We are up to 75% of the patients treated with Lecanemab and they still seem fairly stable. So, for the top 75% of the treated patients, they declined by 0.5 CDR-sb or less. I like; I like even more.

Typical AD patients decline by 2 CDR-sb. 0.5 CDR-sb is SLOW progression. It's only when you move over to the red line intersecting with the blue line that you have the treated patients entering this terminal irreversible decline stage. The FDA in their documents modeled these patients as rapid progressors constituting about 15% of the patient population. As seen these 15% progress from 2 to 5+ CDR-sb which is A LOT!

The same approach could be used to understand the placebo. Notice that ~30% of placebo were non-progressors or better, while 40% of placebo were in the rapid progressor category. Thinking about the results in this way gives a very different perspective of how different parts of the distribution responded. What we see is that the Lecanemab treated patients at the 40th-85th percentiles had large treatment benefit versus placebo. Focusing on the topline average can then be seen to be possibly quite deceptive.

However, a big problem with this interpretation is that it does not correspond to the reported phase 2 results. The average difference from the dots that I grabbed placebo versus treated was 1.43 (placebo) and 0.53 (10 mg/kd *2 treated) for a 0.9 treatment benefit and the posted phase 2 result was ~0.4. So, there's that. I am not clear what the problem is though the small samples of PET scanned patients might be the problem as well the top dose in the phase 2 stopped enrolling APOE epsilon 4s; so there's that as well.

Nevertheless, the other lines from the different dosing arms showed a similar pattern. We will need to wait for a similar dot plot from Clarity to get a better view of these results. The overall insight is that there is likely a strong responder group that really has been obscured by concentrating on the topline number (this general result was also seen with the Aducanumab dataset). For patients these more typical (and larger) responses are really what they are interested in.

In actual clinical practice when patients on Lecanemab clearly entered the irreversible decline stage than doctors at some point would probably suggest that patients call it a day. From the clinical medicine perspective what they would then see is almost all of the patients doing quite well on treatment after selection against non-response occurs. This perspective is absent during clinical trials because you are not allowed to remove the patients that are not responding.


The figure on the top is a qualitative view of the results, this time roughly guesstimating what the percentile distributions would be like if true AD patients could be selected. For placebo, this would mean patients would have at least 1 CDR-sb decline and towards the right probably some runaway cognitive decline into rapid progression. For the treated group there would still likely be some patients who could improve on treatment, while there would not be many who would enter rapid progression. This is perhaps somewhat aggressive as this would give 1.5 CDR-sb benefit, though when Donanemab used amyloid-tau selection it reported ~50% benefit which would be ~0.8 CDR-sb benefit. Perhaps one thing that could be better is to also make sure that the patients were actually in decline phase by using AD pre-enrollment registries.

Percentile 2.PNG
Percentile 1.PNG

https://www.desmos.com/calculator/lgpeq8ishs

https://www.desmos.com/calculator/hbsm4bedx7
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

Happy Alzheimer's Liberation Day everyone!

This has been such a massive day.
Lecanemab is now available for treatment!
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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I have been trying to log into chatGPT, without success to date.
I tried the app below instead.
I asked this app: "Do monoclonal antiamyloid antibodies reduce the rate of decline in Alzheimer's disease?"

The app's assessment was:
12% No
38% Possibly
50% Yes

I am not sure whether the FDA would be happy with 12% alpha error.
They seem to more half cup always empty types.

https://consensus.app/results/?q=Do%20m ... F&meter=on

The ChatGPT revolution has begun!
Having the ability to synthesize the entire database of pubmed etc research into comprehensible knowledge is a massive massive development. There are a quarter million article on pubmed on Alzheimer's. A person could only skim the surface of such a vast ocean of research. These new AI bots will allow us to reach deeply into the research literature.
Last edited by J11 on Wed Feb 08, 2023 5:55 pm, edited 1 time in total.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by NF52 »

J11 wrote: Wed Feb 08, 2023 4:56 pm I have been trying to log into chatGPT, without success to date.
I tried the app below instead.
I asked this app: "Do monoclonal antiamyloid antibodies reduce the rate of decline in Alzheimer's disease?

The app's assessment was:
12% No
38% Possibly
50% Yes

https://consensus.app/results/?q=Do%20m ... F&meter=on

The ChatGPT revolution has begun!
Having the ability to synthesize the entire database of pubmed etc research into comprehensible knowledge is a massive massive development. There are a quarter million article on pubmed on Alzheimer's. A person could only skim the surface of such a vast ocean of research. These new AI bots will allow us to reach deeply into the research literature.
Just don't ask ChapGPT to compose your analysis and posts; we'd miss your unique insights!
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

NF52, thank you for your reply.

Hmm, that's an idea! It would be the ultimate Turing test: the ultimate J11 test!
It is not merely that a computer might be able to pass as human, but the more stringent test would be passing as J11!!?
I am not sure whether computers are non-linear enough for that.

Every once and a while I shoot one across the bow and I go somewhat out there to stretch my range; I am very uncertain whether GPT could do that. I would guess that GPT would be programmed more to stay within its programming lane.

Yet, the ChatGPT revolution brings so much IQ power to the table.
Consensus does not have the feel of a true AI enabled chatbot.
What happens when you have the actual ability of synthesizing all of human knowledge about a topic?
With ChatGPT if you had full pubmed access and perhaps a slight amount of article curation (to remove the retracted articles etc.) you could develop very powerful insights. I wonder how the FDA might view such research?
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by NF52 »

J11 wrote: Wed Feb 08, 2023 5:53 pmWhat happens when you have the actual ability of synthesizing all of human knowledge about a topic?
With ChatGPT if you had full pubmed access and perhaps a slight amount of article curation (to remove the retracted articles etc.) you could develop very powerful insights. I wonder how the FDA might view such research?
I think they'd say "That's an impressive literature search, which we saw a lot of during 2020 when labs shut down; what have you done lately to expand upon that knowledge?"

That's what I like about research--always seeking to push the envelope of what we understand and how it melds with, upgrades or defies our existing schema and the stories we tell.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

NF52, I was thinking more along the lines of how this might forestall pathological science. Sometimes people really are not that interested in discovering the truth, indeed their motivation is all too often avoiding the truth as long as possible and then still delaying the truth. It would be a stretch to say that such a perspective has not been in play with anti-amyloid mabs.

{There are times in science when you have reached the finish line-- you have proven your hypothesis, and yet there continues to be the doubters. These doubters can often not be doubters in good faith but doubters with some ulterior motive. The chatbots would be very helpful in such instances. The chatbots could be called in as referees to call the goals once they have been scored.}

However, with AI chatbots, a superpowerful near omniscient technology now offers us the potential for unbiased answers to our questions. We could synthesize those 250,000 pubmed Alzheimer articles and derive some top level understanding of it all. The potential here is that these chatbots (after perhaps they have been audited in some way) might report to us essentially the undisputable truth. All the efforts designed to create confusion and doubt would be overwhelmed by this truth.

We can go beyond appeal to experts. J11 says this -- J11 says that, towards listening to all knowing chatbots. I think that I called Lecanemab monumental, well AI chatbots are also monumental. I suppose that there might already be efforts to throw the bots a fiver to give the "right" answer. If you can use reinforcement to create the correct answer, then I suppose that you might also be able to use reinforcement to create the "right answer".


I don't want to be pretentious here (by comparing my humble self to one of the greatest thinkers in the history of human civilization), though I can certainly agree with where Newton was speaking from when he said:

"I do not know what I may appear to the world, but to myself I seem to have been only like a boy playing on the seashore, and diverting myself in now and then finding a smoother pebble or a prettier shell than ordinary, whilst the great ocean of truth lay all undiscovered before me."

With the internet that is so much truer than ever before. There is such a massive ocean of truth just beyond from the seashore that is freely available to all who might be interested. So much to read -- so little time to read it all.

That's where chatGPT enters the picture. chatGPT could read it all for you and give you some condensed high level analysis. It could give you the answer to everything. There are questions (such as Aducanumab/Lecanemab/mab) that I have spent years on and yet I still try to be somewhat ambivalent. It would make life so much easier to have some all knowing AI that could provide the answer for us.
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