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

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

Post by floramaria »

J11 wrote:This special season provides us the opportunity to speak about the often difficult truths of living with dementing parents.
J11 wrote:The few problems that we had were amply repaid by the unexpected appearance of many gifts
Thank you so much for sharing your experiences, J11. I found it very moving. You have been able to provide so much love and care for your loved one. That is a beautiful thing.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

Happy New Year, floramaria and all our friends on forum.

2021 could be a big year for Alzheimer's.
Aducanumab, masitinib, methylene blue, hydrogen water (?). https://pubmed.ncbi.nlm.nih.gov/29110615/
Once we make that first block, I see a whole lot of sunshine.

My New Year's wish is that they will stop arresting those coping with dementing illness (when possible).
I am sure that it is all very complicated, though everyone try your best to help out those with dementia.
Best Wishes to all for 2021!
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by roxanne »

Thank you J11 for your optimsm.

Best wishes to you too for 2021! Let's hope that this year will bring much health and happiness for all!
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

roxanne, thank you for your best wishes.

From what i understand aducanumab should be of considerable help for AD.
Looking forward to what the FDA ruling will be.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

Yeah, donanemab!
https://www.alzforum.org/news/research- ... alzheimers

This came out of nowhere for me!
There is now a whole queue of amyloid lowering treatments that have efficacy in the 30% slowing range.
With dona this appears to even extend into the early moderate AD range (MMSE 20).

It is exciting that we are now seeing the scientific process firm up on certain clinical features of the trials.
For example, one of the problems with the aducan trials was that quite a number of the placebos were non-decliners even over 78 weeks and with these patients being amyloid positive. This made it a tough hill to show aducan efficacy.

"Participants had to score between 20 and 28 on the mini-mental state examination, and have had memory loss stretching back at least six months." Requiring established memory loss is a good idea. Going somewhat later also seems like a good plan. This has been debated for almost 20 years without a clear resolution, though if you can select those deeper into the illness you have a much better sense that decline is present (though perhaps this strategy is only effective when using certain amyloid beta targets [here "recognizes Aβ(p3-42), an enzymatically modified form of Aβ adorned with pyroglutamate at its N-terminus. This form of Aβ is only found within amyloid plaques"]). Did the dona trial look at APOE epsilon 4 genotype?

It is not clear whether they did both tau and amyloid PET scans (universal?), though tau PET as inclusion is another important AD clinical trial innovation. Somewhat strange to me that they used fixed doses of 700 and 1400 mg: doesn't this mean that bigger people would receive less mg/kg? Also like the recombining of the ADCS and ADL. We need some psychometric innovation to develop a better understanding of what is happening in AD. However, it would probably still be best to report the standard ADCS and ADL values for benchmarking purposes. Using these well established instruments with a somewhat more advanced trial population than that included in the aducan also plays to the strengths of the tests. With patients around 30 MMSE in the aducan trials some of the tests might simply have not been sensitive enough to pick up on slight differences at the earliest stages of AD.

"while also validating the accuracy of home video-based cognitive assessments" This is another good one! Moving to virtual assessment makes a great deal of sense. One might be able to pick up on much more of dementia decline with essentially ongoing testing. In some way create at home immersive 24/7 testing while respecting privacy. This would probably be cheaper and yet give a near continuous measure of cognitive functioning (instead of the more typical testing every ~ 6 months).

Whoa! "Lilly referred to the second donanemab Phase 2 trial as “pivotal” "
Pivotal as in submit to FDA? Yes!

I like. I like a lot.
When (If?) there is a 343 page (or more) FDA briefing document for dona I'll do another one of these painstakingly thorough threads trying to understand what the document means. This time I hope they provide full documentation for the results of all patients and not have all the points all smushed up together. Including a summary for the cognitive results for the patients by different characteristics as I gave earlier on this thread for the aducan trials would be very much appreciated.

aducan appears to have reset the scoring for AD trials.
In addition now that we have a better idea of the efficacy range of anti-amyloid treatments ~30% companies can more efficiently progress through the clinical trial process.

They did a lot of interesting innovative things with TRAILBLAZER. It definitively feels like the scientific community is locking in on the amyloid target and developing a firm knowledge base. This could aducan's chances of approval as it is now fairly obvious that amyloid is a viable anti-AD target (shown also by BAN2401 and now dona).

One innovation I would still like to see is 18+ month trials. Everyone signs on for the 18 month trial and then the plus part is where patients would still be on trial though now those on placebo or low dose could be re-randomized up to a higher dose.
This would allow for more trial information to accumulate. This is of particular importance as we saw in the aducan trials that marginal doses are of considerable importance. Receiving the first 100 mg/kg seemed to have no real impact, yet at 150 mg/kg
a marginal 10 mg/kg made a large difference in treatment - placebo separation( ~25% relative!). Capturing this information would seem to be highly relevant from the perspective of understanding maximal clinical benefit as well as a return on invested resources.
The clinical trial would not need to be extended to accommodate the plus; the same end date could apply with earlier patients having the opportunity for more treatment.

Possibly the next big headline that we should be looking out for is a pre-AD dementia vaccine.
This has also been talked about for decades, though this would be a dramatic game-changer for all of us.
Instead of waiting until symptoms have nearly emerged (or actually have), why not step decades ahead of the problem?
This would drastically change the economics of AD.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

Whoa! It's raining AD treatments! Things are just popping out of nowhere.

https://www.fiercebiotech.com/medtech/c ... lzheimer-s

If the FDA says they have seen enough, well who are we to argue?
I believe them.
Breakthrough label!

Gamma entrainment could be an actionable item: NOW!
Entrained to light, sound, transcranial stimulation, touch(?) ...
Gamma frequency sound (binaural beats?) is readily available online.


Woa!
"by addressing both the pathological accumulation of tau and beta amyloid while also using non-invasive neuromodulation to effect the restoration of neurological function. "

https://www.businesswire.com/news/home/ ... 9s-Disease

Approve Now!
Approve Now!

If it's GRAS, then let the AD dementia community choose.

Approve Now!
Approve Now!
Approve Now!


Wo!

" ...published a landmark study showing dramatic benefit in treating Alzheimer’s using a non-invasive brain stimulation technique. These compelling results are the foundation of the clinical trials we are conducting today.

Knowing that in Alzheimer’s Disease there is a deficiency in certain brainwave frequencies, our founders discovered that stimulating the brain at a specific frequency had the effect of reactivating the immune system in the brain. This effect correlated with a reduction in amyloid plaques and tau tangles, typical hallmarks of the disease. "
https://www.cognitotx.com/


Number and size of amyloid plaques decrease after 1 week of treatment.
Yeah, I see that.
rsz_sitepng.png




Original research simply used light/sound entrainment.
Find your Light and Sound Machines!
40 Hz.
This should reasonably be understood as GRAS.
I have done a substantial amount of entrainment and have not
noticed side effects. I believe that they do recommend only
certain entrainment exposure (below 60 minutes suggested).


Device: Flicker
The Flicker intervention is delivered with the GammaSense Stimulation System by Cognito Therapeutics and involves viewing flickering lights at gamma frequency (like a strobe light but faster) to drive gamma oscillations in visual brain areas. The GammaSense Stimulation System is a device consisting of a pair of opaque glasses with a light-emitting diode (LED) illumination on the interior of the glasses. Headphones worn by the user during the stimulation session provide the auditory stimulation. When activated for the treatment session, the device will generate light and sound oscillations at 40 cycles per second (Hz) for 60 minutes. Participants will use the device daily during their active treatment period.
Other Names:

driving gamma
GammaSense Stimulation System

https://www.clinicaltrials.gov/ct2/show ... w=2&rank=4
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

One figure that might be considered useful to include in the reporting of AD clinical trials is cognitive change on the y-axis (delta CDR-sb, etc) versus cognitive status on the x-axis (CDR-sb etc). I do not believe this information was actually given with the aducan trials.
This would give us more insight into what patients were driving the change in cognition. The aducan Briefing Document probably did partition the clinical trial patients into disease stage though a chart would offer a more granular depiction of the result.
Providing a spreadsheet of CDR-sb, delta CDRsb, dosage level, dose count, side effects etc.) would allow for a range of interesting such findings to be data mined by people ... well like me.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

Yeah!
https://investors.biogen.com/news-relea ... iew-period

The plot thickens as they say.

So just a quick recap of the intrigue that has been going on at street level with aducan.

Futility analysis established futility. Oops the futility analysis was futile.

Our people inside the FDA then grabbed the ball and ran it into the end-zone; um but the FDA is the referee!
Score that a touchdown for the FDA or an own goal?

The fix is on and then they call in a new team with a statistical analysis that is ah orthogonal to the original assessment. Independent thinking is good, diametrically opposed not so good. The Advisory Committee is not happy with having to decide between two categorically diverging assessments (understandable); they go with orthogonal.

Um, I guess you could say that puts the ball back into the FDA's court.
Now this is brilliant; the FDA asks for a timeout and requests more information.
I had not thought of that one.

It was not clear to me how the FDA could simply ignore the Committee's strongly negative assessment.
Unless ... unless there was more information!
Did the committee consider the information contained in the newly submitted Addendum 3?
Nooooo, Exactly!

By the time June 7th rolls around the Embark extension trial will have a whole bunch more data.
Upwards of ~1,000 patient years! This could make it even more difficult to reject. More data = more confidence.

It is however quite disappointing that the extension results are not considered part of the clinical trial
results. My 18 plus idea would seem to be of relevance here. Instead of going directly to LTE after the
official 18 months are over, while not go to the plus phase? It's like running before you have the ball.
Accumulate all the evidence you can and once the trial has achieved significance then go to LTE.
As noted previously this is especially important with anti-amyloids as so much of the benefit
happens at the marginal doses near the end of the 18 month trial.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

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

Post by J11 »

I have been thinking about all the different measures that were used in the aducan phase 3s. You have CDR-sb, MMSE, ADAS-cog, ADCS-ADL, and the NPI. What I found interesting was to remember that different AD patients will have different strengths on these measures. Some patients with strong cognitive scores on the MMSE (ADAS-cog) might nonetheless still see the pink pokka dotted spiders as captured by the NPI. This feature of cognitive assessment in dementing illness is recognized in biplots of e.g., MMSE versus ADCS-ADL which clearly demonstrate this dispersion. It is disappointing that we have stuck with flat world when we could go multivariate and capture much more of what the dataset could reveal to us. Simply reporting only the individual psychometric instruments loses all of this information. The irony is that it is to some extent this very limitation which is making the therapeutic benefit of aducan more obscure than it needs to be. Basically, it is a data visualization problem. Why throw out useful information merely because it doesn't fit neatly onto the printed page? Give a url (and perhaps 3D viewing goggles) and see a fuller depiction.

What I thought of was: Why not put the information into 3D space like in the dot cloud above? With 3D scatter plots (freely available with R) one could examine the data in different dimensions. This would actually give you a much better idea of what was actually happening with the patients. Here x could be ADAS-cog/CDR-sb (probably best to overlook MMSE as it is not the most accurate of these measures), y could be ADCS-ADL, z could be NPI. Cognition, Function and Neuropysch!

You could actually z-score them all and do this so it makes sense and have negative z-scores to be bad and positive z-scores to be good.
In the figure above the best performing patients could be in the top corner on the other side of the cube, the worst performing patients would be on the bottom facing vertex. Perhaps calculate the Euclidean distance and possibly use this as a score for overall functioning.

It already seems clear that such a re-calculation would favor aducan as many of the other measures were even more strongly favorable than even the CDR-sb. For example, the functional measure ADCS-ADL-MCI for EMERGE reported a 0.0006 p-value (40% reduction vs placebo). This would create substantial separation along one dimension of the 3D scatter plot above. Perhaps such a plot would show us that placebo might cluster in the less well performing octants (?) of the cube. We are just not sure because this information was never disclosed. (Would be somewhat unsure of how the statistics would be constructed for such an approach. Not sure whether you can simply make up some new theory without a conference or something.)



It would be interesting to see how the actual points in the 3D plot would look. It is important to capture these other measures. For example, from the point of view of caregiving aspects of behavior such as neuropsych and function are highly relevant. It is in fact somewhat surprising that more global measures of functioning weren't reported for aducan. The caregiver stress result though would provide a broader sense of patient well-being. Only reporting the individual measures obscures the true results more than would be typically understood by casual observers. Seems like another good reason to move more to an open science model: the people are here and ready to help.
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