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 »

There are so many exciting developments in my on-going accumulation of AD knowledge that it is difficult to know where to begin. The most current news item is the release of the FDA Briefing documents for the Amylyx treatment for ALS. I had not realized that this is the standard plan with the FDA: Study a drug treatment (sometimes for years) and then 3 days before the ADCOM post the documents online. These documents might have been ready even months ago.

For greater transparency and for better democratic engagement the background material probably should be posted at least one month ahead of the meeting. As I have seen with the FDA Briefing Document for Aducanumab it has taken me years to figure out what it all meant. For the public to have a reasonable level of participation in the regulatory process a greater sense of fair access to the documents should be considered. I look back on some of my comments about the Aducan ADCOM and realize how uninformed they were; giving earlier access would offer the opportunity to have a higher level conversation about the important issues involved with drug approval.

The big news with Amylyx for me was: Who is Amylyx? I searched our forum ... No Amylyx?! This one completely blindsided me. However, it has been big news in the ALS sphere for at least the last year or two. I do not want to be caught flat footed again, so I went back to the AD database of all clinical trials on clinical trials gov. Amylyx was there with a phase 2 trial with 95 patients; this just missed my screening. I then went through all of the AD trials down to sample sizes of ~50 patients and found ~50 companies.

What was of particular interest to me about Amylyx is the idea that it might offer AD patients a near term treatment option. If AMX0035 (Amylyx's ALS candidate) were approved by the FDA, then off label use in AD might be possible as early as this June? As I said this came out of nowhere. I had assumed that the only FDA approved AD treatments would need to go through the normal process and this would involve very large trials (into the hundreds). Such treatments could be seen miles ahead before arriving on the market. Yet, with the backdoor approach of going to an orphan indication such as ALS, new treatments for AD could just magically appear.

There are potential shared biological pathways linking AD and ALS ( along with other neurodegenerative illnesses).
AMX0035 reduces ER stress and mitochondrial apoptosis which is a recurring feature of proteinopathies. This is very exciting!

Another AD aspect from my Amylyx reading that I focused on was how ALS is a motor neuron disease. In ALS the brain's motor neurons are destroyed. This results in impairment in Bulbar (speaking, swallowing), respiratory (breathing), fine motor ( writing ...) and walking functions. What I found very striking with these disease features
is that they are the same problems that were the most difficult components that we found in coping with AD.
AD is ALS? On the ALS FRS-R scale that they used to quantify ALS progression in the AMX0035 phase 2 trial, our loved one would have read out as 0s across the board on all the dimensions of ALS illness. Having an increased score on a cognitive measure really did not have anywhere near the importance of preserving basic function as measured by the ALS FRS-R. Loss of these abilities increased our caregiving burden by orders of magnitude. The possibility that AMX0035 might go off label in a few months for AD could have profound implications for the AD community and the nature of AD caregiving.

My rough guess is that there could be a big benefit for middle/late stage AD patients because the motor cortex in typical AD is not the primary focus as it is in ALS. If you could just help out the motor cortex at the margin by preventing these cells from being fully destroyed, then perhaps these critical higher functions could be preserved for longer. The ALS study found ~30% slowing; one could imagine a scenario in which 30% slowing in AD (over say 5-10 years) would prevent progression to severe motor impairment.

This does make me wonder whether we might be close to a .com like mania with AD. The 2021 CTAD poster for AMX0035 described a phase 2 trial in AD that showed impacts on tau, amyloid etc.. The FDA has accepted amyloid as a biomarker for disease progression. This might allow a range of competitors to step forward under this logic and more rapidly move through clinical trials. With Amylyx's product even this route might be avoided as it could be approved over the nearish term in ALS.

As an aid for those wanting to know which companies are working on AD here is a fairly complete list of companies
with a clinical trial of at least ~ 50 patients. There might be some though that for whatever did not pass the screen etc..


Another exciting near term possible conversion of an orphan drug in development repurposed to AD is
zatolmilast (BPN14770) from Tetra Therapeutics that is currently in a phase 2/3 for Fragile X. The proposed mechanism of action for zatolmilast is orthogonal to the typical amyloid paradigm so it could work on top of mabs.


AbbVie
Actinogen Medical|Avance Clinical
AgeneBio
Alector Inc.
Alzheon Inc.
Amylyx Pharmaceuticals Inc.
Anavex Life Sciences Corp.
Annovis Bio Inc.|Parexel
AriBio Co., Ltd.
Asceneuron Pty Ltd.
Athira Pharma
Axsome Therapeutics, Inc.
BeyondBio Inc.
Biogen
Biohaven Pharmaceuticals, Inc.
BioVie Inc.
BrainX Corporation
Capital Medical University|CSPC-NBP Pharmaceutical Co., Ltd.
Cassava Sciences, Inc.
Cerecin
Cognition Therapeutics
Cortexyme Inc.
Eisai Inc.
Eli Lilly and Company
Evon Medics LLC
FUJIFILM Toyama Chemical Co., Ltd.
GemVax & Kael
Genentech, Inc.
Green Valley (Shanghai) Pharmaceuticals Co., Ltd.
H. Lundbeck A/S
Hoffmann-La Roche
Hyundai Pharmaceutical Co., LTD.
IntelGenx Corp.
ScandiBio Therapeutics AB
Janssen Research & Development, LLC
KeifeRx, LLC
MODAG GmbH|Quotient Sciences|Aptuit (Verona) Srl, an Evotec Company
Nature Cell Co. Ltd.
Neurim Pharmaceuticals Ltd.|Syneos Health
NeuroActiva, Inc.
Neurotrope Bioscience, Inc.
Novo Nordisk A/S
Pharmazz, Inc.
Regenera Pharma Ltd
reMYND|NeuroScios GmbH
Scotmann Pharmaceuticals
Shineway Pharmaceutical Co.,Ltd
T3D Therapeutics, Inc.
TauRx Therapeutics Ltd
Tetra Discovery Partners
Theranexus
TrueBinding, Inc.
Vivoryon Therapeutics N.V.
Last edited by J11 on Wed Mar 30, 2022 8:46 pm, edited 1 time in total.
J11
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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All Studies Linear 1.PNG
All Studies Linear 2.PNG
All Studies Linear 3.PNG
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Last edited by J11 on Tue Mar 29, 2022 7:02 pm, edited 2 times in total.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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All Studies Linear 4.PNG
All Studies Linear 5.PNG
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Last edited by J11 on Tue Mar 29, 2022 7:03 pm, edited 1 time in total.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Regression
Regression Model Linear

LINEST raw output
2.1851 0.0689
0.2609 0.0574
0.0854 1.1983
70.1654 751.0000
100.7605 1078.4681

Regression Statistics
R^2 0.0854
Standard Error 1.1983
Count of X variables 1.0000
Observations 753.0000
Adjusted R^2 0.0842

Analysis of Variance (ANOVA)
df SS MS F Significance F
Regression 1.0000 100.7605 100.7605 70.1654 0.0000
Residual 751.0000 1078.4681 1.4360
Total 752.0000 1179.2285

Confidence level 0.9500

Coefficients Standard Error t-Statistic P-value Lower 95% Upper 95%
Intercept 0.0689 0.0574 1.2001 0.2305 -0.0438 0.1817
X1 2.1851 0.2609 8.3765 0.0000 1.6730 2.6972
J11
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

Regression
Regression Model Linear

LINEST raw output
Coeff 2.1614 0.0644
SE 0.2872 0.0622
R^2,STer rg 0.2768 0.5750
F 56.6398 148.0000
SS 18.7260 48.9312

Regression Statistics
R^2 0.2768
Standard Error 0.5750
Count of X variables 1.0000
Observations 150.0000
Adjusted R^2 0.2719

Analysis of Variance (ANOVA)
df SS MS F Significance F
Regression 1.0000 18.7260 18.7260 56.6398 0.0000
Residual 148.0000 48.9312 0.3306
Total 149.0000 67.6573

Confidence level 0.9500

Coefficients Standard Error t-Statistic P-value Lower 95% Upper 95%
Intercept 0.0644 0.0622 1.0363 0.3017 -0.0584 0.1873
X1 2.1614 0.2872 7.5259 0.0000 1.5938 2.7289
J11
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

Regression
Regression Model Linear

LINEST raw output
2.3116 0.0821
0.2731 0.0582
0.4952 0.3837
71.6259 73.0000
10.5427 10.7449

Regression Statistics
R^2 0.4952
Standard Error 0.3837
Count of X variables 1.0000
Observations 75.0000
Adjusted R^2 0.4883

Analysis of Variance (ANOVA)
df SS MS F Significance F
Regression 1.0000 10.5427 10.5427 71.6259 0.0000
Residual 73.0000 10.7449 0.1472
Total 74.0000 21.2876

Confidence level 0.9500

Coefficients Standard Error t-Statistic P-value Lower 95% Upper 95%
Intercept 0.0821 0.0582 1.4114 0.1624 -0.0338 0.1981
X1 2.3116 0.2731 8.4632 0.0000 1.7672 2.8559
J11
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

Regression
Regression Model Linear

LINEST raw output
2.2022 0.0607
0.3038 0.0632
0.6003 0.2872
52.5594 35.0000
4.3353 2.8869

Regression Statistics
R^2 0.6003
Standard Error 0.2872
Count of X variables 1.0000
Observations 37.0000
Adjusted R^2 0.5889

Analysis of Variance (ANOVA)
df SS MS F Significance F
Regression 1.0000 4.3353 4.3353 52.5594 0.0000
Residual 35.0000 2.8869 0.0825
Total 36.0000 7.2222

Confidence level 0.9500

Coefficients Standard Error t-Statistic P-value Lower 95% Upper 95%
Intercept 0.0607 0.0632 0.9606 0.3434 -0.0676 0.1889
X1 2.2022 0.3038 7.2498 0.0000 1.5855 2.8188
J11
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

Regression
Regression Model Linear

LINEST raw output
2.2497 0.0643
0.3619 0.0741
0.6269 0.2880
38.6507 23.0000
3.2048 1.9071

Regression Statistics
R^2 0.6269
Standard Error 0.2880
Count of X variables 1.0000
Observations 25.0000
Adjusted R^2 0.6107

Analysis of Variance (ANOVA)
df SS MS F Significance F
Regression 1.0000 3.2048 3.2048 38.6507 0.0000
Residual 23.0000 1.9071 0.0829
Total 24.0000 5.1119

Confidence level 0.9500

Coefficients Standard Error t-Statistic P-value Lower 95% Upper 95%
Intercept 0.0643 0.0741 0.8687 0.3940 -0.0889 0.2176
X1 2.2497 0.3619 6.2170 0.0000 1.5011 2.9982
J11
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Emerge Percentile 1.png
Emerge Percentile 2a.png
[Edit: The figure below is a correction of the top figure in this post.
When I looked at the top figure I noticed something odd, all the points were above the regression line and the y-intercept was at zero. Something was wrong. I went back and tried again and this time I noticed that the force to zero box had been checked. When I unchecked the box the figure below was reported.]
Emerge All.png
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Last edited by J11 on Tue Mar 29, 2022 7:10 pm, edited 2 times in total.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Engage Percent 1.png
Engage 2.png
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