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

Alzheimer's, cardiovascular, and other chronic diseases; biomarkers, lifestyle, supplements, drugs, and health care.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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I have been reading about lithium and AD. Interesting. Anyone have an idea about recreational, non-prescription dosing?
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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

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Thank you for your reply NF52.

Sorry for reposting these figures, though they are good ones and ones that I think others should carefully consider. What they highlight is how far ahead people will be made aware of their impending cognitive decline. Current technology might already be able to pick up the initial amyloid changes possibly upwards of 30 years ahead of the clinical signal through CDR-sb. Alzheimer's truly is close to the ultimate see it from a mile type illness. I am unsure once Lecanemab is approved whether it will be reasonable to call it good clinical judgment to simply ignore these early warning signs. For someone at especially high risk (e.g., e44) it would be particularly problematic.

The logic ... is what? We'll wait until there is enough neurodegnerative to qualify for a diagnosis? As seen in the figure directly above, the hippocampal memory signal starts ~ 15 years before global dementing illness. It is quite startling. Something will only be done about amyloid when it pervasively effects one's entire global cognition, while merely exhibiting neurodegeneration specific to memory is not quite enough?

I would have to say from a personal perspective that AD has been downgraded in my own perception of my ranking of my personal health risks. There is now a wave of approaching Alzheimer treatments. Even in the last year there has been a transformation as we had approval of Aducanumab, then the Clarity readout, the approaching PDUFA date for Lecanemab, the emergence of subQ dosing for Lecanemab ... . AD clinical management is at the stage of rapid change. My assessment is that for those now 10 years out from MCI onset, they will never progress into moderate - severe illness.

I was thinking today that it could be quite helpful if there were some financial future's contract that would allow for trading of AD risk. The net present value of the government's AD current liability (i.e. without additional treatment options) is probably easily north of $5 trillion. I suspect that many people, organizations and even nations would be happy to have some sort of financial insurance product that could shield them from the risk involved.

Getting back to the End of Alzheimer's thinking that I posted to a thread of that name, it is important to realize how AD is now ex ante perhaps the most actionable leading illness. Typically an illness such as cancer will not have a particularly good way of detection until the illness has grossly manifested. If we could find some biomarker that foretold cancer 2 decades ahead I suspect that there would be much less cancer mortality. Sometimes even when we do have good predictors such as for heart disease (e.g., BMI, physical activity etc.) it is still not easy to convince people to adopt a healthier lifestyle.

Yet, with AD we are now approaching the near perfect situation in which we have good biomarkers (for amyloid etc.) as well as early cognitive tests and we appear to have a disease modifying treatment ready for approval. This would seem a near slam dunk ... instead of all sorts of endless green vegetables and exercise, there is this easy way out and people will be have better cognitive functioning. Admittedly, it would be better if people did buy into the green vegetables and exercise message, though to date they largely have not. If you can create some effective medical intervention that can be applied at population scale the benefits can be profound.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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

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Sorry for reposting this one, though it is yet more excitement in the AD clinical space. Solanezumab is ready to finish up a phase 3 study in early AD and might also offer an approvalable topline.

The above is the readout for Expedition 3 with Solanezumab. It was called a fail, even while it achieved a -0.34 benefit on CDR-sb and all the other usual tests in the secondaries reported positive. It was just the ADAS-cog which they used as the primary that was the problem. We have seen that before with the ADAS-cog.

This is of note at this time because at the end of this month A4 -- a phase 3 in preAD with 3-4 years of treatment reaches its primary completion date. Of additional note is that Sola as more of a monomer mab has low to no ARIA. Clearly this could be exciting if Sola is also found to be an effective anti-AD treatment and this one would have been tested in the pre-dementia phase of the illness. One certainly might wonder what might happen if Leca and Sola were combined. Perhaps this could target amyloid from both sides.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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

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This had been something that I had been unclear about earlier on thread: What percentage of those with symptomatic ARIA had severe symptoms. Some online have noted that they actually felt it reassuring to have mild signs of ARIA symptoms as this likely implied that they were in the cognitive responder subgroup. I was unsure what proportion of those with symptoms experienced more serious complications. As seen above, 2.8% of Leca treated patients experienced any symptomatic ARIA, while 3 in the total Leca treated group experienced severe symptoms out of 25 who experienced any symptoms of ARIA. This was 0 of 4 in the e4- group, 2 of 8 in the epsilon 4 heterozygote group and 1 in 13 in the homozygote e4 group. The heterozygoes did not have a higher rate of severe amongst those treated versus homozygotes it was only that more homozygotes were treated. So for the severe ARIA, it was 2 of 479 ( 0.00418) in the heterozygotes versus 1 of 141 ( 0.00709) in the homozygotes.

I was surprised by the amount of infusion related side effects. I had not realized that there would be as much of this as there was. 7.5% of patients had a moderate side effect to dosing with Lecanemab? 0.8% had a severe response?

My impression is that the reporting about Lecanemab has not caught up with the current evidence on safety. With Aducanumab there was a lot of serious side effects. The FDA Briefing Documents (Round 2) documented 29 serious patient reports. Currently with Lecanemab in Clarity there would be 3 such reports, though there are perhaps only ~ on half as many patients years of treatment with Leca vs Aducan.

Admittedly, it is somewhat disappointing that even now more clinical trials have yet to enroll and treat with subQ Leca. Research suggests that this should reduce side effects even more. The sooner subQ can be offered to patients the better.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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

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Yeah! This is a J11 exclusive!

I finally have the numbers for Graduate 1 & 2 in CDR-sb vs SUVR space.
Oh yeah!
All the big points are now threading the line.


First I datagrabbed the points from the Gantenerumab CTAD slides.

Here's Graduate 1 CDR-sb:


0 0 Placebo
24 0.616915422885572
52 1.4726368159204
76 2.32835820895522
104 3.1044776119403
116 3.66169154228856
0 0 Treatment
24 0.716417910447761
52 1.33333333333333
76 2.06965174129353
104 2.92537313432836
116 3.38308457711443

0 0 Difference
24 0.099502487562189
52 -0.139303482587064
76 -0.258706467661692
104 -0.17910447761194
116 -0.27860696517413



Here's Graduate 2 CDR-sb:


0 0 Placebo
24 0.696517412935323
52 1.29353233830846
76 1.91044776119403
104 2.76616915422886
116 3.00497512437811
0 0 Treatment
24 0.477611940298508
52 1.13432835820896
76 1.77114427860697
104 2.46766169154229
116 2.82587064676617

0 0 Difference
24 -0.218905472636815
52 -0.159203980099502
76 -0.139303482587064
104 -0.298507462686567
116 -0.17910447761194



Next I converted the Centiloids to SUVR.

The formula for the florbetapir amyloid agent is Centiloids = 183 SUVR - 173
I just went with the numbers generated by the graphing calculator.


Here's the url
https://www.desmos.com/calculator/bprkazqto8
https://www.desmos.com/calculator/za0euswr8l

One tricky part was choosing which centiloid to use.
In all other calculations we have used the week 78 SUVR number.
At first I used the week 52 number from the Graduate trials and this was way off the true line.

Then I went with a linear interpolation between the reported week 52 and week 116 centiloid numbers at week 78 and this worked out great.


So for Graduate 1 --> 24.1 week 52 and 57.6 (week 116) became 37.7 ( week 78 interpolated) in Centiloids
Graduate 2 --> 21.1 (week 52) and 46.8 (week 116) became 31.5 (week 78 interpolated) in Centiloids

Grab the SUVR conversion results from the url above
(e.g., Graduate 1 37.7 centiloid --> 1.173 - 0.967 SUVR = 0.206 SUVR)


After all of this we wind up with:
Graduate 1 : (-0.206, -0.259) --> (-0.206, -0.172)
Graduate 2: (-0.172, -0.139)
Emerge : ( -0.278,-0.39)
Clarity : (-0.323,-0.451)

The Graduate 1 CDR-sb was off because there was an unstable placebo at week 78.
I massaged the numbers by forcing the placebo to be linear over the entire trial this gave us -0.172 (instead of -0.259 as reported). These are the points plotted in the figure above.


Here's the url for the figure with some background calculations:
https://www.desmos.com/calculator/d5yy9qgvjd

Here's an updated url now with the new empirically derived parabolic regression.
https://www.desmos.com/calculator/axtb9wb7s5
Apparently, the equation defining the benefit of amyloid removal in AD is:

CDR-sb = -4.536 SUVR^2



[Edit: Here's the latest update.
New best estimate is y8 as the CDR-sb vs SUVR parabola.

y= -4.597 X^2

What I found was that my datagrabbing points were somewhat off for the CDR-sb.
Instead of datagrabbing the points I thought it was best to simply take the topline reported number
(e.g., Graduate 1 -0.31 CDR-sb at week 116 and simply linearly extrapolate back to week 78.
This then gave me Graduate 1 -0.208 CDR-sb and Graduate 2 -0.1278 CDR-sb at week 78.

https://www.desmos.com/calculator/aitzecj3ui

I find it quite exciting that by simply inputting the amount of amyloid removal that we can
predict very accurately at the group level what the resulting cognitive benefit will be.
As can be seen at the bottom section of equations (left hand side of screen) in the above url
the large mab trials have removed us down to within ~ 3 % of a CDR-sb point deviation of the
regression line. That is extremely impressive. Of course, this is exactly what the FDA will
decide upon by January 6th for Lecanemab: Is there a relationship between cognitive benefit and
amyloid clearance? The above url provides a clear answer to this question.

R^2 = 0.9672
R = 0.9835 ]

[Edit 2: I decided to see what happened when SUVR = 0.306 for Clarity as was the reported result for the phase 2.
The 0.323 that I calculated for Clarity SUVR seems heavy. It would be great if they were to provide the SUVR number for Clarity. By making the change to 0.306 it really helped to align the parabola.

R^2= 0.9931
R = 0.9965

https://www.desmos.com/calculator/odewdb9lrh ]


[Edit 3: This time the black parabola is the one prespecifed in earlier research.
This one does quite well. By adding in the slight shift to the left in the curve with the bx term
the fit is good.

https://www.desmos.com/calculator/qvdxeumyrk]



https://www.desmos.com/calculator/dlu5ti4dcb



It is remarkable how close to the regression all the major trials have been.
As a reminder the green parabola was prespecified before Clarity and Graduate 1 & 2 reported.

In the equations column we can see that:
Graduate 1 underperformed by 0.0081 CDR-sb from the regression.
Graduate 2 overperformed by 0.0175;
Emerge overperformed by 0.03135 and
Clarity underperformed by 0.0457.

(I continue to feel that the 0.323 SUVR clearance for Clarity is highish.
My guess is that the true CDR-sb result is even closer to the regression than noted above.)



It is remarkable how closely all of these large trials performed exactly as expected.
Calling Graduate 1 & 2 failures seems highly misplaced.
While they missed on the topline p-value analysis, in CDR-sb vs SUVR space Gantenerumab nailed the regression line in both Graduate 1 & 2. These trials did not offer evidence against the amyloid hypothesis. Anything but. The Graduate trials offered powerful evidence in support of the amyloid hypothesis.

It is very disappointing to me that the coverage of the phase 3 trials for Gantenerumab never even tried to go through the above number crunch to have a better understanding of the trial results. This is important because the amyloid hypothesis has been vigorously debated now for decades. Now that high quality evidence is in people seem completely uninterested in quantifying the outcomes to see how the hypothesis fits the evidence. From what I can see now the results fits the evidence remarkably well. The deviations from expected are in the range of ~+/- 0.02 CDR-sb.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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BioVie popped into my view today. I have done my best to screen the leading treatments in development by the pharmaceutical companies with the help of clinicaltrials.gov. When I scanned the list I would get near to the bottom and just dismiss the BioVie NE3107 entry as too obscure. However, today BioVie broke into the headlines with its drug that might reverse aging/AD. Their phase 3 trial in AD is already nearly enrolled and it is expected to read out towards the second half of next year.

In order not to be taken by surprise again here is the minimum list that we need to know to be reasonably informed about the evolving treatment landscape of AD over the nearish term time horizon. There are probably others though this is a good start.


The mabs: lecanemab, donanemab and solanezumab

LMTM

Amylyx

Simufilam

Agenebio's Levetiracetam

Blarcamesine

Alzheon's ALZ-801

BioVie's NE3107

Semaglutide

periodontal treatment

gamma entrainment

tDCS
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