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.

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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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Above is from another article that considered the longer term treatment effect of mabs.
I data captured it directly above and we can see how the treatment effect grows with time.

The Gantenerumab long term projection that I posted on the last page called it as 5.7 CDR-sb points after 5 years.
With the Lecanemab projection shown here it seems more like 3 points. I am not sure whether I want to devote the next 3 years of my life to figuring out this question in detail, though as a starting guess, yes the treatment effect will magnify through time. Those who might question the clinical meaningfulness of mab treatment will soon see the strong length of treatment effect as we have seen the very strong dose response relationship.


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

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Hmm, not much time for party hats around here even on the big anniversary day! It's just that there is so much exciting research to get to.

Oh well!

One of the strange ideas I came across today was that when the FDA approves Lecanemab in January under the accelerated approval mechanism, the CMS non-coverage ruling would still be in effect. I do not see how that could be politically sustainable over even the short term. While the legislation before congress that rolled back the final CMS decision might null and void the earlier CMS ruling, it would be good to have this perfectly clear before the big day arrives. I am sure that many would not be amused if they were told after FDA approval that Lecanemab was largely unavailable. The Clarity topline posted to date leaves little room for valid questions about Lecanemab.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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I have avoided making a call on Gantenerumab because there seems to be quite a bit of uncertainty involved. I do not see it as overly helpful to make a guess and then for the guess not to be that accurate. However, one idea that has occurred to me is that the 18 month regression should still apply to Gantenerumab. We can prespecify that Gantenerumab will be near the parabolic regression that we quoted for Lecanemab from Clarity. There is a great deal of evidence that aligns with this relationship.
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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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So, this should be how Gante reads out in CDR-sb vs SUVR space at 18 months. When we are given the SUVR, then
f(X) = -5.504274 x^2 -0.240065 x - 0.007866

I thought that perhaps there could be some sort of a program.
We could prespecify that Graduate 1 would follow the f(x) equation and perhaps a correction factor could be applied to Graduate 2. for instance if graduate 1 readout as 0.4 and the expected value was 0.41 (-0.01). We could add in this correction factor 0.01 to Graduate 2.

I also thought about the spending the alpha idea. Basically create a program that would spend the alpha so as to prespecify the actual topline. When you do this, it means that you not merely nailed the result, but you prespecified how you would nail it. In order to do this we would need to use the online stats calculators to have the alpha values.
With Clarity, this spend the alpha approach would have given us a very very near result, with Gante it might be somewhat less clear. This is because the uptitration they are using is somewhat longer than usual; the 18 month time point might not correspond exactly to the 18 month calendar point.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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dona 2.GIF
dona 1.GIF

I responded on the Lecanemab AHEAD thread and promised that I would post the boring long winded complete response to this thread which I will do now.

One issue I noticed was that the phase 2 Donanemab trial was stated as being the top performer of the mabs. AS seen above this is not entirely true. Dona reported out with the iADRS which achieved 32% slowing, though CDR-sb had a 23% slowing. The Dona phase 2 was confusing because they did a fair amount of selection for tau, so it is unclear to me how comparable it is to the other mabs. Of interest in the best reponding subgroup with just the right amount of tau, there was 50% slowing of decline
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Long Term 1b.png
CDR-sb Decline 1 a.png
These figures also show the longer term effectiveness of mab treatment. The substantial effectiveness with longer term use continues to be largely ignored.

The bottom figure shows the longer term cognitive benefits of Aducanuamb from the Prime trial. At 4 years the benefit has extended out to 7 MMSe points. 7 points! You would not need any training in AD to notice such a difference. of 7 points MMSE. I am very unclear why the longer term benefits of treatment have not been more prominently reported. You might not be able to demonstrate "clinically meaningful difference in an 18 month clinical trial, though it does not appear to take that long before the difference is overwhelmingly self-apparent.

The top figure shows what happened when those on Aducanuamb did not achieve amyloid negativity after 18 months and then went on the extension. These were the TREATED patients. As can be seen only one of the amyloid negative patients on the right had run away cognitive decline (above the red line). On the left several of the patients had this trajectory. The regression (black lines) clearly show how much worse patients did when they were amyloid positive after 18 months. Surprisingly, the patients who were amyloid negative had a regression line that was stable for ~ 4 years.
The amyloid negatives (after 18 months of Aducan treatment) were stable for 4 years? That is truly remarkable. It is difficult not to call that a functional cure. People who have progressed to ~mild Alzheimer's by definition will inexorably decline to severe dementia. Stopping progression as shown above is a miracle (for the non-scientists amongst us).

One suspects that the patients on the left that appeared to have done especially well, might have been the patients who were near the 1.1 cut off, while those who did less well were those farther away from the line.

Hopefully, these figures will act as a wakeup call. The Aducanumab trials included patients with supposedly mild AD and MCI, and yet even in these early patients there were many who rapidly progressed to uncontrollable decline when they did not reach 1.1 SUVR after 18 months. The dona phase 2 excluded a large percentage of those who attempted to enroll because they already had tau pathology that was considered too advanced. Perhaps this will be a big lesson that will be learned even over the next few months. People will go into the clinic with MCI or early AD expecting to be treated with Lecanemab only to be told that they are already too advanced. One certainly wonders how this might motivate patients to seek treatment before they are officially MCI.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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