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

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J11
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CDR-sb = f(SUVR) as a Parabola

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Parabola 2.png
Parabola 1.PNG
Along the lines of Clarity schmunching it, there is the somewhat mysterious desmos url I posted earlier that I will explain verbosely now.

In order to understand the Clarity results better I searched back into previous thread posts to find some equation that might be useful to estimate the topline result. The first good one that I stumbled upon was from my post of Wed Mar 16, 2022 11:04 pm. Biogen research published the parabolic dose response result and then in the post one above the 11:04 PM post I had my own parabola which transformed this into SUVR coordinates.

The parabola that I found was y = 5.50 x^2 - 0.24 x + 0.0078 in CDR-sb vs SUVR space.

https://www.desmos.com/calculator/dt1iddnvpz


Future urls (previous)
https://www.desmos.com/calculator/h4eryrat5n (updated to krghlmujx8)
https://www.desmos.com/calculator/uv2jvddd3c (updated to fi57efmvqs)
https://www.desmos.com/calculator/krghlmujx8
https://www.desmos.com/calculator/jxvvz5mun8
https://www.desmos.com/calculator/fi57efmvqs
https://www.desmos.com/calculator/6ruoebujbn


Current
https://www.desmos.com/calculator/2j5ouwdzka [e4s current]
https://www.desmos.com/calculator/sfemav60co [e3s current]
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Last edited by J11 on Thu Oct 06, 2022 7:40 pm, edited 13 times in total.
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CDR-sb vs SUVR Parabola

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Marginal 1.PNG
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Clarity Nailed the Backfitted SUVR ... to 3 Decimals Places!!

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The above is a screen capture of the desmos url with the x-value of -0.3061 shown; the parabola is the one that was determined in the previous Aducanumab research. In the url one can pull the slider of the c variable to see the result for varying values of x. The purple and blue labeled dots to the left show the average slope (in purple) and the marginal slope (in blue) as the y-value multiplied by -1* one tenth. So, here we see that at x= -0.3061 the average slope is 1.47 and the marginal slope of 3.13. The 1.47 slope is somewhat on the high side as we perhaps expected more ~1.35, though the SUVR is more -0.306 with a fixed 0,0. The average and marginal slopes are shown in the equations of the url.

What is of greatest interest though is the -.3061 figure. This number was calculated as the root of the parabola with the CDR-sb result of -0.45 (i.e., the Clarity result). So working it backwards from CDR-sb ---> SUVR using the given parabola we found SUVR -.3061. Why is that interesting? -.306 is the exact SUVR clearance found in the phase 2 Lecanemab study. This is actually somewhat spooky. The calculated result was correct to three decimals places??? I suppose the posted result will not be so accurate, though it does suggest that we could reach such a point
over the nearish term as more results are analyzed.

Our best guess at this time is that the SUVR for Clarity will readout at ~~ -.306 and this SUVR level will gives us roughly the topline reported Clarity result of -0.45. Very impressive! All of the equations and other information were known before the readout. The readouts from all of the near term mabs might help us to have surprisingly accurate equations that describe the cognitive trajectory of MCI mild AD.

One other feature that is of note from this analysis is that at SUVR = -0.45 the CDR-sb benefit exceeds 1. Yet, in previous research it has been found that some patients do experience more than 0.45 amyloid clearance. There should be patient subgroups with more than 1 CDR-sb benefit in Clarity? Yes. The problem though as was noted in the previous FDA documents is that a bunch of covariates are then intermingled with the high clearance patients and it can be difficult to untangle such intermingling.
Last edited by J11 on Thu Oct 06, 2022 7:39 pm, edited 5 times in total.
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Happy Third Anniversary Everyone!

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Oh, yes, I almost forgot; another thread anniversary is approaching.
Happy Third Anniversary Everyone!

Funny thing is that things have been going so great that I am not sure that we are even going to make it
to four candles. It's not so much that things did not work out fine; it's more that everything did work out
and we are about ready to move along to other interests such as sitting by the lake with a can of cashews etc..

So maybe more than 4 years out is not that realistic a chant at this point; as the thread could be out of business by then. Instead I think we should be thinking of the chant as "1 more year! 1 more year!" along the lines that we would then reach the finish line.
Last edited by J11 on Thu Oct 06, 2022 7:36 pm, edited 1 time in total.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by SusanJ »

Have you seen Greyhound's post about soluble amyloid and the comment on lecanemab? Might be the reason why they are seeing success.

viewtopic.php?p=86409&sid=75a872a1c789a ... 90e#p86409
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Maintain Focus on the Clarity Topline

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SusanJ, thank you for commenting.

Yes, this concern about whether the exact form of amyloid is being engaged has entered the discussion on thread before. Biology is remarkably complicated when everyone can be almost right on top of a given pathway and there can still be so much confusion about what the fundamental mechanism involved actually might be.

To some extent it might not be that critically important as the various anti-amyloid mabs have been strongly on the same regression line while lowering somewhat different forms of amyloid. My hunch expressed earlier on thread is that all of the amyloid forms move into equilibrium once some part of the chain is manipulated; so it might not really be that crucially important where the balance is shifted. SUVR might then not be the proximal biomarker of interest (nowithstanding the accelerated approval based upon such a biomarker), yet more a bystander biomarker.

I think that more precise oligomer measures are in development which might provide a better granular view of how cognition relates to that specific species of amyloid. We have seen early results from Alzheon that support the oligomerocentric view of amyloid.

Overall, though, I think it is probably best to stay with the recent headline result from Clarity. It has taken over a century to achieve the Lecanemab breakthrough-- it feels like there is low hanging fruit to harvest after the big news. This is just the beginning!
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Legislation Overriding CMS' Final Decision Introduced!

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News of the day (actually yesterday) is that a bill with bipartisan sponsors has been introduced that would require the CMS to consider each mab individually. I am not sure whether the subtle intent is to reinforce CMS' legal authority to render such judgments (one of those somewhat implicit legalisms whereby "requiring" at some level translates to "recognizing the right of"). I was not completely clear during the CMS Aducanumab ruling whether the CMS actually had the power that they were exercising.

This bill is of course great news because it allows us to start the discussion from our current circumstances and not be forced to maintain the assumptions that were made way back in April. Beginning with a clean slate will allow us to think how the specific features of Lecanemab (and the other mabs one by one) could be accommodated. Notably such a thought process might ultimately mean that the CMS will choose to do nothing.

The legislation helps to extract the CMS from the seemingly unsustainable logic that it itself created in the final ruling on Aducanumab and the entire anti-amyloid mab drug class. With the Clarity topline, I was very unclear how the final ruling could be realistically maintained; even through the accelerated approval process of Lecanemab.
I was all ready to post about where we stood now with the CMS final decision and do another line by line annotation; but fortunately the new legislation rescued me and others.

The political/social power of the dementia community can clearly be seen here where instead of street level protests with much repeating of "Hey Hey Ho Ho, it's got to go" everything can be worked through within the existing power structure. You can almost feel the shifting of the financial and political reality of the AD experience. There's tens of millions of e34s; there's ~10 million e44s that are upwards of decades away from onset. {One certainly could wonder in the approaching political season how much a frenzy of outbidding each other for the favor of the dementia community might occur.} Denying coverage would be unwise. It would provoke the question: What are we paying into the system for?

The other political force now in motion is the question of reclaiming the ~$350 billion + per year in hard cost that is already being spent on AD. Given the expanding list of potential AD treatments now approaching; one could imagine a scenario in which overnight the AD community goes from pulling with all our might for more resources, to dropping the rope. Stopping AD progression which is becoming increasingly plausible based on the best reading of clinical evidence could cause a result as dramatic as a rope drop.

Once AD treatment rolls back before onset of symptomatic disease, the near endless cost perpetuity with possibly $10 trillion net present value stops. At some it might be realized how much money it costs to not invest in stopping the AD conveyor belt as soon as possible. Even on the choice of waiting out the patent and paying nothing versus paying during the presymptomatic period, it might be calculated that paying is better than waiting.

I am not entirely certain about this, though perhaps by unbinding the CMS from its final decision it will be possible that an FDA accelerated approval of Lecanemab could move directly to full Medicare coverage by default if CMS were to simply remain silent. This might then mean that "accelerated approval" could be viewed by funders as legally equivalent to "full approval" in relation to patient access.

The entire process is becoming somewhat of a confusion for me. Accelerated approval or what? The Clarity result feels completely definitive. Accelerated approval seems to be meant for when things are more conditional; that something else must happen to finalize such an approval. I am at a loss to know what this something else would be. It is also a surprise to me that the Clarity result is not even part of the formal submission for the accelerated approval for Lecanemab. If we are supposed to ignore the Clarity result, then it does introduce the somewhat counter-intuitive idea that the FDA might have a more difficult choice to approve than we have have been lead to believe. For CMS had the Lecanemab phase 2 study in hand and on the basis of that evidence did not find the argument overly compelling.
Last edited by J11 on Sun Oct 09, 2022 12:53 pm, edited 2 times in total.
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Solanezumab!!!

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Solanezumab materializes out of nowhere

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So much to keep up with!

Another surprise today was Solanezumab.

I really had not kept up with Solanezumab. Up till this point in the thread, my strategy has largely been to pay attention to the newest generation of amyloid mabs that are on (or over) the approval horizon (i.e., Aducanuamb, Lecanemab, Gantenerumab and Donanemab) and which have all shown to be aligned with the regression curve.

There are other anti-amyloid mabs that did not fit the regression and they have been largely ignored. The justification being that most of them did not remove much if any amyloid and often did not have any cognitive benefit. Sola was an outlier. While it is true it did not remove much SUVR amyloid, it did in some studies appear to offer a fair amount of cognitive benefit.

The above result is from Expedition 3. Expedition 3 was chalked up as a fail after a signal amongst the mild AD patients was detected in the Expedition 1 & 2 combined mild population. In the above figure from the Expedition readout I added the p-values based on the numbers provided in the table. For whatever reason the calculated value of p = 0.10 was found to be 0.121 on my slide rule. This 0.10 primary topline was then stated as a fail which then shut out reporting any of the p-values for the secondaries.

J11 will not be so easily deterred. J11 will report the truth. What did I find?
As can be seen almost all the secondaries reported strongly significant results. The totality of the evidence clearly suggests that the trial was not a fail at all, but a success. All the major AD psychometric instruments in the secondary analysis were in the ~2% range (only miss was the FAQ??). Probably the best of the lot is the iADRS and that was a solid 2.7%. Simply taking a composite of everything would probably give you ~2% -- that is, the totality of the evidence confirms the result. This isn't a cherry pick and it does not overlook multiple correction because there are no multiple comparisons. There is only one totality of the evidence; the topline primary really did not reflect the centroid of the result.

Why did it readout negative? It seems that they chose almost the only measure that read out wrong. The simple workaround that was found with the Dona phase 2 was to simply choose the composite that gives more information. If they had not done that with the Dona phase 2, then it too would have read out negative. If you believe in the evidence that is what you do. The result will then be somewhat more "averaged", though you can then avoid having to follow the bouncing ball to a loss even when you won.

{From what I can see there has been a certain roll the roulette wheel type approach to these results. This is a very odd way of doing things. All that is needed is to accept the total result of the trial. This would have been helpful in many of the clinical trials that seemed iffy. For example, the Emerge and the Solanezumab Expedition 3. By avoiding the full set of evidence there was then an endless argument about the 0.01 for high dose Emerge when ADCS-ADL-MCI for OTC readout at 0.0002.}


This is quite a surprise. It appears as though Sola is now also a potential mab that is still in the game. As further noted in the table above, Sola reported out a 0.34 CDR-sb result in Expedition 3 which it considered a fail. Moreover, the placebo in this trial declined by 2.22 from baseline, so this is a somewhat different era in AD clinical trials and perhaps the current ~1.7 placebo decline would influence the results.

There are several interesting comments to mention. Firstly, Sola is more of a monomer mab and this leads to very low ARIA risk. In fact, the ARIA risk is very close to that of placebo (for some subtypes of ARIA possibly below placebo). mabs that interact with monomers might not have the strenuous struggle against unsoluble amyloid species that can lead to higher rates of ARIA. Secondly, Sola has another phase 3 in progress:THE A4. It is supposed to readout in December and it has PACC as the primary and has enrolled quite mild AD patients. This is yet another exciting result to expect soonish -- one that until now I had been completely unaware of.
Last edited by J11 on Sun Oct 09, 2022 1:04 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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ADAS-cog 14 Clarity 2a.png
CDR-sb Clarity.PNG
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