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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In the above figure I included a red point at the bottom for the preclinical aducanumab result. What I wanted to highlight was how large the cognitive effect found for those who spontaneously made their own aducanumab as apparently some in the community are able to do. To maintain cognitive ability as the healthy agers do, would mean that they experience upwards of a 2 CDR-sb yearly benefit (the expected decline of those with Mild AD). There is a massive cognitive gain that they accumulate. As we saw earlier in a figure those who continue to maintain amyloid levels (those in the high dose with SUVR >1.1) enter a period of rapid and irreversible decline in which a decline in cognitive ability of up to 10 CDR-sb points can occur.

The endogenous production of aducanumab is highlighted in the first quote above from the FDA Briefing Document for Aducanumab. This quote is of such importance that I will translate it into emotivese for clarity and dramatic impact.

Unlike any other :o anti-Aβ monoclonal antibody in development, aducanumab was derived from human B-cells collected from healthy elderly subjects with no signs :shock: of cognitive impairment and from cognitively impaired elderly subjects with unusually slow clinical decline :geek: .


This is a quite startling revelation that has only been mentioned in passing on this thread on a few occasions. However, the implications of the above quote are profound.

Aducanumab is effective.

Aducanumab is effective because it was developed using a reverse translation approach from those people who did not develop dementia; these cognitively intact superagers were also noted as being healthy. Reverse translation is a very powerful approach to a pharmaceutical development which is difficult to rebut. Unbeknownst to the healthy agers they spontaneously make Aducanumab and accrue large cognitive benefits.

with no signs :shock: of cognitive impairment

"Normal" aging is considered to include a substantial amount of cognitive impairment. It is defined in this way because Alzheimer pathology is essentially a universal feature of the modern aging process by age 90. In the scatter figures that I have posted the placebo has always been given as the comparison that seemed the obvious way to construct the diagrams. However, this is actually a restriction of range. We are not even considering what super-agers might be experiencing. These super-agers are being microdosed with Aducan throughout life apparently without side effects.

Those on the anti-amyloid placebo encounter a range of dangers related to their amyloid burdens including ARIA, strokes etc.. If the CMS wants further evidence of Aducan's efficacy, then why not simply sample the super-agers? The samples that were used by Biogen and previously were probably quite small, though large enough to provide compelling evidence of cognitive benefit. However, if more evidence is needed, then there is a wealth of evidence that could be accumulated immediately without the need for longitudinal clinical studies. Such non-clinical research might be even more persuasive then clinical research as those who can auto-manufacture the anti-bodies would not even realize that they were doing so. Enrolling in a clinical trial could potentially bias the results because participants would know that they were being studied. Healthier ager research could investigate results that happened decades before when the participants would have been entirely unaware that their lives would be scrutinized much later.

Further, it is somewhat amusing to realize that even the placebo arms in the anti-amyloid arms also appear to exhibit the make your own amyloid removal treatment that does not appear to have been corrected in the analysis. A fair percentage of those on placebo (~20%) appear able to remove amyloid and become amyloid positive during the 78 week trial period. Some of the placebo are actually a hidden treatment arm? Alzheimer clinical trials are confusing!
From what I understand this complication is never corrected in the data analysis. Perhaps, those who begin producing auto-antiamyloid antibodies could be removed from both the placebo and treatment arms. One could speculate that this could be especially a problem for the MCI arms as the lower rate of cognitive decline could add in more data noise if such auto-antibodies emerged. One could also analyze the placebo group to see what regression emerged on the CDR-sb vs SUVR axes. Presumably, those placebo who removed more amyloid would have better cognition.

Another complication with AD trials was that it became recognized through time that many Alzheimer's patients who enrolled in trials to treat Alzheimer's did not actually have Alzheimer's! Interestingly, in order to avoid this problem it was decided that amyloid positivity was a defining prerequisite for an Alzheimer diagnosis. There is a circular logic that then follows: If Alzheimer's requires beta-amyloid and anti-amyloid treatment has been shown to remove beta-amyloid, then removing amyloid could be considered almost by definition to be a probable treatment choice simply by logical reasoning.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Blaze CDR-sb.GIF
Blaze ADAS-COG12.GIF
Blaze SUVR.GIF
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Cren 1 ABBY p2a ADAS-cog.png
Cren 1 Blaze p2 CSF ab 42.PNG
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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This is a back item that I have wanted to look into for some time, though have neglected to do so until now. I was inspired by recent talk about failed anti-amyloid treatments from the CMS Tables 1 & 2 to investigate crenezumab more thoroughly. I was twigged to do so because quite aways back on thread I posted the cren phase 2 results and they seemed to me to be somewhat encouraging. After the CMS brought cren forward as an unsuccessful anti-amyloid I wanted to investigate this further.

What I also find interesting is that crenezumab is still on Roche's pipeline and a trial is ongoing investigating it. Does cren have any supporting evidence? The above two phase 2 trials Blaze and ABBY did have some positive signals. In the first figure in post two up, we can see the ABBY CDR-sb results. On high dose cren ( 15 mg/kg) there was a 0.80 difference (p= .439) to give a 41.5% reduction ( n= 8, n=13), ADAS-cog on high dose was 3.05 difference p=0.288 and 52% reduction (n=7, n=12). Amyloid SUVR for different regions found 0.024 difference (p-value 0.169) and 0.015 (p=0.131)

In a larger ADAS-cog result in Blaze for very mild AD (n=33, n=70) there was 3.44 difference and p=0.36 and 35.4% reduction. ABBY CSF beta-amyloid (n=8, n=17) gave a p-value of 0.022. The phase 3 trials CREAD and CREAD 2 using doses up to 120 mg/kg were stopped for futility.

Quite a few of the reportedly failed anti-amyloid treatment that went through phase 3 trials are not as clearly unsuccessful as one might have believed. I am not entirely clear whether any of them can be definitively be dismissed with certainty. With cren a range of features of its performance conform to what has been learned from other anti-amyloids. For example, cren reported strong results only for the higher dose 15 mg/kg and not the 300 mg dose. Also as expected it was only the very mild AD (22-26 MMSE) patients that appeared to benefit. One odd feature was that reported a 0.80 CDR-sb benefit on high dose while there was only a 0.02 change in SUVR. That would be completely off the regression that we have seen before. Another interesting feature is the truly massive dosing that was used. They went to 120 mg/kg? That is almost impossible to imagine. This could be one of the safest (? safer?) of the anti-amyloids. Yet, for whatever reason cren went down in phase 3. You really wonder whether going back and exploring the 15 mg/kg region in mild AD might not be worth a try. Perhaps it's an upside down u dose response-- too little dose bad; too much dose bad; in the middle dose good. There was also some small sample anti-amyloid effect. Time for accelerated approval? It would probably be the best to grow the dataset first.

{In the middle figure I divided the difference by the standard error to find the z-value and this confirmed the p-value given.}

The CMS' Tables 1 & 2 could then be reinterpreted less as a definitive statement about the failure of anti-amyloids and more about the relentless struggle science faces to turn failure into success. Finding the right patients at the right dose can take time, though persistence is often rewarded. In the table, Aducanumab actually reported an unequivocal positive topline success for Emerge high dose, Gantenerumab high dose achieved a near perfect fit on the correlation plot (it was an under-dosing problem), crenzumab reported encouraging earlier phase 2 results that still be nudged to success, solanuzumab seemed to have some success in its own way apart from the correlation diagram, only uncertainty left is bapineuzumab.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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AD Staging 2a.png
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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I want to add a few comments about what the CMS is facing concerning the flow of AD patients into their budget silo and suggest some ideas that might prevent a completely unsustainable financial situation for them.

The above figure is from the FDA Briefing Document to which I added the conveyor belt figure. The orange arrow underneath the conveyor belt pointing right indicates the flow of boxes (representing AD patients). AD patients start on the left and progress from stage 1 through to stage 6. The pile up on the right suggests how financial sustainability could become stretched as more and more patients enter on the left and then have their cognitive decline slowed with effective anti-amyloid treatments (such as Aducan).

The purple rectangle on the conveyor belt represents the AD patients that are now under consideration for coverage. The MCI patients (Stage 3) on the left of the purple rectangle and the Mild AD (Stage 4) on the right. I further boxed the Mild AD (Stage 4) patients in green to indicate the especially large reported cognitive benefits they receive from anti-amyloid treatment. These patients as noted recently had a 0.95 CDR-sb on high dose in the Emerge trial, also 1.25 on the leca phase 2 etc..

What needs to be remembered is that while the Stage 3 patients might seem to receive only a small benefit as reported over the short run, it can be tricky to precisely decide the right time to start treatment as decline is occurring. Even in the phase 2 dona trial with intense patient selection many of the patients still were considered too advanced by tau measures. The tau measure can be somewhat out of line with the amyloid measure.

Also note the bright blue rectangle on the right. After Stage 3 & 4 patients have started treatment they can continue with treatment through at least moderate AD. Indeed some of the anti-amyloid trials have enrolled patients who are just above moderate AD and possibly have continued treating them through long term extensions. The Aducan longer term results suggest that there is ongoing benefit to treating these later stage patients who started therapy as mild AD patients. Thus, we can envision how there could be pile up of patients as indicated on the right with the boxes.

What is also of interest to note is that treatment of Stage 3 patients does not stop progression. A few posts up we saw how stage 3 patients continue to progress forward (to the right) even with treatment. This result is illustrated with the green vertical line. Treatment still results in progression through the green line.

So in terms of money what this would mean for the CMS is that once anti-amyloids were covered, MCI and Mild patients would enter the conveyor belt receive treatment and continue receiving treatment as they progressed through moderate AD and at the same time there would be a constant influx of new patients at the green vertical line which might amount of ~~ 500,000 per year. The cost could become somewhat intense.

The one way around this potentially unsustainable model is to consider the red vertical lines. Here patients could receive early treatment and be blocked from further progression at the red lines. Perhaps treating patients 5-20 years out from their age of cognitive onset would mean they would never have a cognitive onset date. Basically the analogy here is that all boxes before the red lines would stop on the conveyor belt while all boxes to the right of the red line would keep on moving to the right. Once all these boxes had moved through the system there would no longer be any expense related to AD for treating those with active dementia.

The total cost savings to government of stopping the conveyor belt would be $350 billion in this year plus compounding for future years --- possibly $30 trillion in net present value. The CMS has not mentioned any particular interest in realizing this $30 trillion windfall which is surprising. All that would be needed is find the right start date to prevent progression to AD. It is known that this is possible because those who naturally generate beta-amyloid antibodies do not develop AD. Funding clinical research into stage 0, 1, and or 2 would seem a natural. It would not even have to be exhaustively researched. For me merely having a good idea of safe dose would almost be enough. My rough guess would be that even 0.1 mg/kg would be a large enough dose if given early enough, such a dose would have close to zero side-effects, would not require expensive MRI monitoring and would be relatively inexpensive. It would also help me to avoid future onset of AD.

Pharma would probably be quite happy with such a result as with Aducan the patent runs out in 2033-2036. Opening the primary prevention market earlier for them would be highly attractive for them and it would also be a massive money saver for the CMS and others. Even if I had to pay out of pocket $1,000-$2,000 per year such treatment would be a great value to me. I could out wait the patent though it would be best to seek earlier treatment. Everyone would seem to win here; why wouldn't the CMS fund such clinical research?
Last edited by J11 on Wed Jan 26, 2022 8:46 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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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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This is also from the FDA Briefing Document for Aducanumab which is highly recommended for those wanting a basic primer on AD (pages ~10- ~20 are particularly helpful).

The above figure shows the various forms of beta-amyloid. Monomers (on the left) are not felt to be overly worrisome. It is more the oligomers that seem to be especially problematic. Basically, the oligomers are aggregated beta amyloid in the brain in a liquid state that are known to be neurotoxic (roughly green toxic goo in the brain), the amyloid plaque on the right (roughly green toxic solids in the brain) are what is typically removed with the anti-amyloids though other species of beta-amyloid are also removed (e.g with Aducan). Given a choice I would want to remove these known neurotoxins that are probably already in place in brain asap. I see no particular benefit in waiting. Health care might pay to remove them at a later date, though if needed I would pay to remove them at a sooner date.

The FDA Document does provide some details on these points. It notes that Aducan is "selective for beta amyloid aggregates including soluble oligomers and insoluble fibrils but not monomers ... ". The document further notes that removing amyloid stops or reduces neurotoxicity which would have caused neurodegeneration and then cognitive impairment.

The document in section 2.4.1 also provides reasons for the non-success of previous anti-amyloids including:

- AD clinical trials with patients that did not have AD
- lack of target engagement
- underdosing
- later stage patients that did not benefit from treatment

To that I could add that placebo patients were included who were actually dosed with active treatment (endogenously).
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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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There are a great number of ideas percolating that I wanted to add to the thread.

Firstly, the scatter plot of anti-amyloids is once again included above. This time what I thought was that up until now I have only included those on placebo and those who receive anti-amyloid treatment. What I suddenly realized was that there was an important group that were missing: Those without amyloid!

The figure has had restriction of range. What about people who do not have amyloid? Where do they fit on the figure? They are on the bottom left. (The figure did not seem to upload properly as their is a ghost image on the right. This is not a problem on my end). So roughly, those who are cognitively healthy should be ~2 CDR-sb more highly functioning than placebo and have ~0.4 to 0.5 less SUVR. The super-agers who have even less amyloid apparently do even somewhat better. In 301, placebo declined by ~1.54 and 302 by ~1.76.

Why does our regression that has until now suggested upwards of 100% correlation seem so off with the "normals".
As a first guess what we are seeing is the overperformance that happens with "normals" who never enter into the neurodegenerative process that is Alzheimer's. To have Alzheimer's one needs to have amyloid and to show cogntive decline; the patients are selected based on these criteria.

The figure while not being overly aligned with the other studies does once again highlight how amyloid is a driving factor. The "normals" who typically do not have amyloid also would not typically have cognitive decline. This is not a strictly correct logic as clearly other features of the pathological process are involved, though nonetheless this view does give us a broader perspective outside of restriction of range.
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