Re: Celebration Thread! Biogen is going to the FDA with Aducan.
Posted: Tue Jan 25, 2022 6:28 pm
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 anti-Aβ monoclonal antibody in development, aducanumab was derived from human B-cells collected from healthy elderly subjects with no signs of cognitive impairment and from cognitively impaired elderly subjects with unusually slow clinical decline .
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 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.
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 anti-Aβ monoclonal antibody in development, aducanumab was derived from human B-cells collected from healthy elderly subjects with no signs of cognitive impairment and from cognitively impaired elderly subjects with unusually slow clinical decline .
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 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.