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.

Post by J11 »

Hmm, looks like there is another phase 3 that was not included in my scatter plots. The AMBAR phase 3 trial reported a top-line positive with largish CDR-sb benefit in Moderate and Mild AD of from ~1-~1.5 points. As seen in the first figure on the right the MILD patients actually appeared to improve from baseline while Mild placebo only declined by roughly 0.5.

The middle figure shows how this treatment fits into the logic of amyloid. It is quite a clever approach. Simply diffuse the amyloid away by carrying away the amyloid that is locked into albumin and then just add in fresh albumin. So this is a genuine amyloid strategy just from a slightly different angle. They appear to have done amyloid SUVR, though I have yet to find this. When I do I would have another data point to work with. This point will likely not be the best fit on the scatter plot as the albumin treatment has additional mechanisms of action.

The bottom figure shows that the treatment effect is quite large.

Apparently the CMS document does not reference this research. Manipulating amyloid levels through albumin is sneaky, so a straight pubmed search would not have found it.
Last edited by J11 on Fri Feb 04, 2022 9:38 pm, edited 1 time in total.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

I was unable to find SUVR results for the AMBAR trial or any other using albumin replacement. The search was more directed to looking at amyloid levels in CSF etc.; this research did seem to show amyloid changes.

I read the first listening session from the CMS page and it was surprising how many of the speakers welcomed the idea of considering anti-amyloids as a class (including The Alzheimer's Association). This perhaps echoed the initial statement of the CMS that this would be their policy.

The CMS introductory statement for the first listening session stated:
"CMS has initiated an NCD analysis to examine whether Medicare will establish a national coverage policy for Aduhelm. This NCD analysis will also include any feature [sic] monoclonal antibodies directed against amyloids with an indication in use for treating Alzheimer disease."

And then of course the CMS decided to use a coverage with evidence development approach and place all other anti-amyloids in this category. Clearly, no one was expecting that implication of including anti-amyloids as a class. It was not an entirely obvious counter-move and seems to disregard the comments made during the listening session. The transcript for the second listening session has yet to be uploaded to their web-site.

One of the most discussed topics in the Aducanumab listening session related to PET amyloid coverage. Apparently PET amyloid also was placed under the coverage with evidence development category. Even after strong supporting evidence was published in favor of the use of this type of PET, delays continued.

It had seemed unlikely to me that CMS would deny the science once it had been published (e.g., upcoming Clarity results). Yet, perhaps that is the strategy, merely delay even when the evidence is undeniable. Don't provide coverage, even after they no longer can debate the point. This has a certain internal logic because the proposed CMS clinical trials might not even have started when Clarity's topline is known. CMS must believe that the Lecanemab phase 3 is of no relevance to the Aducan decision, even though these two anti-amyloid mabs are very similar chemically and fit almost exactly as expected on the regression line and are both in the same coverage class as proposed by CMS.

Transcript cited the IDEAS study which investigated PET amyloid in elderly cognitive decline populations.
Fairly interesting. There were 11,400 patients in the sample.

8,778 (77%) of these patients had an AD diagnosis.
Of these AD patients, 3,100 of the patients did not actually have amyloid? 35.3%? 35.3% of AD patients did not have AD?

Well, I would certainly agree that those AD patients without AD should not be treated with AD medications.
The CMS statement on January 11, 2022 mentioned that one PET amyloid scan would be covered in their clinical trials.
Last edited by J11 on Sun Feb 13, 2022 10:20 am, edited 3 times in total.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by NF52 »

J11 wrote: Sat Jan 29, 2022 9:25 pm...I have been reading up on African American (AA) Alzheimer's. What is of great interest is that AA AD is very different from European AD... Surprisingly, research has found that e4 in Africans with surrounding DNA from European ancestors causes European like e4 risk, while from African ancestors causes African like AD risk (i.e., small risk increase). tau levels do not seem as overly predictive of AD in African derived populations as it does in European ones. In summary, AA AD appears to be extremely confusing even while it has not as yet even been explored that much. There is quite likely a large amount more to learn (which could take some time)....
Yet, the CMS has requested that clinical trials have populations with diversity reflective of the Medicare AD population...such inclusion will merely cause trial failure. ... It is even possible that for some groups anti-amyloid treatment will not show any efficacy. One can only hope that even more research confusions can be avoided by carefully planning future clinical trials. ...
Perhaps setup their own AD expert advisory counsel or something. ...Why do all the top AD researchers (we all have a fairly good idea of whom they might be) only have industry sponsors and not CMS sponsorship? ...

I hope that I am off-base; I would prefer to be wrong than right
Hi J11,

The questions you pose are important. I've been a member of the Alzheimer's Clinical Trial Consortium (ACTC) Research Participant Advisory Board, which is charged with advising major researchers on diversity, inclusive, transparency and communication to improve trials and benefit potential and current trial participants for 2 years and follow clinical trials through AlzForum and other sites. So I have to respectfully take issue with some of your assumptions and especially your conclusions.

I understand that your concern is that anti-amyloid drugs require one to have amyloid beta to remove before they can (hopefully) provide "meaningful clinical benefit". Both the AHEAD 3/45 trial of lecanemab (BAN2401) and the TRAILBLAZER-3 trial of donanemab in people with normal cognition are using blood tests at the start of screening to rule in those likely to have amyloid beta (AHEAD) or tau (TRAILBLAZER-3) and working with respected members of Black communities to recruit those with family history of AD. I know Black and Latina women who have been caretakers for two to three generations of their families with AD; they may have as much risk of the disease as I do.

The Precivity blood test, an FDA-approved predictor of amyloid beta in the brain, as an early screening tool, is an effective way to recruit people in local communities of color. It made sense to the AHEAD researchers, after finding that 75% of those screened in the first year showed a norma PET scan (as reported in the CTAD November 2021 conference). Most of those folks were White and college-educated, with private health insurance or a private supplement to Medicare and lived in or near major metropolitan areas.

So it's not that CMS is seeking to be as exclusive as Yale Law School when it comes to aducanumab or other drugs; they are seeking to determine whether any drug works in the real world. Almost ALL top AD researchers who recently commented on the CMS decision on Alz Forum agreed with it. https://www.alzforum.org/news/research- ... s#comments

Regardless of whether ApoE4 exerts a different effect in Black and White or other ethnic/racial populations, it's important to identify both the mechanisms of risk and resilience to disease. Here's the conclusion from a study of Ancestral origin of ApoE ε4 Alzheimer disease risk in Puerto Rican and African American populations, looking at whether "global ancestry" (i.e. what we typically view as someone's race/ethnicity) affects their Alzheimer's risk or just their "local" ancestry (i.e. the race/ethnicity associated with their ApoE4 allele(s):
Measures of global ancestry showed no interaction with ApoE risk (Puerto Rican: p-value = 0.49; African American: p-value = 0.65). Conversely, ancestry local to the ApoE region showed an interaction with the ApoE ε4 allele in both populations (Puerto Rican: p-value = 0.019; African American: p-value = 0.005). ApoE ε4 alleles on an African background conferred a lower risk than those with a European ancestral background, regardless of population (Puerto Rican: OR = 1.26 on African background, OR = 4.49 on European; African American: OR = 2.34 on African background, OR = 3.05 on European background). Factors contributing to the lower risk effect in the ApoE gene ε4 allele are likely due to ancestry-specific genetic factors near ApoE rather than non-genetic ethnic, cultural, and environmental factors .Our findings suggest that the ApoE region from AF populations may contain protective factors that help mitigate the effect of the ε4 allele. In particular, comprehensive analysis of the ApoE region and testing for protective loci may reveal previously unappreciated biological pathways and provide translational opportunities. Research that focuses on locating protective variants represents a complementary approach to accelerating the identification of more effective targets for drug development. This, in turn, will lead to better treatments, and help reduce health disparities
From the Alzheimer's Association 2021 International Conference:
"There is a well-recognized need for diversity in clinical trial populations to ensure diagnostics and treatments are safe and effective for everyone,” said Carl V. Hill, MPH, Ph.D., Alzheimer’s Association chief diversity, equity and inclusion officer. “It’s imperative that the Alzheimer’s community is aware of the impact of historical racism, and also the current racial discrimination in health care that presents obstacles for inclusive participation in Alzheimer’s trials. And, just as important, it is critical that we evaluate strategies that have been shown to be effective when recruiting historically underrepresented individuals and communities in these vital Alzheimer’s research studies.”..The Alzheimer’s Association is leading two major clinical trials with a strong focus on diverse participation. The New IDEAS study is recruiting 2,000 Latinos and 2,000 African Americans to investigate the impact of a brain amyloid PET scan on clinical care outcomes, including diagnosis and treatment. The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) study is a two-year clinical trial studying the effects of multi-component lifestyle interventions on risk of cognitive decline in a diverse population in the U.S.
https://www.alz.org/aaic/releases_2021/ ... ersity.asp

Finally, very few clinical trials look exclusively at ApoE4 and the NIA is pushing major expansion of machine learning, data aggregation to
more rapidly replicate or validate those variants most likely to lead to the rapid identification of therapeutic targets ... For example, there are reasons to believe that loss-of-function protective alleles may be good candidates for therapeutic targets. Approaches ...that maximize the likelihood of success in identifying protective alleles and therapeutic targets will be considered within the scope of this [award]... conducted by multidisciplinary teams of investigators....
It is expected that the study will result in the confirmation of AD risk and protective alleles in multi-ethnic populations that may serve as therapeutic targets... for rapid sharing with the scientific community through NIAGADS or another NIA-approved database....Data resulting from this study are expected to become available to qualified investigators to enable rapid identification of therapeutic targets.
https://grants.nih.gov/grants/guide/pa- ... nformation

The NIA is assuming that neuroinflammation, metabolic disorders, gut/brain relationships, air pollution, heavy metals, repetitive mild TBI, hypertension, dyslipidemia, gender, early childhood adverse experiences are all issues that may have a significant additive risk of Alzheimer's. It seems likely that in both ALL populations, these need to be explored, especially as they may contribute to the timing and rate of amyloid or tau accumulation, regardless of APOE status. Frankly, most trials haven't analyzed these factors or have excluded people with some of these comorbidities from trials. I think it's time that changed.

We have lots of approaches in clinical trials; I doubt that aducanumab will be the solution for many, even as I know some wonderful people who desperately hope it will be available for them.
4/4 and still an optimist!
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

Thank you for replying NF52.

I am not sure whether it is good form to quote myself, though I think I will do this just to provide a scaffold to respond to your reply.

J11 wrote: ↑Sun Jan 30, 2022 12:25 am
...I have been reading up on African American (AA) Alzheimer's. What is of great interest is that AA AD is very different from European AD... Surprisingly, research has found that e4 in Africans with surrounding DNA from European ancestors causes European like e4 risk, while from African ancestors causes African like AD risk (i.e., small risk increase). tau levels do not seem as overly predictive of AD in African derived populations as it does in European ones. In summary, AA AD appears to be extremely confusing even while it has not as yet even been explored that much. There is quite likely a large amount more to learn (which could take some time)....
Yet, the CMS has requested that clinical trials have populations with diversity reflective of the Medicare AD population...such inclusion will merely cause trial failure. ... It is even possible that for some groups anti-amyloid treatment will not show any efficacy. One can only hope that even more research confusions can be avoided by carefully planning future clinical trials. ...
Perhaps setup their own AD expert advisory counsel or something. ...Why do all the top AD researchers (we all have a fairly good idea of whom they might be) only have industry sponsors and not CMS sponsorship? ...

I hope that I am off-base; I would prefer to be wrong than right

As noted in my quote from above I skimmed through a few articles on Alzheimer's in African Americans and other African derived populations. What I saw was and is worrisome.

In another article I read it was noted that when looking at AA AD with epsilon 4 there was no risk enhancement over AA AD with epsilon 3. Yet, in Europeans those with epsilon 3 AD did not seem to benefit much from anti-amyloid treatment.

What was also surprising to me from another article was the statement that early AA AD did not have a prominent component of hippocampal degeneration. Yet, this is typically considered THE neuropathological landmark for typical early AD in Europeans. Is that AA AD neurotypical AD?

In the phase 3 trials with Aducan the memory subscale of CDR-sb (28% benefit over placebo) showed the largest benefit for those on treatment. If hippocampal degeneration were not present in AA AD then perhaps the psychometric instruments including CDR-sb might need to be modified to be race specific. Perhaps AD tests would not have the same psychometric across races if AD itself was phenotypically and neuropathologically different. Clearly this could add in a great deal of complexity into measuring the decline in different populations. The CMS has specifically stated that they will only accept well-validated psychometric instruments. If it is required that an AA specific AD is needed to capture Alzheimer's in AA that could require YEARS to validate. This is not clear to me, though if the clinical trials with AA only had minimal patient numbers this issue might have been entirely overlooked. An additional problem that could arise is that if the tests are not ecologically valid, then patients might feel they are benefiting (and are benefiting) while the tests themselves might not reflect this because they are not specifically designed for them.

No one wants to talk about race. I do not want to talk about race. Who wants to talk about race? No one. The things that you do not want to talk about are the things that you have to talk about.

My best understanding of what happened is that CMS decided to throw a curve ball and ask to have a non-replication replication of the previous Aducan results which I still think will not replicated because it isn't actually a true replication. If you change the goal posts and then have a new result it is not so much a replication failure as a failure to replicate. This is pretty much the standard go to approach in science when the "wrong answer" problem arises. They keep ask the same question and the "wrong answer" keeps cropping. The problem here is that if you continue to as this same question the "wrong answer" will continue to be returned. Best workaround is you ask a new question and now get a new answer and pretend that is still the same old question.

This has been done numerous times before and it is the worst form of pseudoscience. A clinical trial reports a successful result and then another research team does not even try to fairly replicate a result but starts changing all sorts of variables and then they report that the trial missed its topline. It can take years and years to figure out what went wrong. I have seen that happen enough times and it has been so tragic for the patients involved that my thinking is that any first round replication failure that did not strictly adhere to the original trial protocol is essentially not valid. It has taken decades to get to where we are now with anti-amyloids that they are provably and self-apparently effective under a particular set of conditions. These conditions at this point are not overly robust. Any attempt to discredit the original findings by not replicating the original conditions is not being intellectually honest; it is more an act of desperation-- an admission that anti-amyloids are effective. I would prespecify any miss of such a trial as being non-valid. CMS has simply created a scenario in which tails we win, heads we win: If the trials read out positively on the top-line it is a win; if it misses on the top-line, then they changed the conditions of the trial.

As far as I am aware there has not been a proof of concept of anti-amyliod treatment in AA AD, so it can't even be called a replication failure. If they want to replicate the completed Aducan trials, then why not simply replicate with the same demographics that have already shown success? Adding diversity in during a phase 4 without proof of concept for this diversity in a phase 2 does not allow us to conclude that the previous research was invalid; all it means is that the new research did not have phase 2 proof of concept. All it proves is that they asked a different question and obtained a different answer. If the trial fails, then what? There is no prior expectation that such a trial would succeed. The FDA Briefing Document for Aducan did not disclose how many African Americans were in the trials, though as reported elsewhere it was a small number. Did these patients have a statistically significant benefit of treatment?

It is quite disappointing because it does not take thousands of patients anymore to prove efficacy in AD trials. With lecanemab 50 properly selected patients on treatment and 50 on control would be enough. For whatever reason we are now in the awkward position of not having the results for these patients.

There are ways around this problem. The above does not mean there should not be diversity in clinical trials, it just means that some thought needs to be given to how to do this in a fair and reasonable way. The Alzheimer's Association has been calling for such diversity for some time. It becomes more complicated when you try and go directly into a phase 4 without the earlier research.

I think the easiest way to work this out is to simply move the diversity effort for Aducan into its own clinical trial. There could be a lead-in phase 2 along with a search for cognitively healthy AA seniors who autologously generate Aducanumab. This would form the proof of concept stage. In parallel a mini-phase 3 could accrue. I think the strategy of taurx would then be brilliant. If the proof of concept stage panned out then this could be the unlock for the phase 3 results. Just as with the taurx trial, perhaps there are certain subgroups of AAs with certain gentoypes etc. that do benefit and this could inform the analysis of the mini-phase 3.

My guess was that no one wanted to talk about the problems involved with assuming that race would have no influence on AD. It is not that everyone had somehow overlooked my observations, it was just not thought proper to honestly mention the various issues that could then result.

CMS injected this into the coverage decision without any discussion by them or any of others involved in how this might introduce complexity into the trial process. They merely decided to change the rules without that much consideration of how it could be made to be workable. My concern is that politics could be put before people. The best interests of AD patients who often might have problems advocating their position effectively due to their cognitive impairment might then be disregarded for other considerations.
Hi J11,

The questions you pose are important. I've been a member of the Alzheimer's Clinical Trial Consortium (ACTC) Research Participant Advisory Board, which is charged with advising major researchers on diversity, inclusive, transparency and communication to improve trials and benefit potential and current trial participants for 2 years and follow clinical trials through AlzForum and other sites. So I have to respectfully take issue with some of your assumptions and especially your conclusions.

I understand that your concern is that anti-amyloid drugs require one to have amyloid beta to remove before they can (hopefully) provide "meaningful clinical benefit". Both the AHEAD 3/45 trial of lecanemab (BAN2401) and the TRAILBLAZER-3 trial of donanemab in people with normal cognition are using blood tests at the start of screening to rule in those likely to have amyloid beta (AHEAD) or tau (TRAILBLAZER-3) and working with respected members of Black communities to recruit those with family history of AD. I know Black and Latina women who have been caretakers for two to three generations of their families with AD; they may have as much risk of the disease as I do.
I am glad that you have such an extensive involvement in these concerns. I am not well-versed in the details of the research, though from what I have seen so far I find it troubling that it is thought appropriate to go directly into a phase 4 with what would seem to be scant evidence of clinical evidence in underrepresented populations. Has any substantive clinical research been done with anti-amyloids in AA AD? Are they really going to go to phase 4 without
clear proof of concept? That is hard to believe. That is what phase 2 clinical trials are for! This really seems to me to be yet another exercise in changing the goal posts. It typically results in years of confusion as people try and figure what went wrong. Basically what went wrong is they failed to replicate. On the first round, there should be no substantial changes to the original trial protocol.

That is a good point about amyloid being conditional for enrollment. Perhaps even if community epsilon 4 AA do not have greater risk for epsilon 3 AA this might be a consequence of them not having typical amyloid accumulation. Only those epsilon 4s that did have a positive amyloid scan would be allowed into a clinical trial.



The Precivity blood test, an FDA-approved predictor of amyloid beta in the brain, as an early screening tool, is an effective way to recruit people in local communities of color. It made sense to the AHEAD researchers, after finding that 75% of those screened in the first year showed a normal PET scan (as reported in the CTAD November 2021 conference). Most of those folks were White and college-educated, with private health insurance or a private supplement to Medicare and lived in or near major metropolitan areas.

So it's not that CMS is seeking to be as exclusive as Yale Law School when it comes to aducanumab or other drugs; they are seeking to determine whether any drug works in the real world. Almost ALL top AD researchers who recently commented on the CMS decision on Alz Forum agreed with it. https://www.alzforum.org/news/research- ... s#comments


Yes, I realize that the science is moving forward, though I keep thinking that before moving ahead the previous results should be reinforced and confusion potentially caused by changing variables avoided. This has caused so many problems in the past and cost years of research progress.

My concern is that CMS appears to be repeating the endlessly repeated error of taking a somewhat early stage commercial product and changing too many levers at once. The anti-amyloid result is still somewhat fragile; it is still somewhat proven only under certain specific conditions. It would seem that CMS is not even interested in merely proving that Aducan is effective under the clinical trial conditions under which it was tested. Their actions indicate that they do not dispute these results. They want to expand out the envelope because they accept the original proof as settled and are not interested in duplicating what has already been established. They motivated to ask a new question because they do not the answer to be the same.



Regardless of whether ApoE4 exerts a different effect in Black and White or other ethnic/racial populations, it's important to identify both the mechanisms of risk and resilience to disease. Here's the conclusion from a study of Ancestral origin of ApoE ε4 Alzheimer disease risk in Puerto Rican and African American populations, looking at whether "global ancestry" (i.e. what we typically view as someone's race/ethnicity) affects their Alzheimer's risk or just their "local" ancestry (i.e. the race/ethnicity associated with their ApoE4 allele(s):
Measures of global ancestry showed no interaction with ApoE risk (Puerto Rican: p-value = 0.49; African American: p-value = 0.65). Conversely, ancestry local to the ApoE region showed an interaction with the ApoE ε4 allele in both populations (Puerto Rican: p-value = 0.019; African American: p-value = 0.005). ApoE ε4 alleles on an African background conferred a lower risk than those with a European ancestral background, regardless of population (Puerto Rican: OR = 1.26 on African background, OR = 4.49 on European; African American: OR = 2.34 on African background, OR = 3.05 on European background). Factors contributing to the lower risk effect in the ApoE gene ε4 allele are likely due to ancestry-specific genetic factors near ApoE rather than non-genetic ethnic, cultural, and environmental factors .Our findings suggest that the ApoE region from AF populations may contain protective factors that help mitigate the effect of the ε4 allele. In particular, comprehensive analysis of the ApoE region and testing for protective loci may reveal previously unappreciated biological pathways and provide translational opportunities. Research that focuses on locating protective variants represents a complementary approach to accelerating the identification of more effective targets for drug development. This, in turn, will lead to better treatments, and help reduce health disparities

I agree with the statement above bolded in brilliant pink. I'll repost here as it is quite important.

Regardless of whether ApoE4 exerts a different effect in Black and White or other ethnic/racial populations, it's important to identify both the mechanisms of risk and resilience to disease.

The quote is central to what I am concerned about. It is very important to know what this different effect might be before going into a confirmatory trial. This different effect is important and should not be overlooked. The APOE epsilon 4s drove the response in the Aducan phase 3 and made up a large percentage of the patients. If one group did not have the expected response than it is unclear whether the topline result would be positive. Remember, that the trials are handicapped with 80% mild patients who do not report large CDR-sb benefits. There is a smallish subgroup of patients that are producing most of the benefit. If the composition of even this smallish subgroup is modified so that it adds less benefit, it is possible that the trial might not report out as positive.

I do not disagree that the research should be done, it is just that the proof of concept stage should be in phase 2 and earlier. The phase 3 then replicates and confirms what has already been demonstrated. The big problem that I have is that CMS is pushing this proof of concept stage into a phase 4 trial.

Yes, I did read the article you noted in the quote and I found the exact same quote to be worrying. AA AD epsilon 4 on a European background has a different risk that AA AD epsilon 4 on an African background. That is exactly what I am concerned about! How will they report AA epsilon 4? Will they hyphenate it by saying it is on an African or European background or that it is epsilon 3 with R145C and epsilon 4 with an African/European background? This is starting to become very complicated! The results might need to go directly to exploratory analysis. I am very unsure how all this confusion could possibly squish all net. It took 20 years to pry out the complexity of European AD.

I highlighted several words in the quote above in red. What I wanted to emphasize was that the article was noting that there are a range of hypothesis generating questions that are open to further research. I agree. However, phase 4 trials are not designed and were not intended to investigate such exploratory questions. That is the main focus of my concern with what the CMS has requested. It is not that the research should not be done, it is that proof of concept needs to be established before it can be confirmed.

From the Alzheimer's Association 2021 International Conference:

"There is a well-recognized need for diversity in clinical trial populations to ensure diagnostics and treatments are safe and effective for everyone,” said Carl V. Hill, MPH, Ph.D., Alzheimer’s Association chief diversity, equity and inclusion officer. “It’s imperative that the Alzheimer’s community is aware of the impact of historical racism, and also the current racial discrimination in health care that presents obstacles for inclusive participation in Alzheimer’s trials. And, just as important, it is critical that we evaluate strategies that have been shown to be effective when recruiting historically underrepresented individuals and communities in these vital Alzheimer’s research studies.”..The Alzheimer’s Association is leading two major clinical trials with a strong focus on diverse participation. The New IDEAS study is recruiting 2,000 Latinos and 2,000 African Americans to investigate the impact of a brain amyloid PET scan on clinical care outcomes, including diagnosis and treatment. The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) study is a two-year clinical trial studying the effects of multi-component lifestyle interventions on risk of cognitive decline in a diverse population in the U.S.
https://www.alz.org/aaic/releases_2021/ ... ersity.asp
Sorry for agreeing with you again; it is so annoying when people agree so much-- it is difficult to have a good argument without disagreement. I do not disagree with the above quote. My main concern continues to be that
CMS has decided that diversity would best be added into a phase 4 trial without proof of concept. The Alzheimer's Association has consistently and for years advocated for more clinical trial etc. diversity. It is not easy to argue otherwise and that is not what I am arguing. I am merely suggesting that diversity needs to be done in a way that is aligned with previous research findings in order that diversity is not weaponized to cause trial non-replication.
What is the Alzheimer's Association position on the inclusion of diversity in the proposed CMS trials?

Finally, very few clinical trials look exclusively at ApoE4 and the NIA is pushing major expansion of machine learning, data aggregation to
more rapidly replicate or validate those variants most likely to lead to the rapid identification of therapeutic targets ... For example, there are reasons to believe that loss-of-function protective alleles may be good candidates for therapeutic targets. Approaches ...that maximize the likelihood of success in identifying protective alleles and therapeutic targets will be considered within the scope of this [award]... conducted by multidisciplinary teams of investigators....
It is expected that the study will result in the confirmation of AD risk and protective alleles in multi-ethnic populations that may serve as therapeutic targets... for rapid sharing with the scientific community through NIAGADS or another NIA-approved database....Data resulting from this study are expected to become available to qualified investigators to enable rapid identification of therapeutic targets.
https://grants.nih.gov/grants/guide/pa- ... nformation


ditto: Agree.

Again my concern is that there is potential for substantial research gaps at the genetic and other levels.
The R145C variant was only reported ~2013, even while it is a fairly common variant in Africa. I am not sure
for how long the Exome server has had diversity.





The NIA is assuming that neuroinflammation, metabolic disorders, gut/brain relationships, air pollution, heavy metals, repetitive mild TBI, hypertension, dyslipidemia, gender, early childhood adverse experiences are all issues that may have a significant additive risk of Alzheimer's. It seems likely that in both ALL populations, these need to be explored, especially as they may contribute to the timing and rate of amyloid or tau accumulation, regardless of APOE status. Frankly, most trials haven't analyzed these factors or have excluded people with some of these comorbidities from trials. I think it's time that changed.

We have lots of approaches in clinical trials; I doubt that aducanumab will be the solution for many, even as I know some wonderful people who desperately hope it will be available for them.
ditto: Agree

The problem is that many other AD risk factors correlate with ancestry group. There is so much confounding that could be present; sorting things out could be very complicated. For example, Asians seem to do somewhat better on Aducan. As a first guess this might be related to less obesity and healthier diet in Asian culture. Asians might have an AD that does not compete with all of these other risks, so perhaps they then respond better.

Lately, I have been very interested in air borne lead exposure from the 1960s, 70s, 80s and 90s as it potentially relates to social behavior and possibly AD. Inner city African Americans had heavy exposure to lead during most of that period.

There is a great many factors that are involved with broadly defined cognitive ability. This is exactly what I am concerned about. Adding in a great many new correlated variables also adds in a great deal of potential confusion. Up until the success with anti-amyloids has occurred within a specific context; the same success might not occur in other contexts.

It will be very interesting to watch as the research unfolds.

Yes, the responder group for Aducanumab and other anti-amyloids will become refined through time. For me one of the more important considerations now is for a revenue source to be present in order that there is funding to help sort through all of the unknowns.


Hmm, I am not sure whether I actually disagreed with anything. Can you have an argument when you do not disagree?
Last edited by J11 on Sun Feb 13, 2022 10:33 am, edited 3 times in total.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

APOE 4 var a.png
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

https://evs.gs.washington.edu/EVS/Servl ... mmary.y=10

Above is from the Washington Exome Server result for APOE.
You can find the allele frequencies and other information for any SNP in the table above (a few of the SNPs are missing).
It has only been over the last few years that they included African American populations on this server.

What the annotations that I have added show are some of the more important SNPs for APOE.
There are the two epsilon SNPs rs7412 and rs429358; there are also some other important SNPs.
The SNP between rs429358 and rs7412 with the orange dot inside the purple outline is rs769455.
This is what has been previously referred to as R145C and is much more common in Africans as seen by the allele count boxed in pink.

Near the bottom is rs199768005 boxed in gold is another important APOE SNP, though quite rare.
It is referred to in a publication as epsilon 3b and has a frequency ~0.02% and appears to reduce AD risk by two thirds.

rs769452 reduces epsilon 4 risk by 5 times; it has a MAF of 0.62%. This would be a good one for those on forum to look into because it greatly reduce e4 risk. This subtype of e4 has an AD risk similar to that of an e3.
Last edited by J11 on Sun Feb 13, 2022 9:48 am, edited 1 time in total.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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The comments about how the CMS intends to introduce patients lacking any proof of concept directly into late stage Aducan trials clearly is concerning. From what I can determine very minimal preparatory research has been done to validate the benefit in diverse groups. It is very unclear to me how a path to a positive outcome could be found with this approach. I will be very interested to read more and hopefully my concerns can be proven unfounded.

Lots of other anti-amyloid news to get to.

Possibly not the most reported story was from meeting on Thursday of The House Committee on Energy and Commerce Subcommittee on Health, though it provided some important insights into how the CMS analyzed the Aducanumab data set. The FDA was asked if they consulted with the CMS to help the CMS understand the extensive analysis done by the FDA. Surprisingly, the answer was NO? Anyone, zoom call? Don't even have to go on a plane and get COVID or anything. Um, the FDA supercomputer famously maxed out and the analysis team had to go with only 10 million simulations -- they found that "it was essentially impossible that Aducan was the same as placebo" that wasn't worth a conversation?

CMS was not interested in talking to the FDA people who dimmed the lights in a whole city because they just needed to know the truth about Aducan? The truth that they found was that there was virtually no chance that Aducan was not better than placebo? Admittedly, I would have liked it if the FDA had been more transparent (or at least simplified their results) so that the lay public could make sense of their models presented in some of the FDA Aducan documents. It is very difficult to understand why the CMS decided it was not worthwhile to talk to the FDA who had all of this largely unpublished research that they spent many person years acquiring. CMS decided to read the results from pubmed instead? They decided to take a literary and not quantitative approach to what is largely a quantitative question?

Another newsy item is Lilly's decision to move back the donanemab submission. They had been expected to submit
the filing by the end of the quarter; it is now uncertain when this might occur (perhaps later this year).

CMS' coverage policy is walking back the forward progress made by the FDA. Lilly, Roche and Biogen are now in the difficult position of having to first get through the FDA's hoops and then have to jump through a new set of hoops imposed by CMS. Sentiment is shifting to the idea that only full approval with two phase 3s will be enough for the CMS. Yet, even on this the CMS is unclear. If the CMS considers anti-amyloids as a class, then when three phase 3 trials read out later this year, would not 3 positive results tend to support the totality of the anti-amyloid class?

Perhaps the counter-move that we should push Biogen to make is to file soon for Lecanemab. The Lecanemab phase 2 only required 2 months of uptitration versus 6 months for Aducanumab. Clarity was fully enrolled in April, 2021 so two months later from this April, patients in Clarity will have been on treatment for 1 full year; the same time on full dose as in the Aducan phase 3s. The percent benefit did not grow that much from the 12 month mark to the 18 month mark in the leca phase 2. An early readout or at least an early peek of the data might reset the narrative. A carefully selected sample of patients would provide large additional evidence for anti-amyloids.
Last edited by J11 on Sun Feb 13, 2022 9:54 am, edited 4 times in total.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

The CMS does not seem to have had a good strategy for the coverage decision for Aducanumab and other anti-amyloids. There are now so many open questions that they have never responded to that their "final" decision in April will not have the same finality as that of the FDA's Aducanuamb decision. CMS has not in any way seemed to have been willing to enter into a sincere process of dialogue. There are a multitude of topics that they have introduced into the conversation that has largely created a sense of chaos. At no time during this nearly year long process have they actually responded with clarifications. How is their process legitimate?


One of the more noticeable of these outstanding issues is Down Syndrome. Over the last few days there has been a torrential flow of comments from the Down Syndrome community on the CMS comment page. These comments do not include the "eviscerated" botware. In fact, that botware is being sidelined by post after post from those advocating for those with trisomy 21. They are doing a solid for the AD cause, pharma might think of returning the favor by starting up a clinical trial with an anti-amyloid probably with new stricter treatment guidelines. Trisomy 21 would also be a great population to consider a micro-dosing approach. Why wait for MCI/Mild AD? Trisomy 21 results in a nearly Mendelian form of amyloid dementia; treat early at a micro-dose? This would give their doctors a potential treatment that they could prescribe safely off-label.

The CMS' position on T21 is very unclear to me. The NDSS (National Down Syndrome Society) commented in the first round of comments; CMS noted that they commented in their January document and that was that. CMS' position on coverage for Down Syndrome is a complete mystery (to me anyways).

Many comments from those advocating for those with Down Syndrome and more broader Intellectual and other disabilities on the CMS webpage oppose the potential discrimination that wold occur with national non-coverage. I can understand where this interpretation might be formed from the CMS document: Those with Down's might be excluded even if the proposed CMS trials for AD proceed because of their disabilities? There is the alternative interpretation that they will be excluded from national coverage because they have AD and CMS has proposed that AD will be nationally non-covered. It is surprising that this much legitimate confusion could be present without any attempt at a dialogue to make the logic of the CMS more transparent.

With this and many other unresolved concerns, how will stakeholders consider that CMS has offered them a truly transparent and democratic consultation process? There is no sense of finality to the CMS' upcoming final decision. Without a modicum of credibility, CMS' final decision might simply be seen as a cue to launch an appeal.
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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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