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 »

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Hmm, on second reading the CMS final decision could be interpreted more as victory than defeat. On the first skim through the second clause at the start of the document captivated my attention and seemed to envelop mabs that will receive full FDA approval under a similar umbrella as Aducan. I was aware of the use of the word "registry" from previous documents, though the prospective comparative studies seemed more linked to RCTs than registries and RCTs are later also introduced in certain contexts in relation to these full approval mabs (see second quote below). In the figure above mabs under this class appear to be designated as having moderate evidence.

Color coded to help distinguish the CMS decision from my comments.

"2) Monoclonal antibodies directed against amyloid that are approved by FDA for the treatment of AD based upon evidence of efficacy from a direct measure of clinical benefit may be covered in CMS approved prospective comparative studies. Study data for CMS approved prospective comparative studies may be collected in a registry."
CMS Final Decision anti-amyloid mabs



"In the scenario where treatment is sought for patients who are substantially different from those participants included in the initial RCTs designed for FDA approval, then evaluation would require greater rigor, such as with a pragmatic RCT. Use of pragmatic clinical trials was strongly recommended by some public commenters during the public comment period. Pragmatic trials could be quite large, and involve broad community care settings (e.g., outside of major centers and hospitals). Such trials could rigorously answer whether the clinical benefit seen in the initial RCTs are replicable in broad community practice, when certain major inclusion and exclusion criteria of the FDA-approved RCT are relaxed."

"Thus, appropriate CED study design could assess whether benefits, and also harms such as brain swelling and

Created on 04/11/2022. Page 36 of 67

bleeding (associated with ARIA), are the same, reduced or increased when the treatment is used in broader community practice, in a different patient population (with major trial inclusion and exclusion criteria relaxed), or both.

The question specifically about generalizability of treatment results to Medicare beneficiaries who are substantially dissimilar to trial participants, is not a formal requirement of this CED. Thus, an antiamyloid mAb may move from CED status to full, national coverage under §1862(a)(1)(A) by answering only the CED questions (1 through 3). However, in this case the national coverage criteria would reflect the major inclusion and exclusion criteria of those initial trials on which the NCD is based.
"

The skill testing questions CED refers to above as (1 through 3) are:

"CED questions

Each CMS approved prospective comparative study must address all of the following questions for Medicare beneficiaries with a clinical diagnosis of mild cognitive impairment (MCI) due to AD or mild AD dementia:

1. Does the antiamyloid mAb provide meaningful clinical benefit (i.e., slowing in the decline of cognition and function) in broad community practice?

2. Do benefits, and harms such as brain hemorrhage and edema, associated with use of the antiamyloid mAb, depend on characteristics of patients, treating clinicians, and settings?

3. How do the benefits and harms change over time?
"

So, the complexity that has been added into the decision is that once the 3 CED questions are answered, a mab could move to full payment coverage within the context of the original inclusions/exclusions of the FDA trials. This generalizability concept is a new wrinkle that seems more prominent in the final decision over the initial decision.


"In sum, CMS is issuing a final NCD that concludes with CED for this particular class of antiamyloid mAbs for the treatment of AD. The reason for CED is that even if the FDA were to determine that an antiamyloid mAb is approved because it demonstrates efficacy from a direct measure of clinical benefit, that approval is based on RCT results according to rigorous clinical trial protocols, in relatively few, advanced care settings such as academic medical centers, conducted with dementia experts, and in a highly-selected patient population that is different (e.g., with fewer co-morbidities) from the general Medicare population. It is important that there is evidence that demonstrates that the positive RCT results for FDA approval are generalizable both to broader community care settings, and to the broader Medicare population that includes patients with co-morbidities such as hypertension, heart disease, diabetes, and the like.

Therefore, at this time, CMS concludes that an FDA determination that an antiamyloid mAb for the treatment of AD demonstrates efficacy from a direct measure of clinical benefit is promising but does not meet the §1862(a)(1)(A) reasonable and necessary statute. Prospective comparative studies designed to answer all of the CED questions, which could range from a large, registry-based study with a comparator to a pragmatic clinical trial, are appropriate coverage for the present time. CMS needs evidence that an antiamyloid mAb for the treatment of AD demonstrates improved health outcomes, with reasonable risk of harm, in broader community practice and in the broader Medicare population, that are similar to results achieved in successful but narrowly-designed RCTs seeking to establish safety and efficacy for FDA approval.
"

In further recent post-decision clarifications from CMS, clause 2 is framed more in the context of allowing broad access (in the registry sense as stated in the clause). There are various nuances that need to be read carefully to capture this true intended meaning. For example above, read alone:

"Therefore, at this time, CMS concludes that an FDA determination that an antiamyloid mAb for the treatment of AD demonstrates efficacy from a direct measure of clinical benefit is promising but does not meet the §1862(a)(1)(A) reasonable and necessary statute." suggests narrow coverage. While the next sentence: "Prospective comparative studies designed to answer all of the CED questions, which could range from a large, registry-based study with a comparator to a pragmatic clinical trial, are appropriate coverage for the present time." clearly suggests broader coverage. It would have been helpful to have made the term "comparator" more accessible-- i.e., non-randomized control?

"CMS needs evidence that an antiamyloid mAb for the treatment of AD demonstrates improved health outcomes, with reasonable risk of harm, in broader community practice and in the broader Medicare population, that are similar to results achieved in successful but narrowly-designed RCTs seeking to establish safety and efficacy for FDA approval." The second generation mabs (e.g, Lecanemab) appear to be moving beyond the discussion of risk of harm. From my understanding Lecanemab's phase 3 went directly to maximal dosing without uptitration. Perhaps in follow-on studies [even with the long-term extensions after Clarity], consideration could be given to such uptitrations as an option for patients on placebo. Some patients will naturally tend to be risk averse and in a post-FDA approval environment it might be helpful to see what effects such variations from trial protocol might have.

In terms of generalizability, one certainly wonders how scientifically valid ecological studies might be. The reason why clinical trials are conducted in such near laboratory environments with high precision measurements and highly qualified personnel is because without such precision one could easily only have GIGO. Far too often in science and medicine common place reasoning based upon population scale data sets have been found to have been misguided in contrast to evidence from carefully controlled clinical trials of not much more than ~1,000 patients.

Ironically, probably the best way to establish generalizability would be to simply conduct small scale randomized clinical trials on specific populations. Earlier on thread I did suggest this sort of an era of boutique medicine. Run smallish adaptive trials that used Bayesian strategies to identify responder groups. As noted recently, there are a range of AD covariates likely involved in progression- identifying such subgroups could help to reveal those who had especially large treatment responses. One expects, though, that generalizability in a real world context (i.e., non-academic, non-specialist) could easily produce more noise than signal.

Of note, the final decision expanded coverage under the broad framework to include Down Syndrome. Hopefully, this means that those with Downs will be able to access their own clinical memory networks for their own separate trials that address their specific needs, cognitive testing requirements etc.. This could greatly turbo-charge the development of AD treatment for those with Downs as up till now, virtually no mab had been clinically tested in this population.

Offering coverage to what is a reasonably constrained population group (by size) potentially could potentiate effective treatment for them. It would seem a big win for Downs: pay pharma to develop an existing technology base to help those with essentially ~ childhood onset dementia/cognitive impairment. They already have built out needed clinical infrastructure specific to their phenotype/genotype. In the ordinary course of things this might have taken years and years to move forward. With a payor within the context of a protected population, strong evidence along with firm safety findings would seem reasonable over the medium term. They roughly have monogenic AD and they could offer considerable support for the amyloid perspective in a way that typical heterogeneous AD populations often have trouble providing. Age of onset is typically well defined and in Downs AD risk is almost Mendelian, so there are a range of features including safety, preventative dosing etc. that favor mab development in Down Syndrome.


In totality, the CMS's Final Decision on anti-amyloid mabs might be better understood as aligned with the patient interests of receiving needed care within boundary conditions related to realistic constraints based upon co-morbidities and acknowledging the needs of under-represented populations. There are a few unresolved questions about this decision for me (e.g. I will need to have a better sense of how they define "clinically meaningful benefit"), though the decision seems to be moving everyone back towards being on the same page. The "Lecanemab" 4 month uptitration dosing window is now approaching, so patients could soon be better off waiting for September than continuing the argument.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by JD2020 »

J11,

I do not assume the worst of statin users. My husband is one, and he lives a healthy lifestyle. I was just using the person who refuses to help himself and relies on a pill as an example of a point I was trying to make. There are a million others - the motorcycle rider who refuses to wear a helmet, relying on the ER team, for example.

I can't read all of this technical stuff. Science is not my thing, and I wish I cared about all this detail, but I do not. The bottom line is that you think CMS over stepped. I think the FDA over stepped, ignoring its advisory committee, from which 3 people resigned, if I remember correctly.

I think your most significant sentence is that you don't know much about ReCODE. Here is a summary:

1. Figure out what is going wrong,
2. Fix it,
3. Optimize everything else.

As you know, there are people in this forum who were very ill and now are very healthy. Have you read "the first survivors of alzheimer's". That is the sort of thing that I find compelling.

My very best to you,
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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JD2020,

I think if you review the posts, I did not actually reply to your comment about those with high risk factors.
There are so few posters to the thread that I must be nice, hospitable and even obsequious (if necessary) to all.

Nonetheless, I do have somewhat negative emotional connotations in my personal experience after contemplating the associations that your comment triggered for me. Specifically, when we went to hospital on an occasion one of the resident doctors was probing why our loved one might have progressed into moderate AD with the implication being that it was somehow a lifestyle choice. I never was able to interject that as far as I am aware, our dominant AD has been present in the family tree for centuries and should realistically be accepted as largely genetically predetermined more than something easily avoided through lifestyle interventions. The co-occurring obesity present in our loved one and not in the non-dementeds in our family is probably related to a rare missense variant in the LIPC gene. The way I understand this now is that it really isn't simply eating too much that is the fundamental problem as is a deeply wired biochemical difference involving lipid processing. Even when our loved one was thin, there was still the feeling that there still lurked an obese person in a thin body along with a further sense that there was still an inflammatory response. It was more than slightly surprising that these perspectives alluded the resident. Until now medicine has had so little in the way of disease modifying treatments for neurodegenerative disease broadly defined; those doctors who went into this specialty probably should have focused more on how they would exude empathy and compassion and probably less on what their medical textbooks had to say about neuropathology. A dementia psychometrician wasn't much better. This doctor was highly unamused that our loved one did not know what country we were in, though I was delighted that our loved one was still able to name any country. At a certain point with dementia knowing the right answer seems much less important than having the chance to celebrate even a small victory. It would not be too long before the celebrations even for any word would recede from possibility. However, when we interacted with more senior doctors such as our family doctor, there was a much richer understanding of personness and the life journey that had been taken.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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J11 wrote: Tue Apr 19, 2022 5:24 pm JD2020,

Specifically, when we went to hospital on an occasion one of the resident doctors was probing why our loved one might have progressed into moderate AD with the implication being that it was somehow a lifestyle choice. ...
This doctor was highly unamused that our loved one did not know what country we were in, though I was delighted that our loved one was still able to name any country. At a certain point with dementia knowing the right answer seems much less important than having the chance to celebrate even a small victory. It would not be too long before the celebrations even for any word would recede from possibility. However, when we interacted with more senior doctors such as our family doctor, there was a much richer understanding of personness and the life journey that had been taken.
Hello J11, thank you for sharing this beautiful post. It made me cry and is a moving reminder that regardless of how technical a thread may be, as this thread definitely is, most of us are here on the forums because we have been touched personally by AD, either in ourselves or our loved ones or both. It is a sad situation you point to, where the empathy and compassion from a medical professional that might have been a comfort were lacking. And certainly no one deserves to be made to feel in any way that the progression of the disease is a simple lifestyle choice. That seems needlessly cruel or at best, tremendously insensitive.

Your writing, "It would not be too long before the celebrations even for any word would recede from possibility," struck me to the heart and brought back bittersweet memories.
When my mom was in the later stages of disease, I used to strain, trying to grab onto anything that might be a word from a stream of her babble so I could respond and we could preserve some semblance of the act of conversation, which she still enjoyed tremendously. She loved the form... the back and forth... even when the content was negligible. If I thought maybe I heard "green", I'd reply, "Oh! It was green? you're kidding," and then she'd pick it up and run with it. It was so precious to have that word.

So I get it, J11, that the name of any country could be a victory, and every victory a cause for celebration.
Yes, Personness and life journey all the way around....
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

flora, thank you for replying.

Yes, every once and while I try and drag myself away from the technical aspects of the thread and bring it back more to a human level. These reflections on the human level are important, I realize, as some of the more important insights about dementia are not written up in hefty volumes in distant libraries, but are more these personal observations. Such observations would be of especial importance for those who lack a personal connection with AD.

These reflections open up a whole landscape of dementia topics to explore. One such topic that occurred to me are the memory clinics. What I thought is that these memory clinics have probably siphoned much of the high end medical talent away from the generalist hospitals. This might have been why we had the problems that we did in the mega hospital environment. The memory clinics are actually much more aligned to the needs of dementia patients-- the workers are all dementia specialists and there is no particular need for a highly medicalized context. Often dementia patients can be relatively healthy and once these patients progress through much more than moderate dementia then the clinic is no longer suitable for them. In most of the large mab trials the AD patients needed an MMSE of ~23 for inclusion; this is still reasonably high functioning.

On top of the strictly dementia related topics, your comment about my beautiful writing struck a chord. It reminded me how many people go to university with the intention of never writing a complete sentence because they feel so inadequate in their language skills. Where could such an impression arise? My guess is from the near constant fault finding in their earlier writing courses. When people are only ever told about what they did wrong for long enough, they almost inevitably will become writing phobes. Yet, the occasional kind word can go along way-- who knows what literary genius it might help to develop? Yes, I have become a big fan of replacing negatives with positives whenever possible.

Same sort of process was at play with the name a country item. I saw it as a great opportunity to have some fun, though for whatever reason it was thought that the answer was even more important than working the proximal frontiers of ability. I have become a big fan of going with the fun of the experience-- my writing on this thread has not been to the highest of standards I realize, though I have had a great time writing it and that's enough reason for me to keep on typing.

I greatly appreciate your response as it is comforting for me to know that I can reach those with parallel dementia experiences. I especially appreciate your comment that it made you cry as this speaks to me of the power of words to evoke the shared consciousness that results from life experiences with dementia.

That was an interesting idea about focusing in on a single word and then allowing dementia free association to go from there. I had not thought of that. For us, it was more that we were able to maintain good psychological contact even when we moved well past no vocabulary and bed confinement. Classical music was playing throughout the day and I had near continuous close physical presence, so there was a strong sense of emotional connection.

In contrast to many, I do not view this time as tragic at all, with the assistance that we received it actually worked out remarkably well. We had never discussed how we would manage dementia care with progression to profound disability, though our aging at home solution was quite effective. There was much less medical management than I would have expected-- the only issues that emerged were seizures and muscle tightening. I would have liked to have had a better idea how to cope with these problems (especially the muscle tightening as it seems as if it could be the easiest to manage).

Unfortunately, large numbers of dementia patients typically do not receive a similar level of care in an institutionalized environment. I fully understand how this is almost inevitable, though the experience of these patients is likely quite difficult.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

Sorry everyone for slacking off for the last week or two.

There are so many ridiculous obligations such as grass cutting etc. that I am very disinterested in though obligated to participate in, however, I am very interested in posting to this thread and being part of the dementia conversation. Whenever I can escape from all the other absurdities of life, I am here.

2022 is the breakthrough year for clinical Alzheimer treatments!

This is the exact time that the history books will refer to as the time that the tide truly changed.
I don't want the history books saying that J11 wasn't right up there advocating and participating at this pivotal moment in the life and journey of dementing illness.

We are now expecting updates ... immently. Hours ... days ... things are happening and/or about to happen.
This is no time to be up at the lake! We really do need our own 24/7 news feed! All AD -- All the time! It is hard to keep up with it all. There are so many backposts to catch up with and yet there are always so many new items in the inbox. It is not easy keeping the inbox and outbox cleared out.

One intuition that I have been sensing more and more lately is that a post-dementia life is approaching for me. My perception is that my family that has been on the direct line of dominant AD have been highly disadvantaged in life over many centuries. Those on forum with epsilon 44 will probably be challenged for a generation or perhaps two with dementia, though AD would probably not be a permanent genetic feature transmitted generation upon generation. With dominant style AD, disadvantage accumulates upon disadvantage. When I look at my genome I can clearly see numerous these disadvantages. As a guess, dominant neurodegenerative disease such as AD probably represent the most extreme form of life disadvantage in human populations. In our experience, dementing illness intensified over many decades and a milder though also difficult manifestation was present as mild cognitive impairment during our developing years. Having AD treatments so that children will not have parents with cognitive impairment will be such a large step forward for the community. Such a development could now be on the short term time horizon.

Another intuition related to the above that I have perceived of late is the idea that as I move away from all of this life disadvantage I will also drift away from my connection to the community. In our experience, there was a great deal of need for government and community to help us through our challenges. We needed people to cope with our challenges: we needed doctors, lawyers ... probably the criminal justice system, financial advisors ... We needed a lot help to navigate our way through life. I can appreciate how difficult aducanumab treatment has been for the extended dementia ecosystem in relation to their role as helpers. I can also appreciate the sense in which it could be felt that the professional community would question the benefits that this early treatment would offer. A symbiotic social system has evolved and the helpers in this system have been placed in the difficult position of having an approved first generation treatment that has weaknesses.

Another part of this dementia ecosystem that we have accessed through the centuries has been criminal justice system. My impression, though, is that through time the challenges related to dementia have been increasingly interpreted less in relation to criminality and more as a medical and a social service issue. From my online searches on genealogy sites, it does appear though in the ~18th and 19th centuries family members in the demented line were as children convicted and punished as criminals under the legal system. My best guess is that at that time the life and economic stress caused by dementia moved my ancestors towards a life of crime and the community for whatever reason (probably general poverty) could find no other method of way of coping with it than through legal proceedings. In the modern context, my perception is that criminalizing dementia has become less prominent; in an age of affluence framing dementia as a crime becomes less productive. When the community structures certain outcomes unobtrusively, there is no great reason to drive those in need towards desperation. Such responses can then be seen as quite adaptive and likely involve considerable savings of scarce resources. What I can see now is a life which is largely free from all of these attachments to community. Without dementia, a radical libertarianism becomes plausible. Even the until recently most highly disadvantaged group in the community might no longer see any great role for government to play in their lives. From this perspective we could see a prominent shift towards the right of the political spectrum as a result.
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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.

Post by J11 »

This figure is from a recent alzforum post.

Notice how far ahead memory problems are from the more general global cognitive impairment. Notice also that by Braak stage IV amyloid has already maxed out and is starting to decline.

The AD trials to date have focused more on global cognition. However, this has me wondering if memory were chosen as the phenotype of interest, then the AD patients would be on the upward sloping side of the amyloid hill. The patients on treatment would have their amyloid levels normalized while those on placebo would continue to drift up the amyloid hill. Such clinical trials could be much more powerful than current trials as there would then be this dual separation force-- those on placebo would not have already reached maximal amyloid load.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by mike »

J11 wrote: Sat May 07, 2022 3:07 pm This figure is from a recent alzforum post.
Am I correct in reading this figure that Neurodegeneration continues to occur at the same rate? I'm guessing this might not be a long term help then...
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

mike, thank you for commenting!

I appreciate it when the thread can be more of a conversation and less of a monologue.

The above figure (and other similar ones) has me thinking.

First, the biomakers for AD are far far in advance of the actual decline.
The cognitive tests for memory and general cognitive decline happen many stages downstream of the CSF amyloid changes (and PET amyloid). All of this is to say that potentially much of the phenotypic level hallmarks of AD might be avoidable with early treatment over the short-medium term.

Second, there have been recent reports of FDA approved tests for beta amyloid etc. that could help avoid the expense and hassle of a PET amyloid scan.

Third, I am very interested in seeing how anti-amyloids will affect AD progression when given early on during memory decline. The current round of AD clinical trials has focused on global measures of cognition. Yet, this would mean that amyloid had already invaded these critical brain regions. What happens if the memory regions (e.g., the hippocampi) had been seeded with beta amyloid, though the other higher brain regions (e.g., in the frontal cortex) where the dementia behaviors had not been so exposed? Could treating at the memory stage truly stop progression into dementia? That would be a dramatic result! It is quite disappointing that a more vigorous research effort has not been directed in this direction. It highlights the critically important need to have that first funded AD indication for anti-amyloids. Once such funding is secured, then a colossal amount of clinical research could be directed at such questions.

The possibility of a full service early AD diagnostic test with early treatment could rapidly change the scale of the dementia pandemic. Everything appears almost in place to achieve this post-dementia life.
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