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 »

Percentiles in this first figure refer to the percentiles for the patient samples from Engage and Emerge considered separately.

Engage Emerge Residuals.png
Percentiles in this first figure refer to the percentiles for Engage and Emerge considered as a combined sample.

Engage Emerge Residuals Apart.png
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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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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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Very exciting everyone!

The AAN meeting will be held in Seattle from April 2-7.

There will be a Lecanemab presentation and there is a potential that there will be an announcement that Lecanemab has been filed with the FDA. This would be massive! We are now already approaching the five month window until the end of the Clarity trial. The results are getting close! Getting this before the FDA sooner than later would seem the best strategy, otherwise the FDA will be seen as lagging and not leading the story. With the results that can be imagined for Lecanemab, the FDA might already find itself in the awkward position of not having approved a safe and effective product for dementia that tens of millions of people worldwide are desperate to access.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

The recent CMS decision has added additional burden to moving the AD treatments to the tens of millions of people who would benefit from them. In this respect one notable revision in the final decision from the preliminary one was the expansion in the scope of non-coverage: Now the decision is including mabs that will win full FDA approval based upon clinical efficacy over the near term. It is not entirely clear to me how that could be legally enforceable. Does the CMS truly have that level of authorization? They are overriding FDA approval and further they are now introducing the condition of clinically meaningful benefit (without actually clearly defining it or acknowledging the pre-existing conceptions of this term within the clinic). Not so long ago it was thought that full FDA coverage would essentially guarantee CMS coverage; this is no longer true. The CMS has now explicitly stated as much.

The FDA stated that they felt that achieving statistical significance was sufficient for approval. It is not difficult to recognize now that it is not so much that better cognitive tests are not available to further refine even slight cognitive benefit from mab treatment in AD, as it is that the benefits need to have real world translation. Thus, one can realize that the tests in the aducan phase 3 (especially the topline CDR-sb) that were used were crude enough so that only truly meaningful signals of treatment effect would be sent. Clinically meaningfulness was thus embedded with the original approval. Were the Aducan trial results corrected for the lack of precision in the tests themselves?

Current IQ tests are calibrated down to a single IQ point which is likely a much finer gradation than is achieved by typical AD psychometric instruments. At the limits of sensitivity AD cognitive tests might recognize treatments effects of no consequence. Nevertheless, now that effective AD treatment has arrived, there will likely be mainstream interest in tracking even slight cognitive changes in the pre-AD setting as early treatment should be much better than later treatment. Perhaps pharma can actively participate in such outreach. Instead of the non-valid have you forgotten your car keys lately test, accredited possibly freely available online psychometric tests for pre-AD could help people to manage what is a largely universal risk of AD.

The CMS (and everyone else) presumably can now imagine the results that are rapidly approaching and are expected in months. However, even if Aducanumab had been granted full approval with an uncomplicated topline readout, the CMS' current policy stance would have (presumably) been to still only cover with CED (number 2 below).

"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."

For their final decision to have any relevance it needed to address what will happen in the near future when statistical efficacy with mabs is no longer open to question. They have done this with the above appended number 2 clause. The goal posts have changed to "clinically meaningful benefit" - a term that never appears to be operationally defined in the final decision. The preliminary decision opined that 1-2 CDR-sb points would qualify as clinically meaningful, though in the context of an 18 month clinical trial this approaches a logically unachievable standard as the entire expected decline is on that scale (e.g., in Engage placebo decline was only 1.56 CDR-sb. This lack of placebo decline in Engage should probably have been highlighted more on thread in relation to Engage high dose missing its primary.) Until now, "clinically meaningful benefit" in the context of AD clinical trials was understood (e.g. the Lecanemab phase 2) as ~25% slowing of decline. Aducanumab reported 21% on the topline high dose Emerge with CDR-sb, though even on the topline other equally if not more compelling measures reported up to 40% benefit. Of course, in the high dose subgroup that actually received the full treatment (due to PV4, manageable side effects etc.), even their topline results approached 40%. It is not clear how such overwhelming benefit could continue to be ignored.

In the Aducanumab phase 3s, this strong sub-group performance was somehow talked away. Such deception clearly was aided by the lack of a more complete depiction of the results. For example, ordering the CDR-sb by dose (similar to what has been done in recent thread posts) would clearly highlight the effect of dose. In fact, one of the earliest posts to this thread considered the cognitive benefit in the phase 1 Aducan trial of those who were 1 SD above average in amyloid, even with the small sample size there was a large benefit- they did not progress on MMSE.

Obscuring the results in this way will not be possible with Clarity. Almost 1,000 patients will have been treated at high dose with a mab without the protocol changes etc. that occurred in the Aducan trials. Pretending that mabs are unable to offer large clinical benefit will soon no longer be possible. This is seen especially with the Aducan extension trial where apparently one third to one half of patients achieved a functional cure.

This is another point that probably has not been belabored enough on thread: the clinical benefit reported in AD clinical trials continues to underestimate true benefit to the "core" AD population. Why did original AD clinical trials not succeed? Partly because they were not treating AD patients- many of the patients did not have amyloid; they did not have AD (as defined as positive for beta-amyloid). Yet, there continues to be a classification problem. Many in the AD clinical trials continue not to have canonical AD. They might have beta-amyloid, though this is not truly the driving feature of their cognitive impairment. Something else (e.g., TDP-43, etc.) is of more central importance. They are amyloid+ non-AD patients. The clinical trials are therefore underreporting the actual benefits to the responder class. What is happening now, is that there is a selection force operating such that after the official clinical trial period ends those who tended to most benefited carry forward and continue to benefit from treatment: These are the 1/3 to 1/2 who achieve functional cures.

Surprisingly the CMS did not include this insight into their clinical trial design. Basically, some patients truly do have large responses to mabs; some others are non-responders, even some of the placebo are non-progressors.
An innovative trial design to accommodate this perspective could be treat patients for some time (perhaps ~ one year) and then if they did not appear to be responding to discontinue treatment (They had been identified as non-responders and they possibly would not respond. Clearly, this would need to be carefully investigated as some early non-responders could become late responders. The long term extension did however find that those who had not responded by 18 months tended to spiral into progressive rapid and irreversible dementia.). It is true that such a treat and reassess approach really is not the optimal strategy, though at this time it is still not possible to unambiguously identify responders prospectively. By covering mabs all of the various research questions could be answered as the clinical science evolved. Treat and reassess might add some complexity to the statistical analysis, if you merely remove the non-responders then it would ensure that the result was better. Yet, if this were done in the same proportion in the placebo group, then the objection might be resolved.

Such a trial would align with the CMS' perspective of being pragmatic; it is not currently feasible to clearly identify the responder class prospectively-- then why not identify the responders retrospectively? This is what will likely occur in a real world context naturally. Patients that respond continue treatment those who don't respond don't continue. This could be a substantial money safer. Yet, for whatever reason the CMS has not mentioned such an adaptive trial design in their final decision.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by JD2020 »

I am sorry that you are so disappointed. But to take the other side...if FDA approval guaranteed CMS approval, then what would be the point of having an approval process by CMS? In discussion and articles about this drug, I have never read anything that gives me confidence that this drug is helpful, safe, or went through an FDA approval process that was balanced. If someone wanted to put my very ill family member on the drug, I would provide the volumes of data to the decision maker to show that there is a lot of uncertainty, at best, as to the effectiveness of this drug and real risks of dangerous side effects. As a taxpayer, I don't want to pay for this drug. If it were the magic bullet, I would be all in. It's not, not at all. It is a dangerous drug that gives very ill and vulnerable people false hope. Biogen greedily overpriced the drug and had to cut that cost dramatically. The system is working. Now all we need is a drug that actually does reverse dementia and/or broad acceptance of the importance of ReCODE for optimal health.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

JD2020, thank you for replying! There are many lurkers on thread and not many posters (aside from me). It is great to have additional perspectives occasionally to deepen the conversation.

I will take your points and respond verbosely to each.

Regarding my disappointment, I would characterize it more as annoyance. The approval of Aducanumab has set in motion what now seems like an inevitable endgame for Alzheimer's. Aducanumab is that first generation product that shows that success is possible with some tweaks. As we have discussed previously on thread, Lecanemab appears to have the ingredients for a more substantial success.

It is, though, disappointing that the CMS has so consistently worked against potentiating an Alzheimer treatment. When I read through the CMS listening session for Aducanumab that they posted to their website (this was the first listening session, for some reason the second listening session was not posted to the web; perhaps they had heard enough?), it was unavoidable not to notice the prominent role of the CMS' previous CED for beta-amyloid PET scans.
It was noted that the CMS chose not to cover these scans even once definitive evidence in support of them had been published. Notably and ironically we have now entered an analysis universe in which these scans play a highly central role. The FDA approved Aducanumab and has granted accelerated approval for other mabs based upon a biomarker
(i.e., PET amyloid) correlation to cognitive benefit. The CMS has been highly resistant to potentiating AD treatment advances. Updating the PET CED to include all of those in AD clinical trials would seem reasonable at this stage in AD clinical development, though it is unclear whether this is now their revised stance. This would seem to be money well spent; perhaps 2 or 3 such scans could be included during a clinical trial. As mentioned earlier on thread, one PET amyloid scan is not able to offer the delta. Possibly additional scans could be included PET tau and FDG. These are research stage scans that at some point might no longer be felt to add clinically valuable information and a new policy could then be introduced curtailing such coverage

CMS final decision url
https://www.cms.gov/newsroom/press-rele ... -treatment

https://www.cms.gov/newsroom/fact-sheet ... rs-disease

https://www.cms.gov/medicare-coverage-d ... &ncaid=305



With respect to CMS approval, the question that leaps to mind is: What CMS approval? A new layer of government regulation has spontaneously emerged and for whatever reason this has been largely overlooked.

Admittedly, I have been something of a complete novice in the FDA regulatory world before Aducanumab. I have had to navigate their institutional cultural logic the best that I can. From time to time, I have realized that there is a certain making it up
as we go along approach that has applied with Aducanumab as it does not seem overly likely to me that there is
a comprehensive manual entry for how to move a product through the regulatory process that declared futility and then declared the futility announcement was not correct. Even still the FDA had clear regulatory authority to decide on Aducanumab and they did without legal challenge.

What I perceive with the CMS approval is that there is very very little precedent for what they are now attempting to do. While the FDA might have went somewhat off road on the Aducanumab approval, the CMS is out there making their own trail. This is very much making it up as you go along. It is not obvious that they actually have the organizational authority to do what they propose (specifically, their clause 2 at the top of their final decision that seeks to override an FDA full approval based upon clinical efficacy) and could thus be considered ultra vires their legal authority. This might need to go to Congress for a more thorough talk through.

With the FDA through their decades of regulatory experience they have learned how to develop what is widely seen as a balanced process that upholds scientific standards and truly listens to various stakeholders. During the Aducanumab process this resulted in the somewhat embarrassing predicament in which there was open disagreement among different FDA departments on how to interpret the clinical trial results. Ultimately, such disagreement seems to me to add value as it helps to highlight weaknesses and drive innovation towards resolving such weaknesses. Such disagreement in the current regulatory configuration might no longer be as possible. Everyone will be compelled to agree because discussion is no longer seen as a strength but a weakness.

It is particularly noteworthy that the CMS chose not to offer such opportunity for internal disagreement. They forwent ? their own Medicare Evidence Development & Coverage Advisory Committee (MEDCAC) and also
an external technology assessment. On such an important decision not allowing a comprehensive discussion of the issues involved clearly must be seen as a weakness and lessens the legitimacy of any decision that the CMS produced.

To reiterate, the emergence of a CMS approval process for Aducanumab is perhaps without precedent. There does not seem to have been a prominent CMS approval process before Aducanumab. It is one of those times in which someone in government simply steps forward and proclaims new power for their department and the people nod and accept such overreach without question. Corporations sometimes will call the bluff and litigate with the government on the basis that the law does not support such assertions of power.

Regarding the FDA process itself, my evolving understanding is that the Aducanumab evidence is stronger than I have typically expressed on thread to this point. The FDA Aducanumab Briefing Documents especially the second round of these documents were unequivocal. I have quoted on thread the original Briefing Documents on several occasions that went on at length about the "highly persuasive" paraphrase essentially conclusive results of the phase 3 trials.
The CMS did not reference any of these comments in their decision background. This is odd as this is the direct clinical evidence that could answer the question of Aducanumab efficacy. If anything the second round of Briefing Documents were even more unwavering. The widespread view adopted in the CMS decision that Aducanumab demonstrated low to moderate evidence (Figure 1 of their decision -- not clear yet whether the CMS considers the evidence low or moderate) would seem flawed. The actual FDA Briefing Documents (II) were actually leaning with a majority opinion to grant full approval to Aducanumab. I am not sure whether I would have voted for such full approval as allowing the evidence to ripen in a post marketing sense does seem justified, though partially as a result of less than full approval the CMS somehow talked down this near unanimous opinion for full approval to coverage with evidence status.

It surprises me that many of the highly informed posters/readers on forum have also not had a more favorable impression of Aducan. The topline result in Emerge was highly obscured by various trial features including change of dose etc. so we would up ~21%. It is not a large assumption (as others have asserted) that more treatment should lead to better results if the treatment were in fact effective. One might even consider that to be a logical tautology. With more dosing we saw benefits moving towards 40%. APOE e4 did better than e3. ... Clarity approaches.

I have not finalized my thinking on the likely readout on Clarity etc., however I would not rule out a large result for lecanemab; the other mabs do not have as obvious a clinical trial provenance and so their topline is less obvious to me. Yet, with the Lecanemab phase 2 we saw 50% benefit in the smallish group of e4s on the highest dose.
If some sort of training sample could be explored with the results and a responder group found according to PET tau genotype etc. then even larger results could be reported in the holdback sample. The e44s might have especially strong cognitive benefit.

The second generation of mabs (e.g. Lecanemab) appears to have significantly improved safety over Aducanumab.

Regarding treating very ill family with Aducanumab, I have less insight. In our family experience AD occurred within the context of nearly complete health; there were virtually no other comorbidities involved- except for seizures that developed in advanced illness that were possibly directly related to AD progression. When I saw all of the medications that some of the patients were on who experienced side effects from Aducanumab (from the FDA adverse reports website) I was surprised. Within a clinical trial context it is not difficult to imagine that Aducanumab could be administered with relative safety (considering exclusions, high level expertise etc.). When you bring it out to the wild/the field life becomes much more complicated. The longer term view of this is that people could be treated much much earlier at a time point in which such comorbidities were likely not present. One might expect that many of the typical MCI patient or early AD patient might not have such complex comorbidities.

With respect to paying the bill, it is not obvious to me that the best policy continues to be not to pay the bill. This idea that actually confronting the AD problem directly and with firmness could ultimately turn the tide. Once the $5.40 crowd realize that they aren't paying $5.40 but $355 billion and exponentially compounding, there could be a parting of the waters. Banks were too big to fail; Alzheimer's is too big to ignore. I have learned from personal misfortune that ignoring small problems (leaky roof) leads to much more expensive solutions. At some point the mind virus might go viral that spending $100 billion on AD treatment will offer enormous short term payback. The basic idea is to let the capitalist system do what the capitalist system does so well. Give them the money and let them do all the needed background research that can lead to better treatments and better patient identification. Potentiate the cure. My impression is that we are already there. We have already reached the critical mass where spending more for AD means spending less for AD even over a shortish time horizon.

The big cost reducer would be bringing the 50 million e4s and the 10 million e44s ( and possibly the 5 million e444s as of the latest GWAS). Once mabs go to a lifestyle medicine with lifestyle pricing and lifestyle safety, the $355 billion compounding yearly cost would over the medium term recede. There is a mountain of cost perpetuity that could rapidly change to a cash cow. When the sociopolitical system recognizes how much of an expense reversal is possible with AD, the protests could rapidly shift in favor of treatment funding.

Personally I am inching towards this pre-treatment strategy. With a nice safe mab such as Lecanemab and with the right price point, it would be difficult not to seriously contemplate such treatment. From my family experience, it is clear that AD begins long before stark cognitive symptoms are present. As I noted earlier on thread, though I will repeat for emphasis, our loved went back home over a decade before an AD diagnosis and yet none of the inner circle of friends and family knew who our loved one was anymore. You do not need to be tested with the MMSE to know that there is a cognitive problem in AD. Other prominent and cognitively important brain structures (e.g. the hippocampi) are destroyed years before symptom onset. Why wait for such progression before acting? The next generation of AD biomarker probably should be exactly such brain structures and should be allowed as the basis of FDA approval. There might not be any obvious cognitive benefit as reported in cognitive testing, yet it is nonsensical
to consider that such brain changes would not have impending effects on mental well-being.

Regarding the magic bullet idea, I am less enthused with the insistence that cognitive benefit needs to be demonstrated with the mabs. This seems to me to have been what has needlessly delayed AD clinical treatment advance. The mabs are treating the upstream disease driver. This should effect everything downstream (especially when given early enough). To potentiate a cure for AD, removing this driver should be a strategic priority. Once the driver is removed, all sorts of downstream treatments would be expected to further enhance the effect. There are now a wave of these downstream treatments reaching shore. Ironically, the CMS rejecting the upstream disease driver could then lead to endless such downstream treatments being needed-- a veritable hydra head of treatments could be needed when the upstream problem is not addressed right from the start. there might be upwards of ~10 such downstream treatments that could be needed.

What we have seen with the ecological trials was that nano-dosed endogenously produced Aducanumab was all that was ever required to maintain superior cognitive performance throughout life. An entire closet of downstream treatments were never needed. From this perspective, mabs can be seen as the best value for the money because in the right context they are all that is needed.

With respect to the dangers of Aducanumab, the FDA considered it safe in its accelerated approval and did not require special monitoring as it is allowed to insist upon. I found this regulatory decision somewhat unexpected.
During the phase 3 trials there was no mortality assessed to be associated with Aducan treatment, though the
FDA Briefing Documents II did report some troubling patient incidents.

The CMS appraisal of mab safety did not consider the contextual quality of the risks involved. Progressing through to early AD represents substantial risk. When our loved one progressed through to moderate AD and needed to go to hospital, almost immediately anti-psychotics were prescribed. These anti-psychotics were the subject of a massive (the largest in history) class action lawsuit in the context of AD because of the substantial mortality risk involved in the use of these drugs in these patients. Yet, within the typically resource constrained environment of typical modern hospitals chemical strait jackets are the goto treatment of choice notwithstanding the potentially severe consequences. Without such contextual background, some pristine remorse free option for a no risk paradise can
be presented when no such paradise option is available. Given the massive treatment benefits reported for the responder class in the aducan long term extensions which constituted 1/3 to 1/2 of originally enrolled phase 3 patients one should expect that the net mortality effects across responder classes must overwhelmingly favortreatment. Those patients who were either placebo treated or did not respond to Aducanumab (the emerging reason for such non-response is slow amyloid removal and/or beyond treatment high tau) would be those not expected to survive.

I do not see mabs as false hope so much as a potentially highly beneficial treatment option. The CMS completely ignored the evidence that a responder class has been observed. As noted previously on thread, there is a largish subgroup of between 1/3 to 1/2 of treated patients who apparently do not progress over the long term. That is quite startling; so much so that I still can hardly believe it. The thread has focused too much on -0.39 CDR-sb and not enough on what reasonably could be described as a cure for Alzheimer's. The science is not quite at the stage where this responder class can be identified before treatment, though why should this matter? The patients who are long term responders will self-select through time for more treatment. The clinical trials can then be seen more as an illusion of non-success, when in fact there is a clearly present patient sub-group who receive large benefits. This responder class is usually completely invisible to the general public, though the FDA and clinicians are all too aware of their existence. The FDA has probably been aware of an AD responder class for over a decade. It then becomes more obvious as to why they would approve a drug such as Aducanumab: it would be immoral not to. Yet, people still thought it made sense to bet against the dealer.

In a treatment context, this would unfold as a patient being treated for about a year and then an assessment of response. If patient did not respond, then treatment could be discontinued. If the patient did respond, then treatment could continue and possibly large benefit could then be expected in the long term. This seems like a reasonable algorithm that the CMS could consider even now. Treat the patients over the long term who actually derive substantial benefit.

Throughout this thread I have had a pro-pharma stance. It is not that I cannot see the problems with the pharma model in other diseases, but that pharma offers substantial advantages in the Alzheimer context.
Pharma often charges ~$300,000 per year for drugs with minimal benefits and typically a range of side effects. It is not easy to be overly enthusiastic about such drugs.

Yet, with AD, pharma could offer compelling value to patients. AD develops over the course of decades and early treatment could essentially prevent clinical manifestation. The research that found that micro-dose Aducanumab endogenously generated did prevent cognitive
decline over the life-span. This introduces an entirely new and potentially much more lucrative pharma economic model: lifestyle AD treatment. Treat decades before clinical onset with a highly safe and possibly remarkably inexpensive medication that still generates large revenues. The CMS decision might actually drive this marketing perspective forward. Pharma typically is seen as predatory when vulnerable often very ill patients are charged massive amounts of money for treatment. In the new model, treatment would be more voluntary and would be in the context of much greater ability to outwait patents. Considering the truly massive potential markets for such a preventative approach ( 50 million APOE 4s, 10 million e44s ....), the clinical AD population might at some point be seen simply as a loss leader. Given the logic above, pharma potentially could be induced into a very pro-patient
stance, while at the same time satisfying the demands of investors. Pharma greed could largely be tamed for social benefit.

I am not overly familiar with the ReCode protocol, though my current thinking is that addressing the upstream driver with a mab, would then give more holistic protocols such as ReCode even a better chance of helping patients. It would seem that once we move through the mab debate, there will be very large benefits to patients who then also address downstream disease processes.
Last edited by J11 on Mon Apr 11, 2022 5:17 pm, edited 1 time in total.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by JD2020 »

There is a lot to your post and I cannot read it carefully right now. I do taxes, and 4/18 is bearing down on me. I scanned your response and I will read it carefully later. But overall, in your last paragraph, you say something that I think I've heard Dr. Bredesen say, which is that there may be a place for these types of drugs when combined with a protocol that removes the underlying problem that causes the creation of the plaque. That makes sense to me.

To me, as this drug is proposed to be used now, it is like a statin taken by an obese person who refuses to exercise or eat anything other than processed food, except with much more cost and dangerous side effects. Ultimately, the statin is just a bandaid that is not going to make the difference that needs to be made, and to me, this drug seems the same.

Based upon my limited knowledge, I don't think the FDA should have approved it. If CMS had approved it, we would be further down the path of Medicare insolvency for a dangerous drug that doesn't do much.

But as I said, I will read your post in more detail later. This is just first impressions so that you would not go without a response.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by NF52 »

JD2020 wrote: Sun Apr 10, 2022 11:16 am ...there may be a place for these types of drugs when combined with a protocol that removes the underlying problem that causes the creation of the plaque. That makes sense to me.

To me, as this drug is proposed to be used now, it is like a statin taken by an obese person who refuses to exercise or eat anything other than processed food, except with much more cost and dangerous side effects. Ultimately, the statin is just a bandaid that is not going to make the difference that needs to be made, and to me, this drug seems the same.

Based upon my limited knowledge, I don't think the FDA should have approved it. If CMS had approved it, we would be further down the path of Medicare insolvency for a dangerous drug that doesn't do much.

But as I said, I will read your post in more detail later. This is just first impressions so that you would not go without a response.
Hi JD2020,

I admire anyone who can do taxes for more than themselves, which must be great mental exercise for the brain, if not great for your sleep for these months. I happen to believe that Aduhelm poses a high risk (about 44%) of ARIA-E for ApoE 4/4 carriers, and more importantly that several current drugs in Phase 3 clinical trials (lecanemab/BAN2401 in AHEAD 3 and AHEAD 45 and CLARITY) and donanemab (in several TRAILBLAZER studies) and ALZ-801 (in APOLLOE4 for 4/4 carriers with MCI/mild AD) show far less or no ARIA (ALZ-801 is a pill) and far greater evidence currently coming out and likely to increase of "meaningful clinical benefit", as well as documented and persistent reduction of amyloid beta below "positivity" thresholds and reduction of tau in significant, but not yet fully measured, levels.

I have to take issue with your hypothetical patient seeking Aduhelm or any other drug. I have met individuals or spouses of people in the Aducanumab trial with MCI or Mild AD who were nothing like your "obese person who refuses to exercise or eat anything other than processed food". I know many others who have been in prevention trials for people with normal cognition, including several on this forum. Neither those with AD or those at risk, fits your profile. They include:

MDs and PhDs/ Judges and Lawyers/former CFOs/ Journalists/Presidents of non-profits
Ministers/Competitive bridge players/Vegans/Intermittent fasters/Active caretakers for preschool-aged grandchildren

In fact, it is highly unlikely that the person you describe would have been eligible for a clinical trial, because they might have unstable coronary artery disease, history of TIAs or strokes, Type 2 diabetes, uncontrolled high blood pressure, etc. When I have been in a clinical trial, I am asked every three months how often I exercise to a moderate or vigorous level, how often I eat smoked foods, or drink alcohol, how much sleep I get. I also do several hours of cognitive tests and daily functioning questionnaires, give a urine sample and have about 10 tubes of blood taken. I know of someone who does that now 300 miles roundtrip monthly---without knowing whether they are in the placebo arm or study drug arm.

While any drug approved for broader use could (and should) be more inclusive than clinical trials, I doubt that the hypothetical person you describe would be willing to travel roundtrip every two or four weeks for an one-hour IV infusion, followed by 30 minutes of monitoring, updated medical history every 2 weeks for any changes, MRI and PET scan before starting and approximately 5 MRIs in the first year to monitor for ARIA (for now at least)--and to do that for anywhere from 26 weeks to 2 years, depending on the initial level of amyloid and the drug used.

And as I am a statin user also, with a father who died of cardiac arrest at age 67 and a genetically inherited high lp(a) score and extremely high LDL particle number, the fact that I am not obese, exercise daily, (including hauling fifteen 43 lb bags of mulch today) should give you pause before assuming the worst of statin users. One person I know and treasure has never weighed more than 100 lbs in her life, had a cholesterol score of 300 at age 18 and is the first in her family to make it past the age of 55 alive--in part due to the 80 mg/day of statin taken for the last 50 or so years.

Here is a chart and some results from 2021 and 2020 on the strongly differential risk of ApoE4, including early "seeding" of amyloid beta which supports the need for these drugs, regardless of lifestyle: [emphasis added]:
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Association Between Apolipoprotein E ε2 vs ε4, Age, and β-Amyloid in Adults Without Cognitive Impairment

I have been fortunate to virtually attend several presentations by Dr. Oskar Hansson. MD, PhD of the University of Lund in Sweden. He is likely the leading authority on use of brain imaging to determine biomarkers of both Alzheimer's pathology over time in cognitively healthy individuals and is actually a proponent of directly attacking the many pathways by which ApoE4 produces both amyloid beta and other causes of dementia. Here's what he says about ApoE 4, noting that amyloid beta is associated with decreasing scores of the PACC (commonly used composite score of change over multiple administrations in clinical trials); the difference is that ApoE 4 carriers get to elevated amyloid a decade over more before non-carriers.
The protective outcome of carrying an ε2 allele in the presence of an ε4 allele against Aβ accumulation may inform future development of disease-modifying Alzheimer disease therapies...The association between Aβ and decreasing Preclinical Alzheimer Cognitive Composite scores did not differ by APOE genotype, and the reduced performance on the Preclinical Alzheimer Cognitive Composite in APOE ε4 carriers compared with noncarriers was completely mediated by Aβ (unadjusted difference in composite scores between ε4 carriers and noncarriers = –0.084, P = .005; after adjusting for 18F-florbetapir = –0.006, P = .85; after adjusting for 18F-florbetapir and cardiovascular scores = –0.009, P = .78).
From Alzheimer's Research and Therapy, Nov. 2020: "OR" in the quote below stands for Odds Ratio: Having two copies of ApoE 4 increase the odds of having Alzheimer's by almost 15 times versus someone who is ApoE 3/3. Together ApoE 3/4 and 4/4 represent 56% of those with AD; whereas the 75% of people with ApoE 3/3 represent less than 44%.
When broken down by the specific genotype frequencies, APOE3/4 individuals represent about 21% of the cognitively normal Caucasian population, vs. about 41% of Caucasian AD patients (odds ratio [OR] 3.2), whereas APOE4/4 individuals have a genotype frequency of about 2% in the cognitively normal Caucasian population, vs. about 15% in the AD-affected Caucasian population (OR 14.9)
APOE4 is associated with cognitive and pathological heterogeneity in patients with Alzheimer’s disease: a systematic review

We do need the right drug and I believe the revised CMS decision will help with that. The people who will progress from MCI or mild AD to moderate AD while they wait for the right drug should not be castigated, any more than someone who needs a tax professional to do their taxes should be.
4/4 and still an optimist!
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