Celebration Thread! Biogen is going to the FDA with Aducan.

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CindyM
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Postby CindyM » Fri Oct 15, 2021 6:59 pm

dee wrote:I have almost no idea what most of this says. But it sounds very promising. Thank you! I needed some hope today. In fact, I joined the forum instead of just being my normal lurker self so I could say thank you. :)

Welcome to the forum, Dee!
Thank you for reaching out to us and joining the discussion. You're in the right place to learn about APOE4 and see that there is hope in prevention and reversing Alzheimers disease!

Since you are a new poster, I'd like to share a few links that will help you navigate this sight.

The primer is a fantastic resource which explores areas such as the science behind the ApoE4 gene and the lifestyle factors that impact its expression.

Our how-to guide is another helpful resource on how to search for topics and how to subscribe to topics of interest and more.

If you feel like sharing, we invite you to introduce yourself in our stories.

Feel free to reach out any time!

Wishing you well,

CindyM

J11 wrote:The phase 2 Lecanemab results for the APOE epsilon 4s were stunning. Admittedly this is a delayed headline (almost reading history than your newspaper as this result was published in April), though it is still worthwhile to highlight these results.

The bottom figure from the above post is an attempt to convey the information in Supplementary Table 16 of the article in a more easily understandable graphical format. What we can see is that the APOE epsilon negatives did not appear to have much of a response relative to placebo on ADCOMS for any of the doses. However, the APOE epsilon positives appeared to have a quite large % response versus placebo. At the highest SUVR on the left ~ -0.31, the percentage reduction in decline was ~50%. That is worth repeating:

There was a ~50% reduction in decline on ADCOMS at 18 months for APOE epsilon 4s in the phase 2 clinical trial for the highest treatment arm of 10 mg/kg twice monthly (n=45 treatment; n= 168 placebo).

Slowly Alzheimer's progression in epsilon 4s by ~50% in this population of early mild AD patients constitutes a near functional cure. This represents a substantial treatment advance. Extrapolating this result forward one could imagine that with such a magnitude of slowing of progression the most severe stage of AD would likely not manifest for those somewhat younger than their expected age of cognitive decline onset. It is startling to recognize that for the ~50 million American epsilon 34s, the vast majority could have a clinically proven treatment option that would prevent their manifesting AD.

Nevertheless, this is somewhat speculative as the highest dose that achieved nearly 50% reduction in decline only had 45 APOE + patients. Nonetheless, the next lower dose of 10 mg/kg once monthly with n=218 recorded a 23% reduction in decline. Table 2 from the article further notes that the Bayesian ADCOMS at 12 months for the combined group of APOE epsilon plus and minus had a 32% decline in progression versus placebo. One has reason to assume that much of this benefit would also be driven by the e4+s as they demonstrated almost all of the benefit at 18 months. 1200 of the Phase 3 patients in Clarity now have 12 months data, though perhaps only half would be epsilon 4s.

This is extremely positive news!

The lecanemab results appear to be driven almost entirely by the epsilon 4s. They are not receiving a benefit of ~20% as reported with Aducan, but closer to 50%. Perhaps with some data filtering these numbers would increase. For example, what were the results for the patients with more amyloid clearance? How could the placebo be corrected for the hidden placebo treatment effect? or the rapid progressors or non-progressor placebo? ...

The upper figures in the previous post highlight the superior performance that was also noted in the 302 Aducan trial for e4+s. It is becoming increasingly unclear whether epsilon 4s actually do receive benefit from anti-amyloids. Combining these two subgroups merely obscures the large difference in response. If Clarity had pre-specified e4+s as a top-line result, the trial might have already been halted for success. The e4 results are large. It does seem that some of the e4-s are likely benefiting though it could take some effort to determine exactly the covariates that determine their response.

Also highlighted in the figure for the 302 results is the consistent statistical significance across all measures for the high dose arms for the e4+s, while all of the high dose arms in the e4-s are far wide off such significance. Also the 0.53 CDR-sb gain versus placebo for the high dose for the e4+s is somewhat better than the overall 0.39 gain for the 302 high dose arm. Yet, 0.53 reflects closer to a 30% gain for Aducan versus ~50% gain for the high dose e4+s on Leca in the phase 2. Perhaps this difference relates to the higher SUVR result for Leca and possibly as well as the cleaner trial results due to reduced side-effects etc..

Given the above, It would be very helpful if we could find an early approval mechanism for leca. There is a large dominance of naysayers in the regulatory process. Considering the near perfect 100% failure rate of AD drugs for almost 20 years this is possibly inevitable. However, the results above suggest that we need some more yea sayers. Leca has shown some large positive benefit for epsilon 4s and realistically this would seem to offer substantial benefit. Perhaps let Clarity run to March which would be 12 months of full enrollment of 1800 patients; then begin the up titration for the epsilon 4s who were on placebo while maintaining randomization and then open up Right to Try on a profit neutral basis until full approval were granted. Of course, Depending upon what the regulatory time line is this might not be needed. It is not clear to me whether the plan is to approve leca even while Clarity is ongoing. The rolling submission for leca only mentioned including safety data for Clarity.

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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Postby J11 » Fri Oct 15, 2021 9:49 pm

dee, thank you for stopping by the thread and leaving a comment.
Very much appreciated.

Yes, if you really do not want to read the endless back posts from the thread, at this time my basic message is one of cautious optimism. There is wave of anti-Alzheimer treatments that will readout over the next ~12 months that could (likely will) redefine the clinical course of AD.

I am not totally sure how I'll be able to keep up with it all. This is the golden age of AD clinical medical development. As you are aware (referencing your introductory post that described your personal connection to AD), coping with dementia without any disease modifying treatments is extremely difficult. We are now seeing treatments that appear to have substantial treatment effects (in particular epsilon 4s).

In fact, I am somewhat more than cautiously optimistic about this thread right now. For some reason in the last 24 hours there has been a lift-off in the view count. This is the best day ever on thread! Yeah! Perhaps everyone is getting ready for our two year anniversary celebration approaching in the next two weeks. It could also be that the grammar police is tsk tsking the shockingly low level of English composition that is regrettably demonstrated on thread. Opps! Whatever it is, I'll interpret the thread's liftoff in a positive way.

Some general comments that I hope you might feel helpful.

I think it is a very good idea that you have decided to investigate your dementia genetics. I realize that many people might not want to know about such things, though it also can be liberating and quite useful. It hasn't been that long since epsilon 4 testing expensive and difficult to access. Now that people do know their status (especially the 44s) this forum and an entire social political force has emerged to try and speed the trajectory to a cure. When people are aware that dementia likely will become part of their life, they can become highly motivated to help change the trajectory; as is demonstrated by the strenuous contributions of many on this forum.

I have been a strong advocate on forum for genotyping, exom sequencing, and now full genome sequencing. Full genome sequencing has now been reduced in price to ~$300. This represents a fantastic deal. I have just run my 23andme results through the impute.me site and I have found even more highly insightful polygenic results. impute.me provides thousands of phenotypes.
This is another reason for a personal celebration. My genome is now unlocking and I can see an entirely new life path emerging for me. Genetic knowledge is now ready to profoundly restructure our society. I will be fascinated to see how this unfolds.

Knowing what you are up against medically can be so critically important. Before the polygenic scores we were always rushing off to
the hospital for some medical crisis or other. One time a family member suddenly experienced intense abdominal pain and a large (large sized grapefruit) "growth" (non-cancerous) had to be removed in emergency surgery. Other examples could also be cited. With the polygenic scores we can see all of these medical problems written in our genomes. We are hopefully through forever with ER medical management. Understanding what your medical problems will be by carefully scrutinizing your genome has to make sense. The genetics of Alzheimer's is now becoming ever more well refined.


Many of those on forum are highly aware of practical ways to address AD. Interestingly, the forum leaders have played a central role in constructing their own non-pharmaceutical Alzheimer treatment plan. I am not fully informed about their efforts, though I am very impressed by their initiative. My focus has recently been more concentrated on pharmaceutical development for AD because it is more grounded in exacting and reproducible science. There is a mountain of non-pharmaceutical research, though typically even high quality initial findings are unable to advance through the trial process. It is not so much that these ideas are wrong, but simply that the investments involved become prohibitively expensive.


So for an action plan:

1. Get genotyped.
2. Read up on the forum primers.
3. Buy a gamma light, and consider other amyloid lowering strategies (better sleep, curcumin etc.).

Thank you for posting dee and offering encouragement!

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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Postby NF52 » Sat Oct 16, 2021 4:35 pm

Hope this helps, J11:
J11 wrote: I have looked on alzforum for the lecanemab article on September 10, though I was unable to find it. Might you supply a url?
https://www.alzforum.org/therapeutics/lecanemab

... From what I remember there seemed to be some confusion about the enrollment from China into Clarity. They were continuing to enroll Chinese, even when the trial had apparently completed enrollment?
Haven't seen that, but of the 259 study sites (!) most appear to be in the US, with others in Canada, Australia, China, S. Korea, Japan, Germany, France, Russia (one site) Spain, Singapore, Sweden and the U.K. (Britain only). I assume they are looking to get data on diverse ethnicities and populations so that they can apply to the EU and countries other than the U.S. if the data looks good.

This April 2021 article in Neurology reports on the participants as of June 2020:
As of a data cutoff of June 22, 2020, a total of 801 subjects were enrolled in CLARITY AD. The median age of subjects was 73 years (range: 50–89 years), with 83% of patients 65 years of age or older. Overall, 51% of subjects were female and 78% were Caucasian.
BASELINE CHARACTERISTICS FOR CLARITY-AD: A PHASE 3 PLACEBO-CONTROLLED, DOUBLE-BLIND, PARALLEL-GROUP, 18-MONTH STUDY EVALUATING BAN2401 IN EARLY ALZHEIMER’S DISEASE (3021

My understanding of the AHEAD trials of lecanemab is that in the US at least, all data is centralized and assessments are recorded for quality and uniformity of administration. Similarly, since CLARITY- AD specifies a positive Amyloid PET scan, with a specific cut-off for "elevated', and specific inclusion criteria, I would assume that the data should be fairly uniform in capture--but then I'm an optimist!...
I am interested in the titration schedule for the phase 3... Basically, patients are at full dose after ~2 months?
Yes; patients are at full dose after 2 months in both Phase 3 AHEAD 3 (intermediate amyloid and normal cognition) and Phase 3 AHEAD 45,(elevated amyloid and normal cognition).

One difference is how often they have to come in: AHEAD 3 participants have monthly infusions (drug or placebo) for the entire 216 weeks of the trial; AHEAD 45 partipants have biweekly (every 2 weeks) infusions for the first 96 weeks, to get the amyloid down fast, and then switch to monthly infusions until week 216. You can see the details in the Arms and Interventions section of the Clinicaltrials.gov: AHEAD3-45 Study...
What I only recently realized was that lecanemab could possibly readout much sooner than I had thought...It certainly has me wondering whether at some not distant time in the future the trial could simply be stopped for success....
The CLARITY-AD trial reports this on https://clinicaltrials.gov/ct2/show/NCT03887455?type=Intr&cond=Alzheimer%27s+disease&titles=CLARITY-AD&draw=2&rank=1"
Estimated Primary Completion Date: September 8, 2022
Estimated Study Completion Date : August 29, 2024
Since they are fully enrolled as of about Spring 2021, it's likely that they will need at least a full 2 years to finish the 18-month study and the analyze results. Even "short" studies have enormous data collection and analysis requirements!
Yes, with the 3-45 Phase 3, I can see the logic in moving to the next generation of psychometric tests....What I am unsure about is how much clinical evidence might be expected to demonstrate this? Proving that anti-amyloids stop neurodegeneration at the early stage might take 5-10 years
"Proving" is tricky; having "a pre-determined statistically significant clinical benefit with an appropriate sample size" is assumed in the AHEAD trials, to require about 4 years--since a significant percentage (not a majority) of people with "elevated" amyloid in the AHEAD 45 are expected to show clinical decline over 4 years, even if they do not yet meet the requirement for a diagnosis of MCI or AD. The AHEAD-3 group is far less likely to show clinical decline over 4 years; the Primary outcome there is a change in Amyloid biomarker on PET and the secondary outcome is a change in Tau biomarker on PET. In effect, I assume if CLARITY-AD shows a benefit in those with MCI and AD and AHEAD-45 shows a clinical benefit in those with normal cognition, they would argue that safety and efficacy in removing amyloid and tau is an appropriate "secondary prevention" of clinical decline at the earliest signs of AD biomarkers.

Enough to chew on for now!
4/4 and still an optimist!

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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Postby J11 » Mon Oct 18, 2021 8:42 pm

NF52, I had this half-formed memory about enrollment in China being somewhat odd. Here it is. The url below is the Clarity trial.
Here is the odd part scroll down to the History of Changes. Notice how on the April 8, 2021 Submitted Date that many clinical trial sites for Clarity opened in China. What I found so unusual about this was that the clinical trial actually stopped enrolling in March. Yet, even now the clinical trial gov site is reporting that it is open for enrollment.

https://clinicaltrials.gov/ct2/show/NCT ... w=2&rank=3

The readout on Clarity and how the rolling submission will play out is confusing me. With the guidance on amyloid as a biomarker could approval for lecanemab be granted before Clarity is completed? When should the rolling submission be finalized with the FDA?
This is very exciting as soon as the submission is submitted, we would approach a 6 month count down to possible approval.

Perhaps the rolling submission could include results from the trial while it is in progress. From the previously reported results from the lecanemab phase 2, it should not be unexpected that the phase 3 could announce large gains for the epsilon 4s especially. They would not seem to need the full 1800 patients in for a year till next March to announce such findings. It will be very difficult to wait and wait for these results and this is all the more true as the FDA has given a strong indication of what their regulatory stance is on anti-amyloids. Aducanumab's approval has largely been vetoed by other stakeholders. The seemingly obvious counter-counter strategy to reinstall the policy lean would be find an early approval route for lecanemab.

With the secondary prevention of lecanemab, I somewhat surprised that there is not more consideration of the neuroanatomical pathology as a potential marker. From what I remember, there is clear neurodegeneration on brain scans years before the clinical progression to MCI. Wouldn't it be enough to simply accept prevention of neurodegeneration as an early marker before the clear cognitive problems emerge? I am not sure why everything needs to be about using cognitive measures. Amyloid removal as a biomarker for AD can be easily be demonstrated. Preventing the loss of brain structures in pre-AD with aducan treatment might be equally as easy.

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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Postby J11 » Tue Oct 19, 2021 7:23 pm

One of the ideas from an earlier post that I want to explore further is the "invisible hand" that has been at play with aducanumab and the anti-amyloid treatments. Adam Smith's "invisible hand" from economics for a student can be perplexing to divine its meaning. Clearly, one expects more of the dismal, though level headed, study of economics than to appeal to the mystical and metaphorical concept of an "invisible hand". Yet even in our rational day and age "invisible hand" is perhaps as good as it gets.

How does all of this apply specifically to aducanumab? Well as I noted earlier, I pulled that rope as hard as I could for our side and everyone else pulled as hard as they could for their side as well. I thought aducanumab was the best choice that we had within our near term window of proximal opportunity. I realized that lecanemab was within sight though it could be somewhat out on the horizon. I had thought that the main referee here was the FDA. They were the ones who seemed to be nominally given the power of decision. Surprisingly, though as we have seen, even with approval of aducanumab other stakeholders have been able to keep on pulling for their side and deflect the full practical meaning of the approval.

Nevertheless, the stale mate that has resulted can be understood to be the optimal outcome. The treatment was approved, breakthrough designations were granted to several anti-amyloids and these now seem to be on the way to a speedier approval than would have occurred otherwise. Everyone is now highly aware of what needs to happen for approval: amyloid biomarker with some confirming cognitive readouts along with strategies to improve safety.

And all of this happened without a supreme government commission. There was no obvious super-authority that orchestrated the entire performance. If anything, the FDA was in this position and then other powers overturned their authority. So much for control freaks. Basically, an organic organizational structure spontaneously emerged and managed to create what I think is a fairly brilliant workaround.

Going through the process of setting up a commission to make sure that this never happens again would seem somewhat counter-intuitive. What went wrong? Non-structure came up with the right answer. If we worked really hard at it we could probably create a highly dysfunctional organizational system that could create a very bad answer. Is that what we want? Do we really want to work hard to make worse outcomes? One might reminisce of the previous century which had some superlative exemplars of such planned failures. Why not marvel instead at the mysterious and magical "invisible hand", though perhaps not as open to rational explanation as a rigid bureaucratic hierarchy nonetheless has the undeniable simplicity of having been highly effective in deciding how to manage aducanumab.


“It is not from the benevolence of the butcher, the brewer, or the baker that we expect our dinner, but from their regard to their own self-interest. We address ourselves not to their humanity but to their self-love, and never talk to them of our own necessities, but of their advantages”

"The rich ... consume little more than the poor, and in spite of their natural selfishness and rapacity, though they mean only their own conveniency, though the sole end which they propose from the labours of all the thousands whom they employ, be the gratification of their own vain and insatiable desires, they divide with the poor the produce of all their improvements. They are led by an invisible hand [emphasis added] to make nearly the same distribution of the necessaries of life, which would have been made, had the earth been divided into equal portions among all its inhabitants, and thus without intending it, without knowing it, advance the interest of the society, and afford means to the multiplication of the species. When Providence divided the earth among a few lordly masters, it neither forgot nor abandoned those who seemed to have been left out in the partition. These last too enjoy their share of all that it produces. In what constitutes the real happiness of human life, they are in no respect inferior to those who would seem so much above them. In ease of body and peace of mind, all the different ranks of life are nearly upon a level, and the beggar, who suns himself by the side of the highway, possesses that security which kings are fighting for."

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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Postby J11 » Wed Oct 20, 2021 7:09 pm

There is some big news about the breakthrough designations. I suppose it is not so much news per se but a clarification. An article on alzforum today noted that Clarity is a C-O-N-F-I-R-M-A-T-O-R-Y study. I had some reading comprehension problems with CONFIRMATORY. Just as aducanumab is supposed to have a confirmatory trial completed sometime in the next 9 years. I have been very unclear about this aspect of the FDA process. Basically, submit the BLA and then the confirmatory trial can report back sometime or whatever?

I have questioned several times on thread how the Clarity trial will relate to the rolling submission. From what I understand now, the main submission for lecanemab is the phase 2 trial. It seems as though the submission would be considered complete even without the readout of the Clarity trial. Roughly, submit all of the phase 2 results in the rolling submission and then the confirmatory study could just drift forward. Obviously a fair dose of skepticism is warranted that such clean separation between the phase 2 and an interim peek into the phase 3 would apply in the real world. The expectation is the Clarity trial could provide strong additional evidence
for lecanemab and the anti-amyloids. How close might we be to a time where the confirmatory trials are no longer even thought necessary?

Nonetheless, this is an exciting clarification. It means that the time line for lecanemab might be somewhat closer than I had expected. There could be some more slow walking behavior to move us closer to the September, 2022 close out of Clarity, though the actual approval (conditional) decision does not appear to depend on its actually completing the phase 3. I am now greatly looking forward to more background research for lecanemab. Perhaps another FDA Briefing Document (hopefully without joint collaboration) will soon be posted online. This is exciting! Aducanumab moved the ball upfield. I am very interested to see what lecanemab can demonstrate.

Another exciting piece of news that has went largely unreported (here at least) is the success of semorinemab in mild to moderate AD in a large phase 2 trial called Lauriet. It slowed decline by 44% on ADAS-cog. I thought that this one had not worked out. When I checked up on this a year ago the Tauriel phase 2 in prodromal and mild AD did not achieve its target.

Notice the tricky anagram with Lauriet and Tauriel. I tried out an anagram solver and the only official 7 letter solution is uralite-- a hornblende formerly called actinolite. The interesting 6 letter words are rutile, retial, and arteli.

Semorinemab is exciting news! We have tau mabs on board already? I have posted all of these hundreds of posts for amyloid mabs because well new treatments don't pop out of nowhere, now do they? The amyloid mabs can trace their lineage back to Elan's 1792 from 20 years ago. Here we are 20 years later after numerous I guess you could say "could do betters" and we are still struggling
to see a breakout. And along comes a tau mab and it nails it on close to the first try? Not bad.

Combination or sequential treatment then starts to make quite a bit of sense. Treat with an amyloid mab to clear out the initiating event, and when/if progression occurs rotate to a tau mab? Not a bad plan. The tau mab might also not have the side effect concerns related to amyloid removal.

I will need to get up to speed on these tau mabs, though it does seem somewhat surprising to me that they would lead off with the non-success of Tauriel in the prodromals and early AD patients. With the anti-amyloids the strategy to emerged was to go earlier before the disease had progressed beyond what was thought as a point of no return. The tau mabs offer the more optimistic perspective that they will be able to treat once the anti-amyloids lose effectiveness. How was this logic missed? It seems obvious (admittedly in hindsight). Just ask J11, I am here to help!

These tau mabs could help reduce that panic that I have noted on thread that can develop with patients as they feel that they might be inside the event horizon of unstoppable AD progression. In an earlier post I noted how aducanumab apparently demonstrated an ability to curtail out of control AD progression in those who had good clearance in the 18 month phase 3s. Those who did not have good clearance in the phase 3 had this runaway rapid progression into moderate and possibly severe dementia. That clearly would be a substantial concern for those coping with dementing illness. It appears that the tau mabs could offer a second line of defence if/once the front line anti-amyloids were breached. This development should be a considerable relief for everyone in the dementia community.

Moreover, these tau mabs might have a clearer path to approval. If the ARIA problems are not a problem for them, then it seems like green lights as far as you can see. These could create a large scale money drop and spark a dementia perpetual research machine with a solid economic foundation.

I realize such money talk is not exactly popular, though there is this simply reality that treating illness involves risk and an expected payback. Almost every new treatment for AD in the past 20 years has been unsuccessful. A 100% failure rate? Such odds can be somewhat discouraging. It can also drain away the needed resources to move things forward. Many times in biotech/pharma there needs to be at least some glimmer of possible success to keep up the spirits. If tau treatments (also amyloids and perhaps others) could at least offer real promise and suggest that there could be some reward at the end of the money pit, then is a big win for us.

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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Postby J11 » Mon Oct 25, 2021 6:27 pm

Happy Second Thread Anniversary Everyone!

It has been a great 2 years for the thread and for Alzheimer's clinical progress.
2 more years! 2 more years!

This has all been the warm-up for the party.
We could now be moving more from the party planning stage to the party celebrating stage.
I am greatly looking forward to 2022!

I must admit that when I look back on the inaugural thread post, I am not entirely sure where I was going with some of my comments. One of my more glaring missteps was with predicting that all the yelling and screaming would have been over not long after the start of the thread; hmm, the yelling and screaming continues-- Even now. I had thought that with even 3 more months of results form the aducan phase 3 trials that the numbers would rapidly stabilize and preclude further debate. What has happened instead is that once the patients migrated to the OLEs there has not been many updates. With the numerous large phase 3 clinical trials that are set to readout over the next ~ year perhaps the arguing will finally be over.

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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Postby J11 » Tue Oct 26, 2021 9:05 pm

Sometimes with anniversaries the most important part is the relief felt that it was remembered and that one could avoid the dog house. Yet, with this 2 year thread anniversary, I think it should be more of a week long celebration than remember and move on.
The progress made in the last 2 years towards a viable potentially breakthrough approvable pharmaceutical through regulatory channels is notable. As caregivers it can be so disheartening that there is nothing that will help, especially with AD there is this relentless decline that at a certain point can become alarming.

From my experience I would suggest though that it really should not be thought of like that. AD dementia has been a long term decline into total disability, though it is striking how well caregiving can adapt to the challenges. Before the era of enteral feeding pumps, simply maintaining nutritional intake likely became completely unmanageable. This is one clue that I have used to reveal suspected ancestors who developed AD. After about age 85, a feeding pump becomes a near necessity. In a pre-technology era such AD patients probably would not have been able to survive. In the current era, AD can be managed past such limitations.

There are a few items of interest that I want to post to the thread as a reminder of topics of future posts. Firstly, there is the wider pathological range of amyloid illness that does not seem to have been discussed enough. We have mentioned CAA (other brain amyloid) a surprisingly common feature of aging but especially present in AD as a co-morbidity. There are also other amyloidal based illness. Amyloid can show up in many other locations in the body. Apparently amyloid is even a feature of some types of cancer. I really start to wonder to what extent the anti-amyloids that we are interested in Aducan etc. might have a treatment role in these other forms of illness. For whatever reason though there has not been much discussion of such applications in the online chatter.

Secondly, another topic that has been largely overlooked on thread to date is the potential application of micro-dosing in pre-AD patients. It is surprising to me that this has been such a neglected aspect of the anti-amyloid dialogue. Microdosing (perhaps starting at 0.1 mg/kg) would seem a reasonable preventative strategy for millions of the worried well especially those with APOE epsilon 4 genotype. Clearly there is much less sense of urgency for these people and they should approach this more in the lifestyle category of treatment and probably wait it out during the next ~1 year as there is clarification of the properties of the current anti-amyloids.
It would be quite helpful if there were more efforts shown by the pharmas to signal their interest in this market opportunity. The same acrimonious struggle over pricing will likely be nearly absent from micro-dosing discussions as AD typically evolves over many decades. The choice offered will not be $56K per year forever. With micro-dosing, the economics could be highly favorable for patients while offering pharma a highly reasonable rate of return.

I was going to go to thirdly, though I think I'll call it with secondly.

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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Postby SusanJ » Wed Oct 27, 2021 12:06 pm

J11 wrote:The progress made in the last 2 years towards a viable potentially breakthrough approvable pharmaceutical through regulatory channels is notable. As caregivers it can be so disheartening that there is nothing that will help, especially with AD there is this relentless decline that at a certain point can become alarming.


Yes, it is disheartening for caregivers seeing the relentless decline. Thanks for all your analysis on this, because I don't discount pharmaceuticals from being part of a dementia treatment plan, even though recent research hasn't panned out. Realistically, many older folks can't follow the full Bredesen protocol, mostly due to finances. It's expensive and so much is not covered by Medicare. But an approved drug, that could make a big difference for many people if it comes on the market fairly quickly.

Happy second anniversary!

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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Postby J11 » Fri Oct 29, 2021 10:02 pm

SusanJ, thank you for posting your anniversary congratulations to the thread!

My basic hunch is that pharma is going to offer the non-symptomatic patients a very compelling value proposition. To date it has been all about "maximal wealth extraction" etc. and that is not overly helpful. What I can see though is the patients walking with a fairly large amount of consumer surplus in their pockets. As soon as this moves to pre-symptomatic (pre-pre AD) and the market is seen to be enormous but quite price sensitive, I could see the compromise emerge that anti-amyloids will be priced as a lifestyle treatment at compelling value. Otherwise these patients could simply wait out the patents, though if they had a reasonable offer on price then they would likely be motivated to treat themselves preventatively. Pharma would still make a large amount of money in such an indication.

The decades long pre-Alzheimer's stage is possibly one of the best examples where these putative patients could exert a substantial amount of consumer power to override near monopolisitic type pricing behavior. In our experience perceptible cognitive decline did not occur at the point of an AD diagnosis but decades and decades before. At some point we hopefully can move away from $56,000 per year pricing and think more about how these much earlier consumers might benefit from anti-amyoids. This returns the micro-dosing that I have suggested earlier on thread. I would greatly like to see the next step be made and declare clear markers of neurodegeneration (atrophy of the hippocampus, etc. as biomarkers for AD). As we have seen it is much easier to move biomarkers
then have unambiguous clinical trial results. With brain shrinkage, why not call that a biomarker with reasonable likelihood of predicting clinical course? How exactly could brain shrinkage in a critically important brain structure such as the hippocampi possibly be seen as anything other than a bad thing. This would push back the on label indication for anti-amyloids by many years.
This is an exciting aspect of the anti-amyloid story that could unfold once we have some more approvals.

Clearly when patients have reached the clinical stage and the decline is in progress, desperation does become part of the caregiving experience. The decline progresses and progresses like the income tide and you think that everything will be fine and then you move below some critical functional threshold (probably for most this would be the inability to walk -- MMSE ~~5.).However, my sense now is that such desperation (especially for the earlier stage patients perhaps now should be scaled back somewhat. There are a wave of AD treatments approaching and we are possibly nearing the turning of the tide. For patients towards the earlier spectrum of impairment we might have already reached escape velocity from the profound level of impairment that has been inevitable with AD through all of recorded time.

There is so much good news swirling around AD lately; really is a great feeling.
For quite a while -- I guess for about a 100 years -- the prospects for an Alzheimer's clinical advance seemed so remote. It remarkable how many unsuccessful clinical trials there have been over the last 20 years; before aducan non-success approached 100%. That proportion of setbacks clearly could wear down one's optimism. However, now good news is popping up everywhere. I can hardly keep up,

In the last few days Lilly announced that they are going to start a phase 3 trial with aducan vs. donanemab! It is just like I thought: they are calling it with a completion date of ~late 2022. Awesome! No 5+ years. Possibly under a year? As was mentioned earlier on thread the newer anti-amloids -- lecanemab and donanemab can rapidly remove amyloid and the clinical benefit can then show up quickly. Combine that with possibly tau imaging and tau selection and you might begin to see AD trials happen at close to warp speed.


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