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.

Postby J11 » Thu Sep 30, 2021 7:47 pm

Leca 5 Bayesian Reduced.JPG
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Postby J11 » Thu Sep 30, 2021 8:04 pm

Now that Leca is starting its rolling submission we should reacquaint ourselves with the background research.
Compared to Aducan, Leca should be a walk in the park.

With Aducan we had to work through the 301 high dose being in high earth orbit above all the other Aducan results, the PV-4 confusion (which I must admit I still have not fully resolved- they changed the dosing in the middle of the trial, the patient accrual was different, the placebo decline was different between 301 and 302-- err! they were supposed to be identical trials!), oh how could I possibly forget, the trials were called for futility and then were uncalled and 302 hit all of its top-line primaries.

Leca is going to be BORING! They missed their top-line result (some might object nasally)! It all depends on where you draw the line for failure in life. The threshold that they established in the phase 2 was an 80% probability of being 25% better than placebo. They missed this target; they only achieved 64%! It no longer seems that relevant to even think in terms of merely being better than placebo. Goal posts have been moved. High dose APOE4s had a 99.2% chance of being numerically better than placebo and in fact achieved ~50% reduction in cognitive decline versus placebo. This was with a mere 45 patients in the APOE high treatment arm. One of the few migraine moments with leca is related to the decision to stop dosing into the high dose APOE arm for safety. The numbers for the trial likely wold have been even better than reported if the trial had been allowed to go to plan. Leca appears to be able to reduce cognitive decline by ~30% as a topline result. Figures above are the endlessly reposted correlation plots; leca is very very on the regression line.

Fortunately, there could be much less drama to be concerned about with leca.

https://alzres.biomedcentral.com/track/ ... 0813-8.pdf

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

Postby J11 » Thu Sep 30, 2021 8:06 pm

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

Postby J11 » Thu Sep 30, 2021 8:41 pm

Leca is an impressive treatment and from what I can see already deserves a provisional pass. Ideally it would allowed to be marketed as early as possible because it is a considerably better product than Aducan. Almost feels like I could return to the lake and let this all sort itself out -- Vacation!

However, there are a few asks that would enhance the strength of leca. Near the top of the list would be an alternative titration schedule. The figure above was highly surprising to me. It shows the Aducan ARIA events by number of doses. The top highlighted rectangle on the right (orangey yellow) shows the 3 mg/ kg doses in the titration and the rectangle below (in red) the 6 mg/kg doses
for the serious ARIA events. I posted this before, though I think it is reporting this, it is notable how many of the 29 serious ARIA events occurred with fairly modest doses. In fact, 24 of the 29 serious ARIA events happened during dosing with 1, 3 or 6 mg/kg. Remarkably only 5 of 29 occurred on what presumably would be high dose 10 mg/kg. A fairly obvious risk reduction strategy could be to consider an alternative titration scheme. For example, perhaps two 2 mg/kg doses could be added in between the 1 and 3 mg/kg doses. Perhaps 5 mg/kg doses could replace the 6 mg/kg and then 8 mg/kg doses could be added in. The evidence suggests that it is not so much the dose itself that is the danger as the manner in which the dose is titrated up. Establishing the risk involved for different titration schedules would likely be something that some patients would appreciate. Not all patients would be in a rush to dose up to the maximum and indeed some would likely prefer an added margin of safety even for a relatively safe product such as leca.

These alternative titration schemes might be attempted when patients on placebo migrated to active dosing in the trial extension. During a trial such experimenting would interfere with determining efficacy as rapidly as possible. Yet, once the patients are moved onto the extension such time pressure would be reduced.


Another ask would be to start early studies for those patients who likely would request to go off-label once Leca is approved. This was a weakness with Aducan; there was no clinical research for these patients to consult. Those with Down Syndrome amyloid dementia, pre-AD, and moderate/severe AD clearly would have an interest in trying an anti-amyloid off-label once approval is granted, without clinical evidence though this would become a difficult decision. Having at least some early phase 1 research would be a great help for them.

There are not that many asks that I can think of right off the top, though these two are a start. Leca has been in development with the phase 2 trials for so many years that most of the issues related to it have already been worked through.

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

Postby floramaria » Thu Sep 30, 2021 9:13 pm

Hi J11, good to have you back with us! I just read through your most recent posts and also re-read the post about your polygenic score for PTSD. I’m curious about how learning that has impacted your life. Has knowing what is behind the reactivity (ie the trauma of burn toast) helped you?
I appreciate that you’ll be with us to provide your analysis as new drugs are rolled out.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Postby J11 » Sat Oct 02, 2021 12:23 pm

Thank you for your reply and welcome back, Flora !

I have had a taste of a post-dementia state of consciousness, I like it and I wasn't sure if I would ever return to the grind. Perhaps some day I won't. Without the ever present concern about dementing illness life is going to be like always being on vacation. The dementia community must have been near the center of keeping the focus of humanity on the quest for progress and not on relaxing at vacation properties. Someone needed to drive technology forward-- for some purpose: That was probably us. To solve AD we needed substantial technological infrastructure-- genome sequencing, mass society etc. etc.. For many outside of the dementia world progress probably seems largely paradoxical and possibly even counter-productive: Life gets more and more technologically advanced with minimal improvement in their standard of living. Yet for us who needed progress to resolve our problems it has been essential to build up broad high tech infrastructure.

Aducan (and more particularly its progeny) are the result of all these decades of effort. It has started the process in which the Alzheimer's conveyor belt will stop and dementia can recede from our lives. I along with other close family are probably on this conveyor belt, though my best guess now is that the approaching wave of treatment choices will prevent us from actually ever experiencing clinical AD. This is a miracle because in the direct line of our family's dominant AD this has not occurred, probably in centuries.

I have been internalizing this realization over the last few months. I suppose some could say "J11, that is a fairly slow learning curve; pick up the pace a little." Yet, Alzheimer's dementia has been the central defining feature of my life. What else is there? It is going to take a while to rewire my brain for a post-Alzheimer existence.

Strangely, my family tried everything to obscure our dementia history and a whole bunch else-- jump on a plane, move into a large modern anonymous city, never talk about your life -- your past simply disappears -- an instant society without complications. We have been remarkably successful at never revealing the truth to ourselves and others, until now. However, such secrecy is no longer that effective (or relevant) anymore as current genetic technology can effortlessly reveal extremely powerful insights into a range of phenotypes. The mum strategy can be used as much as people like, though genetic technology can already peer through to the truth with laser focus. There are personal traits that even when I am trying to be honest cannot easily be described in words-- there are just some odd features of my perception that did not have an obvious route to description. The full genome sequence with the polygenic scores provides an operationalized vocabulary and it is highly helpful to understand various patterns of behavior without adding in lots of emotional drama or outside interpretation. This new era of genetics offers a powerful workaround for those who are unable to put experiences into words: Genetics will do this for us with the certainty of science for assurance.

This game plan of omitting reference to a range of our personal traits (e.g., dominant Alzheimer's dementia), wasn't overly successful in the longer run to avoid the underlying pathology or the resulting personal life challenges that the pathology caused us-- the past has a way of being present, even when you do not talk about it; in particular as it is written in our genes. Genetics simply does not just vanish when you ignore it, but will essentially continue to be eternally present. The full genome sequence revealed a range of lurking issues that were of high explanatory power for me.

The PTSD result was close to the top of this list. There were hundreds of reported polygenic scores, so there were a few other surprises, though the PTSD finding was the most startling. Of course, it all has to be taken somewhat with a grain of salt, as the technology is still in evolution and there can be a tendency to try and oversell findings that sometimes can be suspect. In this category would be a TREM2 finding for AD that said this meant I was super-high risk for AD. That result simply seemed wrong -- glaringly wrong. 50% of the population supposedly has this variant-- a variant that I had never heard of. So there are underlying quality issues remaining, though the mega GWAS are now starting to be reported that have substantial scientific credibility, unlike small scale GWAS from ~2015.

Nevertheless, the PTSD polygenic score was fairly extreme and it really jumped off the page for me. It clicked with what I had experienced in my life. A Eureka moment (fortunately I wasn't taking a bath at the time I received the genome reports ). It has actually been similar to religious in intensity; I would go as far to call it a born again like event. The new J11 has arrived! Yeah, J11 2.0! I had not been all that clear what being born again was all about. Is this truly sincere? Well, for me YES!

I had previously specifically explained what I had experienced, though strangely even close family, who were almost certainly carriers of high PGS for PTSD did not seem to understand what I was talking about. At a certain point you just give up in even trying to explain to others how you are responding to life. In fact, when I mentioned the near medical crisis like responses (e.g., severe hypertensive responses to largely mundane daily experience) that I was having even that was dismissed as largely non-believable. I am very glad that genetic sequencing will likely make ignoring such signs in the future much less likely. Science will simply be able to recognize what is happening and help those who would otherwise be misunderstood. For me such responses continued for years.

Nevertheless, it is still now somewhat difficult for me to believe that this was so completely disregarded. Close family almost certainly must have shared the exact same memories of emotional reactivity, though they completely denied awareness of these experiences. A genome sequence would have helped so much to introduce honesty into the discussion. However, part of the problem with PTSD is that the problem itself and in any way talking about the problem is avoided. It is a fairly odd feature of the trait. Even when something is objectively present people will still claim that it is not. How could problems ever be solved under such circumstances?

This is a notably near universal feature of the trait. In fact, I have tried to post to one of the main PTSD online forums, though I have been banned; they did not like my ideas. With this phenotype it can be so difficult to move beyond all the various things that people find triggering. As I look through the posts on this forum it is quite surprising how many of the posters have likewise been banned.

Even still, these forums are one of the other major wins that I have achieved with the genetic scores. When you know exactly what the problem is then you have somewhere to go where others share your specific experiences and genotype. I can go online 24/7 and there are thousands of other posters talking PTSD non-stop. It is great to have a people to call your own (just as it is great to have the APOE 4 forum to talk AD non-stop -- outsiders just don't get it -- when I talk about the pumpkin pie that we had that lacked, well pumpkin - making it I guess, one could say more correctly "the nominal pumpkin pie", others on forum here probably have a pretty good idea about what that is all about, those without dementia experience not so much) and understand intimately the valences of your words.

Funnily enough I had not realized that the entire new generation of sub-culture related to triggers, safe spaces, avoidance etc. had all emerged from the PTSD community and the unique psychology that this spawns. I had largely dismissed this as part of a new age youth culture. It was only as I was reading on the PTSD forum that I realized that this set of ideas was trying to create a more accepting and nurturing environment for those with PTSD. Once all of this background is made explicit, it clearly fits in well with the post-traumatic world view.


It is tragic that even now PTSD is largely a solvable problem. Reordering the environment in specific ways would resolve it. A simple polygenic score calculated early in life along with allocation to the appropriate life track would avoid the problem from ever activating. There are few (if any?) other psychiatric illnesses that I am aware of that have such a reasonably straightforward path to a cure.

The scale of the existing problem is also something of a surprise to me. PTSD must apply to many millions of people -- ~~ 30 million Americans. The discovery really isn't that PTSD exists -- that is fairly obvious and well recognized. What is more of a revelation is the idea that PTSD can actually exist as part of a typical life experience. That had not been clear to me, even though this reflected my actual lived reality. It made PTSD something that had been hiding in plain sight for me for years. I had read quite a bit about PTSD and it never once occurred to me that this had anything to do with me. The strange part of this, is that when I recently went to the Merck Manual diagnostic checklist I hit almost every item on the symptom list (from past life experience at least). I think what this reveals is that when you have an activated sense of what the terms mean that you recognize symptoms as they are meant to be understood in a way that is not possible when you do not have this awareness.

From my viewpoint now, I think that it is possible that the Merck organization for psychiatric illness probably could be completely
rethought. Instead of placing PTSD as a subcategory of a subcategory, it probably could be placed more as possibly one of the top level headings -- perhaps there could be mood disorders, PTSD and a few others. It is not a rare trait in the community; it is actually reasonably common. The way it is organized now, substance abuse disorders, psychiatric emergencies, and others are listed as separate categories, even though from my perspective these categories largely seem to reflect symptoms of PTSD. Placing PTSD near the top of the list would make it much easier for others to recognize its importance outside of the traditional traumatic disorder label.

You cannot solve a problem until you know what the problem actually is. This is essentially as far as I am concerned a near axiomatic fundamental. My PTSD problem had been treated for years (mentioned previously with a wide range of pharmaceutical and other interventions), though after enough non-success there was the decision to essentially stop trying. The level of non-success for mental health professionals must be highly discouraging. However, what I find very encouraging now is that PTSD could now have a highly successful intervention path going forward. At population scale with a coordinated intervention strategy, PTSD could rapidly disappear from the community. The main problem is that there are so many activating triggers present in the non-conditioned environment that a reinforcing cycle emerges that becomes highly resistant to quelling.

After all of the effort in trying to treat my problem I largely felt like some sort of super-freak: I had some an unspeakable and embarrassing mental health problem that was actually never explicitly described to me. Part of the born again part that I have experienced over the last few months is that I now have fairly definitive proof that I am not a super-freak-- which is always reassuring.

Those who maintain that I am are not basing their opinion on actual scientific evidence-- their opinion can simply be dismissed. It no longer would be regarded as legitimate. This is a powerful shift in the power relation and my awareness of my life. Pseudo-scientific medicine has until now largely been beyond challenge because considerable expertise would be required to make such counter-claims. With genetic screening it is easily within reach to obtain a high degree of diagnostic insight merely with a full genome sequence with polygenic scores. The power of experts to diagnose with labels that entirely lack scientific credibility has now ended.

Without such intermediation by experts, I can offer my own first person interpretation of the PTSD perspective without appealing to technical language which tends to pathologize and dehumanize instead of actually reveal the truth. For me PTSD has largely been about episodic stress events. It probably can be best understood in analogy to 2 year olds whose locus of behavioral control is external. Basically, other people need to actively intervene to regulate their emotional responses. More lasting problems manifest when I tried to exist in longer term social environments. In those contexts, there was a tendency for PTSD to activate, remain activated, and my cognitive ability tended to degrade through time as my triggered behavior provoked a cycle of environmental responses. Within the context of virtual interaction, PTSD has almost been entirely absent.

When it was medicalized and not given a clear diagnostic description, my PTSD was fairly embarrassing to me and I never talked about it (largely because I was not really that clear what the problem actually was). As it is of now, PTSD is fairly mundane to me and can be explained to others in a way that doesn't add that aura of being some very weird mental illness that puts alienates me form others. Getting away from the hushed whispers of some supposedly weird, very likely completely uncureable mental illness is certainly a big step forward for me. Yeah, go me! In fact, my particular flavor of PTSD can be made entirely silent by simply virtualizing. The power of the labeling of pathology to ruin one's life quickly vanishes once precise and scientifically accurate
genetic scores are introduced. It all becomes somewhat banal, dull and largely not overly inviting for those seeking financial enrichment. Clear explanations remove the power of the mysterious.

So, the PTSD genetic "diagnosis" has been a tremendous relief. With my specific flavor of PTSD diagnosis is cure. By specific flavor of PTSD I am referring to the dimensions of the trait that have been identified. We had this discussion earlier on thread about the factors of AD. At the adcomm there was an interesting I guess you could say argument that was about to start about the factor structure of AD and then it was thought best to steer clear of what would likely be a somewhat technical exchange. My feeling is that AD is probably best thought of as largely a ~1 factor illness -- it is largely an illness of reduced g (reduced cognitive ability), though admittedly with other features. AD perhaps could best be thought of as a unidimensional illness. The other features (e.g., functioning) etc. load onto the cognitive ability factor.


PTSD is somewhat more complicated- PTSD's genetic description includes several dimensions. There are re-experiencing, avoidance, and hyper-arousal dimensions. It turns out that I scored quite extreme on the hyper-arousal dimension, though fairly low on the other dimensions. This also corresponds to the pattern of PTSD behavior I observe. When the milk is spilt or the toast burns there is an existential crisis and then there isn't until the mini-fridge leaks. With other forms of PTSD like behavior what seems to happen is that the traumatic experiences are constantly replayed creating essentially a positive feedback system for the trauma. That is not my particular flavor PTSD. A treatment approach using eye movments has been developed that apparently helps to reprogram the brain's re-experiencing of trauma; though for me I suppose that would not be that helpful as I do not actually re-experience the trauma that much anyways.

For me, PTSD like behavior was only active while I was part of mainstream experience (bricks and mortar school etc.). The bricks and mortar world largely creates an inherently PTSDish environment for me-- once activated PTSD behavior becomes self-reinforcing as increasingly lower levels of cognitive performance generated from the PTSD itself illicits additional environmental response. I have been aware for quite some time (well before the genome results) that online environments do not recapitulate bricks and mortar risks -- virtually no self-reinforcing downward spirals occur because in some online environments there is minimal to no social interaction. What social interaction that does exist online can often occur asynchronously so emotional reactivity might never occur.

I have actually been in what would best be described as the non-activated state PTSD for quite some time. What has typically always happened in life is that those in quiet mode for an illness are largely completely ignored. The focus is then almost entirely on those who exhibit florid symptoms. Largely through trial and error I realized that whenever I was in a bricks and mortar environment I would activate PTSD and it was in my best self-interests to avoid such environments whenever possible. This has been a highly successful strategy that has counter-acted the underlying genetics. The problem was that I had to struggle for years against the wishes of my family and social structures. I am sure they meant well, though the only actual result from the effort of the community was to simply activate PTSD illness. My big wish is that now that the genetics can be identified prospectively that such absurd struggles will not be needed in the future.

Hopefully others in the community will also recognize their best self-interests as well. PTSD like behavior is highly corrosive for social functioning. It creates intense oppositional behavior that erodes social cohesion. As I mentioned in an earlier post, you do not form memories as much as post-traumatic experiences. The post-traumatic memory simply overwhelms all other emotional nuances that are universally present in life. This creates the fairly bleak prospect that the only lingering reminisces of the past will be life as a post-traumatic experience. In their stead I can attest that my online educational experiences have been anything but dominated by a sense of trauma; in fact, I have many years of happy memories from online learning. With my online learning, there has been close to a complete absence of any sense of trauma.

My family's dementia experience also became intertwinned with the PTSD. I was the 24/7 primary care giver for our lived one for years. In this role PTSD like potential largely vanished. There were some activators when trying to interact with the health care system, I did not at that time have a way to clearly articulate the trait, though caregiving was remarkably free of initiating events. Time felt like it simply melted together for years and years at a time. In the regular flow of life it is typically entirely unknown what might happen on the freeway from one millisecond to the next. Living in such highly present time focused reality is especially risky for PTSD. When you get into the flow of time, PTSD largely disappears.

Yet, this was not how other family members experienced the dementia years. For them, they continued to experience the traumatizing effects of life during all of this time. There was no PTSD cure for them. That is where the burnt toast and spilt milk examples arise from. They are not current examples from my personal reactions, though similar examples did occur when I was in the active phase.

I am very unsure even with my knowledge how to help other family to cope with their behavior. They exhibit typical PTSD like behavior of thought blocking, avoidance etc.. It is a classic example where I know the solution to the problem though it is very unclear how to actually help. When I suggested a full genome sequence-- that was rejected. Genetics seems to be fairly high on the trigger list of PTSD. I am only guessing but the PTSD like behavior that I have seen from family must be the result of quite extreme polygenic scores. This is compounded with chronic drug and alcohol coping behavior which only makes things worse. The drug and alcohol scene creates endless triggering events that then reinforce the substance abuse behavior.

My PTSD result is now just so blatantly self-evident for me, it is almost unbelievable to me that this was never recognized before. I mean I could go almost anywhere and just start reeling in the post-traumatics-- it would be essentially obvious. Even with quite minimal awareness it should be possible to easily spot the trait. The reason why this would be helpful is because when it is that self-evident it means that the community is not providing a safe environment for those with PTSD. It represents de facto abuse. This becomes all the more troubling when children are involved and reasonable standards of care are not being adhered to. Giving children a handful of pills to try and cope with the problem that is caused by the environment that they have largely been compelled to attend introduces significant concerns whether their human rights are being respected and the criminal and civil liabilities of the institutions involved.

This is where the banging on tables came in. Solving this problem seems so obvious. The consequences for not solving are all too plainly obvious. What does it actually require for social change to occur?

Hmm, this has all been somewhat wordy. I'll give the bottom line summary on the questions.

- Impact on life about learning about PTSD's role in my life.
Yes, very important impact on my life. PTSD has not been active for me in quite a while, though the genetic diagnosis provides very powerful insight into explaining how my life and what paths in life will be the most successful. Not sure how to help other family who actively exhibit PTSD while using maladaptive (though highly entrenched) coping strategies.

- Awareness of reactivity helpful?
Yes, explicitly having a label to work with gives me an anchor to ground coping strategies especially with other family members. Can go online and access a near endless resource of others in the community have the exactly same problems and learn from their experiences.

Also recognizing that reactivity is present (and in particular the nature of the triggering mechanism) has allowed me to be conscious of trying to control the triggering events. Over the last few months there has been a fairly noticeable shift towards a more constructive emotional tone with other family members as I have consciously applied emotional calming strategies. Typically this normal pattern of positive emotional bonding with others was largely absent because the cycle traumas was almost continuous ( spilt milk, burnt toast etc..). The reactivities can become essentially non-stop. There is never an opportunity for normal relationship patterns to ever develop. Yet, recently I have been able to engineer periods where positive experiences have become more dominant than the traumatic experiences. If we can simply get to the point where the positive vibe is the default, then the reactivity pattern simply might largely stop.

The big problem with that is that external reality is always throwing in trauma that must be repaired. COVID has been one of these external traumas in particular COVID vaccination. The public dialogue encouraging mass COVID vaccination has not been especially
sensitive to PTSD psychology (those with PTSD like behavior are probably some of the last remaining members of the community left to be vaccinated). We are living under a mandate, so when it came time to help other family to cope with the vaccine order it was reasonably easy to use PTSD informed psychology to help them comply. It was especially useful to simply stay with speaking in rational terms and complete sentence. Many of those trying to encourage others to accept vaccination simply seem to have given up
in frustration and have reverted to argumentative approaches that would especially alienate the PTSD community. Once again it is only when you have the PTSD concept in your backpocket do you even realize how counter-productive various strategies can be for certain sub-populations. The informed observer would then look at the strategies being applied and recognize the futility.

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

Postby J11 » Sat Oct 02, 2021 7:39 pm

There is a lot of exciting AD news to get to!

Something that I misinterpreted from the recent Biogen press release about the rolling submission for lecanemab was the expected timeline involved. I had thought the plan was to have a rolling submission and then keep on rolling with the data flow-- basically every once and while just send in more. That apparently is not the plan. The idea is to submit and submit and then to stop the submission and let the FDA set a PDUFA. Hmm, but the PDUFA is supposed to be set for 6 months after the FDA has formally received the submission on priority review. Ah, 6 months? I thought the time line would be for the PDUFA to be in about a year just as with aducan which had a submission in July -- one month for the FDA to formally accept receipt and then decision time for the following June. It is only when I looked back on this did I remember that the original timeline had been for a decision by March (i.e., in 6 months).

This could be earlier than next September? The plan is to approve before Clarity ends? Perhaps a May-June time line and then a party at a ICAD? This might not be so dull after all. An early unlock of the Clarity results? Don't want to say it-- another futile futility analysis (hee hee nervous laugh)? Greatly look forward to guidance on how this is all supposed to flow through the process. This could happen quite a bit faster than I had expected. There might be an adcomm meeting in a month or two? Oh, great! Can't wait.

One of the great parts of the leca trial is that we should be able to avoid another round of extremely unstable results. 301 high dose was not merely up there in high earth orbit it was also rapidly descending for splashdown. The high dose results were in rapid evolution over the last 3 months of the trial towards confirming all of the other arms. Remember from earlier posts that the CDR-sb number moved from +0.22 to +0.03 during this time. Who knows how much more the number would have moved in the right direction if they only had even another 3 months to work with? I would not guess that a typical clinical trial would show such motion.
Shouldn't the results be stationary? The only thing that would change would be the p-value.

With Clarity, we could have all of these stability numbers for months before the final read out. If the results were bouncing around, then this would be a clear sign to reject any early readout. Valid numbers should not be in evolution. One might expect that in a trial with a set dosing schedule and set patient recruiting (from defined clinics) there really should not be any momentum to changes in final readout through time. The Clarity results should be expected to have achieved stability when reported.

One of the features mentioned earlier on thread related to the substantial proportion of those on placebo in the leca phase 2 who actually converted to amyloid negative -- ~20%. These placebo really are not true placebo. It is as if they were secretly dosed with leca and are in fact part of the treatment arm. These patients somehow just start to spontaneously make their own anti-amyloid anti-bodies etc. (possibly even self-producing something similar to leca). I do no not know how this was treated during the
Aducan trials, though this time around we are ahead of the game and a discussion could happen before all the arguing begins. It would seem to me that a fairly reasonable idea would be to create a regression for the placebo which set the cognitive zero point right at the 0 amyloid removal position. We do not want those who have been in a treatment like arm to confuse the result of "true placebos. Those in placebo with ~0.30 SUVR amyloid removal might have substantial cognitive benefit. Such regressions should be explicitly reported and perhaps a cognitive benefit vs amyloid removal figure for all of the patients (regardless of treatment arm given). This would be even more powerful if such a figure included all of the patients from the Aducan trials. With enough patients, the covariates could be adjusted for and we could develop a better idea of how a wider range of amyloid removal changes cognitive scores.

This again refers to earlier thread posts that noted that SUVR removal for group reporting might have a hard limit somewhere around 0.30 to 0.40, yet some of the patients have amyloid removal up to ~0.80. Considering that there is a strong linear trend between amyloid removal and cognitive scores, it would potentially be highly persuasive evidence if regressions with patients further out on the amyloid axis had even greater cognitive improvements. Having a good sense of the effect of treatment at ~0.50 SUVR adjusted for covariates could be highly informative (and persuasive). The dataset on the table is now becoming quite extensive and such results could be reported this time around. I would really like to see an isorisk curve that showed the contours for those with varying covariate risk.

Further to this point is the recent press release for leca that mentions that group and individual level correlations between amyloid removal and cognitive measures support the effectiveness of leca. The individual level correlations for Aducan were seen as not being overly strong (largely as a result of the results not being balanced for covariates). If leca has achieved higher individual level correlations this would be a very strong piece of evidence demonstrating efficacy. Possibly such efficacy is based exactly on the considerations above on creating regressions based upon isorisk contours.

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

Postby J11 » Sun Oct 03, 2021 12:35 pm

It is now 8:35:00 PM CEST October 3, 2021.

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

Postby J11 » Sun Oct 03, 2021 12:53 pm

This is very exciting everyone!

CEST stands for Central European Summer Time and is the red area in the map below. It includes almost all of Western Europe with a few exceptions such as the UK and Portugal.
Time_zones_of_Europe.svg.png


Isn't that interesting?
No, I suppose it's not ... until you know what could happen tomorrow (October 4) at 11:30 AM CEST.

It's Nobel medicine time!
Nobel in medicine 2021.

Yes, tomorrow in the middle of the night (American Eastern time or Pacific time etc.) the winners will
be notified of their contribution to the betterment of human health ... with a 100 decibel bugle call in
the middle of the night? Seriously would it really be too much to ask to accommodate American time zones?
Maybe leave a voice message or something?

Ok, enough of all of this ... here is the top-line blue sky:

Nobel Prize in Medicine 2021 awarded for anti-amyloid treatment that has shown clinical benefit in Alzheimer's Disease.

Yes, I will have to work on that somewhat-- really not all that snappy, it's not enough like a tabloid headline. A Nobel for AD tomorrow would be amazing! So many of the Nobel prizes in medicine or physiology (?) have such minimal actual clinical relevance. The prizes are often awarded for very deep basic science that infrequently translates directly into improved human health.

However, the AD research that has been endlessly posted about on this thread will have profound clinical importance for tens of millions of people. The breakthrough that is now being reported in AD is bigger than the typical breakthroughs that earn Nobel prizes for cancer. The anti-amyloids appear to have a broad clinical range that will help an enormous number of amyloid dementia patients, while cancer is often thought of as being upwards of hundreds of different illnesses all with their own highly specific genotypes that all must be addressed one by one.

The single genetic variant- APOE epsilon 4, the focus of this forum and often a mono-causal of dementia (unlike most other diseases) - drives an enormous amount of the pathological burden in AD. Alzheimer's Disease is typically considered worse than cancer in the consequences it has on the patient, their family and the broader community. The anti-amyloids that we have discussed on this thread (e.g., Aducanumab, Lecanemab, Donanemab inter alia) will change the trajectory of the illness. Treatment with these agents when begun early enough (i.e., pre-frank cognitive impairment) reasonably could be expected to completely prevent progression to dementia. It should be stated explicitly: This thread has been devoted to a once in a century leap in human medical well-being. There
are few comparable breakthroughs across the last many decades and perhaps for decades into the future.

Furthermore, there are a range of other protein agglomeration type neuropathologies (including Parkinson's Disease, Lewy Body Dementia, et cetera) that reasonably could follow the same treatment strategy that has succeeded in Alzheimer's. This is a once in a century breakthrough in clinical medicine that clearly deserves the Nobel. A Nobel for AD research would be well-deserved and would help to put a spotlight on the substantial medical benefits that patients will derive from currently evaluated treatments along with the significant social improvements that this will enable.

Typically, Nobels are not awarded too far ahead of the curve; they want the dust to settle and have a clear view on what actually helped people and what ideas/technologies drove the field forward. What we see now with the anti-amyloids is that the dust pretty much has started to settle. Aducan was somewhat of a brawl, while Lecanemab does not have many edges to argue about. If anything the curve has shifted from a prospective perspective (hope for tomorrow) to more of a retrospective point of view (we're over the hump and we can coast). Awarding a Nobel for AD research would no longer be thought of as being an especially radical idea; perhaps more so it would be a radical idea not to award the prize to those who have made such a significant contribution to human welfare.

The big question now might be more about which researchers (of the many potentials) deserve the award, for that I am very uncertain.
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J11
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Postby J11 » Mon Oct 04, 2021 6:10 pm

Not overly surprised that the Nobel didn't go to AD research, though the dedicated research that has spanned more than a century would clearly have deserved such recognition. This research will reduce an overwhelming burden of human suffering. Once it is recognized that proteineuropathies are solvable merely by removing the protein agglomeration a long list of such illnesses could be effectively treated. AD has lead the way and amyloid dementia now appears to be a surprisingly straightforward illness to fix. I suppose we will have to suspend our state of incredulity for another year and wait to see what other branch of biomedical research might be foisted in front of us and claimed to be of more population scale medical relevance than neurodegenerative proteinopathies.


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