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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NF52, yes I have read this article.

Here are my annotations, quibbles and questions.

-I think in the first sentence I would have highlighted more that this is the most monumental clinical trial result in AD ever. The anti-Ache drugs from 20 years ago did not have the same potential for broader disease modification as we have seen already with the mabs. For those outside of the AD world, Clarity represents the start of modern AD treatment.

-Now to the second sentence ... What I continue to find unexpected is that the Clarity results are not in the accelerated approval package before the FDA. It's mostly the phase 2 result. If it were me, I think I would go full approval just before Christmas as a Christmas present for everyone. The rationale behind accelerated approval was to strengthen the association between amyloid and the cognitive readout. Clarity no longer appears to require an anchor to amyloid to achieve highly significant results.

- I was somewhat confused with the article when the CMS is brought into the discussion in the context of the proposed bipartisan legislation to roll-back the anti-amyloid mab final decision. The legislation seems to be saying that the final decision was the wrong answer; if the CMS responds with another ... ah ... wrong answer ... hmm, would they introduce another bill? Might be better to just tell us what the right answer is.

-- I think the clinical trial question is an especially important development. As soon as you have that first treatment, then combinations are forced to include the standard. This would largely lock in mab therapy as the base. This happened with cancer therapy where chemo and radiation pretty much had to be combined with everything else, even when traditional chemo had never shown a great deal of efficacy. With AD, mabs are disease modifying so they do have a base level of efficacy and they have the potential to amplify other treatments. I am most excited about combining with anti-tau drugs (e.g., semorinemab). If you could stop the amyloid mechanism perhaps that would give a direct treatment against tau an even better chance.

- In terms of ADAS-cog for Clarity, I am not as sure whether they will replicate as cleanly as with CDR-sb. ADAS-cog has repeatedly caused trouble in clinical trials; betting the house on it as the primary has been very costly in the past. Averaging it out with the iADRS seems to be best and then we could expect something 35%. If ADAS-cog hit 47% that would obviously be a coffee volcano moment.

- Yes, for me the highlight of the Clarity full report will be the ARIA risk in the e4 heterozygotes. I am just not sure whether an ARIA risk where e34 = e33 is believable. Perhaps this resulted from small numbers in the phase 2.

- My url above considers how the benefit of mab treatment grows through time. I will explain in a later post, though looking at the figures in the url it does ask me to wonder why Clarity did not have a rolling end style trial design as this would have allowed for a much larger topline result (will explain this later).

- I am also wondering now about off label prescribing. Will doctors be able to legally prescribe Lecanemab off label? A fair number of people would be interested in such prescribing.

I continue to find it surprising how much risk is involved in ignoring cerebral amyloid angiopathy (CAA). How much of stroke is actually related to CAA? Current best medical care is to simply do nothing? ... and then they treat with high dose mabs leading to ARIA side effects? But these side effects are simply the manifestation of the underlying untreated CAA. It does not seem to me to be honest to push back and call ARIA the cost of AD treatment; the more realistic description would be that this is the consequence of not controlling amyloid angiopathy. When this reasoning becomes more widely understood would people really choose to overlook this risk instead of managing it with low dose mabs?

I wonder how this will play out clinically. Will people who are approaching mab treatment be pretitrated as I suggested in an earlier post? Will there be a push for people to go off label and manage their CAA risk as part of regular health maintenance? If this early pretitration were adopted the risk of ARIA might be substantially reduced from current levels. e44s would have an especially high motivation to consider pretitration given their relatively high ARIA rates.
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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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Only recently have I realized how close Gantenerumab is now to a readout for Graduate 1 & 2. When I did some light reading about these trials I realized that there are features of these trials that could give us all a surprise; best not to be surprised-- be ready! The phase 3 trials have a 116 week treatment interval, with 9 month titration and with subq dosing. That is quite a bit different from what we are used to. Subq and slow uptitration should give reduced ARIA, and the 116 week treatment (even with slowish uptitration) could give us bigger treatment benefit. It will not be as obvious about the magnitude of the treatment effect with gante (without the phase 2 trial as guide), though very roughly it should be somewhere in the ball park of our well worn regression.

Out of all of this, however, what has caught my eye was the alzforum post https://www.alzforum.org/news/conferenc ... -grow-time from August. How big will the treatment effect grow through time? Almost all of the posts to this thread have been fixated on the 18 month readout, not much thought has been dedicated to the question of the longer term benefit. The middle figure above provides the answer to the larger term benefit-- IT could be MASSIVE! 5.2 CDR-sb??? They are even calling the gante readout as 0.87!!!

The focus has been almost entirely on Clarity and we have not thought that much about Graduate 1 & 2. It could readout at 0.87? How?

That is what the top figure is about. It takes the middle figure and adds to it.

The first quadrant with the red and blue lines is the replication of the middle figure. The black dotted line in the first quadrant is the average percent benefit multiplied by 10. So as shown, the benefit at 1.5 years is 18.93%. It wasn't easy getting the early part of the figure aligned properly so this 18% should be mostly ignored; it gives a rough ball park of where mabs should be at 1.5 years. The 5.2 point CDR-sb predicted difference for the 5 year time point is enormous!

In the fourth quadrant we have the difference between placebo and treatment. Of interest, I added the results from Clarity and the Prime OLE results as points and they align very well with the green difference curve.

In quadrant three there is the first derivative of the treatment (in blue) and placebo (in red).

Quadrant 2 has the difference of these first derivatives in purple. The hatched black line is the marginal percent difference between treatment and placebo multiplied by 10. So, here at 1.5 years, the marginal percent reduction in treatment versus placebo is 65.84%.

So, what does all of this mean? The big standout topline for me from the top figure is how rapidly the marginal treatment decline flattens out. Even after only 1.5 years, the marginal slowing from treatment is 65.84%!!! Yet, this happens at the same time that the actual reported average decline is only 18.93%? At the margin the treatment benefit is moving to its asymptote much faster than a casual observer might realize. If you are fixated at the 18 month
result and it is 0.45 (27% slowing) it is easy to be fooled that this means that it is slowing by 27% at month 18. That isn't true. At the instant of 18 month exactly, the slowing would likely be much closer to 70%. This aligns with the results that have already been posted.

Upcoming thread discussions will no doubt move on to this finding. The inevitable consequence of this observation is that we will soon begin talking about much much larger CDR-sb benefits. The until now high hurdle to reach 1 CDR-sb for a clinically relevant difference will then be effortless. In fact the purple curve to the bottom left, indicates that 1.5 years, the treatment benefit on CDR-sb is gaining 1.2 points per year over placebo. At the asymptote this would extend out to a yearly gain of 1.8 points. That is how the overwhelmingly large benefit of 5.2 points accrues by year 5.

The first big struggle was unequivocally establishing statistical significance. Clarity established such significance.

Next struggle is to establish unequivocal clinical significance. The Aducanumab (with Gantenerumab and Lecanemab to follow) extension largely has sketched this out. We can already see very large separation between treated and placebo through time. I am not sure whether the curve was fit with Prime specifically in mind, though as seen in the figure above, at 4.3 years Prime is almost completely aligned with the curve.

I am not completely on board with this analysis as of yet, because there is a great deal of selection involved. Yet, I am not a fence sitter either: the quadrant 4 curve is already known to largely be correct from existing clinical evidence. When we learn the 18 month slope we will have an even better idea as we know that even at 18 months the curve has flattened to ~65% slowing.

As has been repeated several times on thread, the Aducanumab phase 3 extensions had ~1/3 -1/2 of patients who were nearly stable for upwards of 5 years. They would also confirm the quadrant 4 long term outcome. The proviso is that those who achieved this stability were the self-selected patients who did well on treatment. It was further noted that those who did not do well on high dose treatment, typically rapidly progressed deep into moderate AD.

This line of reasoning is of considerable importance. Moving the discussion to 5 CDR-sb points would also end any attempt to minimize the clinical relevance of mab therapy. We know that placebo will definition continue to worsen ad infinitum. Once it is clear that mabs permanently reduce decline, then it naturally follows that the benefits to the patients will be overwhelmingly large.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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CMS is to decide on updating its NCD on PET amyloid scans by December; they reopened this final decision back in June perhaps as a result of the comments from the mab NCD.

I have been trying to think of other prespecifications before Clarity fully reports. One additional one that I have thought of is to toss the 1% tails of placebo and treatment and concentrate more on the central part of the dataset. In the Aducanumab phase 3s a disagreement arose because there were some rapid decliners and they had a heavy influence on the outcome. The "average" CDR-sb effect simply sums up all the changes in treatment without considering how "average" some of the patients actually are. My feeling is that these patients should not be given overwhelming weight. With Aducanumab some of the rapid responders carried the weight of ~20 or more other typical responders on the topline. The results of these handful of patients had a relatively large effect on the results of the trials. It is known that some patients will enter a stage of rapid and irreversible decline; overlooking this fact would tend to understate the true treatment effect. What AD patients are more focused on is typical response -- on how much typical patients will benefit from therapy.


https://www.desmos.com/calculator/fhk5vps09i

I have been migrating to a new way of thinking about the mab results over the long term. The question of statistical significance has now largely been answered: Anti-amyloid mabs do have a positive effect on cognition in early AD.
The question then shifts more to how much of an effect through time. The above url continues with some of my recent posts to think about this. This time I have tried to align the numbers closer to the readout with Clarity. In the above url, we have a CDR-sb benefit of 0.45 at 1.5 years and this represents a 25.7% benefit at that time (instead of 27%).

The big brain wave that I am excited about is that the 27% is actually a lagging indicator. It is the average over the first 1.5 years. Yet, notice that the treatment effect line (1st Quadrant blue line) is concave increasing. The secant line from the origin is always below the curve. However, when you look at the tangent line or the one year forward secant line you can see how much greater these marginals are from the average.

Here marginals are 52.2% and 61.3% for the tangent and one year ahead secant lines. What does this mean? While the average benefit for the first 1.5 years is 27% (here 25.7%) for Clarity on CDR-sb, the patients after a 1.5 years of dosing likely would not be overly interested in that 27%. They might ask something like what is my marginal benefit of taking another dose or what is my marginal benefit at the tangent of the treatment curve right now (i.e. 1.5 years) or even what will more prospective 1 year marginal benefit be of continued dosing with Lecanemab. For these questions the answer is no longer 27%. For the instantaneous marginal benefit at 18 months the answer is 52% and for one year forward is 61%. That is on the entire treatment population and does not account for the larger responses sizes of APOE e4s. The green hatched line to the bottom shows the 1 year forward expected benefit for another year of treatment.


I am not sure why this style of thinking was not more prominently featured in the trial description. What could have been done is the patients could have been staggered across each month or weeks so that the treatment response curve would be precisely known for the entire 18 months. One could then draw a continuous curve as given above and the obvious result that the percentage of marginal treatment effect would be much larger than that which was reported. For the instantaneous marginal at 18.5 months there would be no assumptions needed to project into the future.


This line of thinking clearly suggests that very large longer term treatment effects will be reported. Patients themselves who were being treated could keep a very close eye on their cognitive scores (perhaps weekly) and have a sense of their marginal benefit. The long term extension for Clarity is maturing, so perhaps it will not be a long wait to have more details on how patients fare with up to 2.5-3 years of treatment.

alzforum reported research on the metabolics of AD. There will be several of these exciting avenues to pursue once the first disease modifying treatment is available. Also considering that there are now a handful of toplines about to report, it is no longer that speculative to wonder when clinical trials of combinations might begin. Such trials might achieve the minimal clinical relevance threshold even within the confines of an 18 month trial.

One idea that I came across online that I found of interest was the suggestion that peer reviewed journal article for Clarity might occur before CTAD (possibly within the next month). Publishing Clarity in this way would offer everyone the opportunity to carefully read and consider the results and be fully informed for the big meeting. For me such advanced preparation would be helpful as there can be a numerous surprises in clinical trial results and having extra time to contemplate them before making proclamations does create a better environment for informed dialogue.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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The big excitement for me today was developing an understanding of off label prescribing. I commented above about off label treatment, though my impression was that this might be in some way be illegal or conditional in ways that would potentially exclude patients from getting the treatment that they need. My guess was that in order to receive off label anti-amyloid mabs you might need to go to a back alley at night pay all cash and not ask that many questions. I thought the market for mabs would devolve into an illicit black market.

It was only when I read up on the off label mechanism did I realize how far off I was. In fact, the FDA has no legal authority to enforce how drugs are prescribed; it only has regulatory power to approve drugs. Once approved doctors are free to prescribe how they see fit. Doctors do not even need to prescribe an approved drug for the labeled indication at all.

This is of enormous importance for AD. If patients with impending transition to an on label use of mabs sought treatment 1 year ahead of their diagnosis, then their risk of ARIA would likely be greatly reduced. Under this scenario, ARIA might vanish within as soon as 2 years. The actual base level of risk that we saw with Aducanumab after the uptitration was 10 fold lower than that the titration phase. If everyone with clinical AD as of now were treated with mabs then their risk of ARIA would resolve over the next year; and if those who were pre-MCI were pre-titrated, then their risk would also be minimized. The risk set for ARIA would then largely be resolved over the near term.

I think it is critically important that the research be done to establish the safest dosing level for those with various times to expected disease onset. The goal would be to strive to achieve near zero ARIA which seems achievable. In an 18 month clinical trial where the topline is efficacy, it is difficult to be infinitely patient with ARIA. Yet, with pre-titration you almost have all the time that you want. As a complete guess, I would think that 2 years of pre-titration and then followed by the standard mab dosing protocol would achieve very low rates of serous ARIA on the scale of less than 1 in 25,000. If the research proved this to be true, then it would certainly be very comforting to patients.

One of my other discoveries related to off label was that pharma companies are legally prohibited from marketing their drugs off label. There have been numerous large fines assessed to pharma that did not comply with this rule. Off label is the truth that cannot be spoken. J11 will speak the truth!

Lecanemab once it is approved will be available for off label prescription treatment to everyone notwithstanding their AD disease stage!

It constantly surprises me how much is left unspoken. I could largely give up on my incessant posting if others simply were able to say what often seems overwhelmingly self-apparent. However, there seems to be many restrictions placed upon free speech within the regulatory context; many people do not appear to be able to fill in the blanks .... ergo, J11 and my near continuous posting.

Off label prescribing is a startling development! ARIA could disappear over the near term. Everyone at risk will move through the system and then no one will remain at high ARIA risk. My impression is that a great many people are not aware of this off label rule. Many people even on this forum are still in a state of panic due to their dementia risk from e4 etc., though seem completely unaware that within less than 3 months they would have a FDA approved treatment option that they could go off label with. For many who were possibly decades away from their expected cognitive decline onset, early treatment probably is not something to consider over the near term. However, for those who are now within sight of potential clear decline, thinking in terms of microdosing over the short term would not seem an unreasonable consideration. The only uncertainty is the actual risk involved in such a plan. I sincerely wish that this question will be studied and resolved over the near term time horizon.

One additional and somewhat amusing additional feature of off label prescription involves a recent court ruling that found that the CMS was responsible for funding these prescriptions for Medicare recipients. I am not sure, however how this might relate to drugs under accelerated approval.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Roche has recently announced that the Gantenerumab phase 3 trials Graduate 1 & 2 will read out simultaneously. It is also possible that there will be a topline report before CTAD.

I continue to be somewhat uncertain about what to expect from these trials. There are a number of new features with Gante including subQ dosing, a treatment interval of 116 weeks and a longer uptitration phase-- it is not clear how all of these factors will change our usual regressions. I will probably want to see what the 78 week numbers look like and see how they fit the previously determined dose-response relationships. There is also the potential for a largish topline due to allowing the treatment period to extend out into 2 years.

I find it interesting that they chose to go with a simultaneous readout as if they were to read out sequentially perhaps they could change the statistical plan if needed. This strategy worked out very well for taurx when they discovered in the first AD phase 3 readout that traditional AD medications interfered with the treatment effect of leucoMB.

This also motivated me to think about the Clarity readout. What I thought was given the existing science into anti-amyloids, why not spend alpha by selecting various treatment effect levels instead of just allowing the alpha spend to happen automatically? For example, the alpha spend to "buy" the treatment effect of CDR-sb >= 0.45 is as we know 0.00005. Before the readout there was a band from ~0.42 - 0.48 that was prime territory for the topline to fall in; why not just buy this with alpha? There is a total alpha of 0.05 to work with. Spending ~0.0001 alpha would seem a very good deal. It also removes the possible criticism that there was a sense of luck involved. By prespecifiying the outcome by spending alpha, one is in effect calling the 8 ball in the corner pocket. It is then no longer that you sank the 8 ball, but that you prespecified this outcome and it occurred exactly as you called it. I am not sure why this approach is not considered more often.

Admittedly, this line of thought was partly inspired by PMID: 34425883. This article prospectively established the road map for a phase 2b trial for Varoglutamstat. This would be a great feature to include for clinical trials. Why only have a retrospective article, when you can also have a prospective article? Yeah! The article could add in prespecifications and provide an overview of what could be expected. Often what we have seen is that the trial is completed and then there might be a problem and ... then things are very confusing: with AD confusing clinical trials has largely been the norm. When such confusions happen, it then becomes very much an off road journey without much in the way of knowing how to get back on the road.

{Incidentally, the VIVIAD trial will include an automated speech recognition method based measure of disease (WLA) as an outcome. These speech cognition tests have been in development for a while and could be quite handy as a method of monitoring cognition on a more continuous basis during clinical trials. Such a test might be a good one for the big pharmas to toss out into the public space as a way for the general public to keep in touch with their cognitive functioning. Instead of the marketing that we have seen for mabs with the not overly clinically precise "Do you know where your keys are?" type questions, natural language analysis has a higher level of validity. We have also already seen that even so called early AD patients can have advanced tau progression that largely excludes them from having an expected benefit from anti-amyloids. This suggests that we are now right on the frontier of an era in which people will need to be more mind aware and seek treatment before they have progressed through the range of effectiveness of anti-amyloid mabs.}

I have mentioned several times on thread on how I hoped that we would see a waterfall in some of the results. I realize that this might be thought jargony by some {I also know how frustrating it can be when people use their own idiosyncratic language that can be uninterpretable by typical readers} so I have included a waterfall from the phase 2a trial of PQ912. Such a figure would be of considerable interest in the mab trials. We could then see how much separation there might be on cognitive measures. Earlier on thread we saw how on amyloid clearance, there was very substantial separation between the high dose and the placebo in the waterfall. What would the separation look like for CDR-sb? for APOE e4s? for mild AD? ... We have only seen the data from certain perspectives, I am greatly looking forward to seeing additional perspectives that could bring the results into better focus.
Waterfall 1.PNG

There is a great deal of exciting news in AD; it's not easy keeping up with it all. Apparently there is another late stage treatment we should be aware of Sovateltide (endothelin-B receptor agonist). This has recently completed a phase 3 trial in India for stroke and is now in front of the Indian FDA. A phase 2 randomized trial in AD with Sovateltide is expected to reach its primary completion date next month.

I am not sure of the rules for accessing a drug off label for a drug (such as Sovateltide) that has not even received FDA approval. Perhaps the company will initiate Western clinical trials after a potential approval by the Indian FDA .
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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US Alzheimer 1950 2018 Extrap.png
This is a super super exciting time for AD clinical research. We are now just over a month before the big CTAD meeting. CTAD has one strong presentation after another; it's almost all net!

This has me thinking again about the End of AD conjecture that I have posted previously. Roughly, AD could possibly be one of the few diseases of the last century that might essentially disappear over the medium term. The treatments that are now before the FDA or in late trials could potentially achieve such a result. That would be startling! AD (and neurodegenerative illness more broadly) could be considered as one of the 4 big diseases of modern life. Most of the other biggies (e.g., cancer) have seen erosions in their disease rates through time, though this has typically been at most 5% per year.

AD could be very different. With Alzheimer's, the gradual erosion model might be displaced by an accelerated disappearance. A chronic illness that could be deflected by 50% or more through time would largely push back the onset of severe disease symptoms beyond the horizon: AD would no longer be a life-limiting disease- it might not even be a meaningfully lifestyle limiting illness either. In our personal example, if we had had access to LMTM at the mildish stage (starting ~22 MMSE), then the slowing of progression that we have seen in the clinical trials of 75% would have possibly prevented the progression into very severe impairment. We are already beginning to see a future where treatment could potentially contain the cognitive and behavioral manifestations of AD into a range that is plausibly manageable through the life course.

{I have also thought that LMTM could help with making mabs safer. The dilemma that we have been faced with is that there are ~ a million or more people with AD impairment on the threshold of descent into a tau mediated decline that until now had been thought largely untreatable.

Not treating patients on this frontier is not without cost. Without treatment, all true AD patients would essentially progress into severe dementia over the course of even a few years. When considering safety, the near inevitable decline into severe dementia of those without a disease modifying treatment should not be casually overlooked.

This has been the predicament that we have been in for years now. LMTM offers a potential way out of this dismal logic. For the patients who are at risk of ARIA, have progressed into tau dementia, have extensive comorbidities, are of an age in which treating the amyloid accumulation might not be clinically sensible etc. LMTM might offer a very good alternative. LMTM could be an alternative to mab treatment which would lower ARIA risk. While mabs are the furthest upstream treatment available, the symptomatic type treatments (such as LMTM) could still be a good approach for more advanced patients and in combination with mabs for those somewhat less advanced or at lower risk. }

I am not sure whether those outside of the AD life experience are fully aware of the brewing revolution that is now imminent. What we can anticipate is a new era of superaging, in which people's life span is no longer limited by their brain span. This could be the start of pushing the frontier of vibrant living forward a decade or more into the future. Don't worry, when it is time to celebrate this extreme advance in human well-being, I'll be there with the party hats.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Remember everyone party hats for tomorrow!

Happy Third Anniversary!

There is so much to celebrate and the thread anniversary is yet another opportunity.

I am starting to see the social utility in social planners.
I mean there can just be so many parties to attend-- well it's a full time job keeping track of it all.

This is pretty much the all time high for AD clinical research, so everyone better party before
it's all over. I am not sure whether we'll even need a fourth anniversary!

CTAD will possibly be the all time high water mark for AD.
It will be epic.

Perhaps the Global Alzheimer community should observe the Lecanemab topline presentation at 4:50 PM
San Francisco time on Tuesday November 29 as a focal point in the history of clinical AD progress.
Hopefully, given the extreme nature of the importance of this presentation perhaps it would be appropriate to
allow open real time access to the slide deck-- release the media embargo as soon as the presentation officially begins .
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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It's the big day everyone!
Third Anniversary Day!
Yeah!

We have made so much progress in the last 3 years to a brighter future for those with AD!
Now there are so many AD treatments popping out of everywhere that I cannot even keep up with the Celebration threads. This is super-exciting!

In the new year perhaps we could even see the first amyloid tau combination trial.
We just needed to get over the first hurdle and then everything can fall into place.
Once the anti-amyloid mab has cleared away the driving disease force, then a whole
range of treatments would have a much better chance of working. Before when these
treatments were applied, they were facing an uphill battle as the disease relentlessly
advanced. With the mabs as the front line, the entire treatment landscape opens up.
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