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

Alzheimer's, cardiovascular, and other chronic diseases; biomarkers, lifestyle, supplements, drugs, and health care.
J11
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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roxanne, I fully understand how difficult it will be for so many patients as the first treatment in almost 20 years for AD is approved and so many will feel cast outside of the potential benefit. $56,000 per year is an enormous amount of money and there is still a paucity of evidence to how this translates to the longer-term trajectory of the illness.

One correction I want to make from an earlier post was with the longer run 103 results. One of the obvious things that I overlooked in the figure was that there is a strong selection effect with the long-term extension. Basically, those who drop out of the treatment arm over the long run will be those patients who were not receiving benefit. This would also apply to the placebo. Some patients would reach a stage of illness that they simply could not continue to attend clinic. Probably the best way to interpret the 103 trial and its LTE is less in relation to the average cognitive score and more in terms of percent responders. About 10 of 30 patients on high dose on the 103 appeared to have sustained benefit with treatment. I am looking forward to an update for the 301/302 studies.

The concern that arises is that a new form of "super-Alzheimer's" could arise in which the moderate stage of illness might be prolonged out for years. A few months of coping with not sleeping as our loved went 24/7 was difficult to manage. I am not sure how anyone could cope with any extension in this phase. Hopefully, there will be awareness that caregiving needs could increase for those transitioning through a longer stage of moderate illness. I am not sure whether this is typical though I remember our loved one bundling up clothes into big piles and then throwing them out the window at that stage. It was fairly intense. We didn't resort to anti-psychotics or the z- sleeping pills, though with extended moderate illness that might need to be more discussed more carefully with caregivers. Once the moderate stage was over and complete disability occurred caregiving was much easier.

I continue to be quite optimistic that capitalism will be able to find a workable solution on a society level to provide aducan for AD. There is simply too much money raining down; there is massive downpour of wealth. The companies will only monetize a small fraction of this wealth. Basically, positive externalities will pop up everywhere. There is this strong reflexive Pharma Bad feeling, though there are many features of AD which suggest that general public perception might ultimately be more Pharma Good regarding AD. One strong reaction I have is that many people simply do not appear to have any conception of the amount of resources that are already being spent on AD. $200 billion per year really is only a base line estimate. When they inevitably say how could we afford $10 billion on aducan treatment, my mental response is how could we afford not to spend the $10 billion?

The wealth generating potential of aducan is truly startling. The analogy here is stopping a toxic waste spill. Treating the patients as they appear at the clinic would be merely coping with the problem as it is. The market has valued this approach as being worth $100 billion. The much much more powerful approach would be to go right up stream to the source and turn the toxic waste tap off. That would stop all future disease for those with amyloid. That is treating amyloid at its earliest stages. The even more powerful approach would then be to freeze the river; lock in all the toxic waste in place. This would be equal to treating all those along the preclinical stages of illness. This would almost immediately stop the AD conveyor belt. No more patients would then progress into clinical illness. That would clearly be an enormous wealth generation event. Over the course of a year or two, it would be equal to a $2 trillion money drop. This appears to be the current game; treat the cognitively normal. As a society, there is simply too much potential to improve the lives of hundreds of millions of people not to move forward with such an opportunity. This truly is an opportunity that we cannot afford not to embrace.

Yes, treatments do already seem to be popping up out of nowhere. Almost immediately after the aducan approval, anti-amyloids attracted investment interest. I am wondering about some of the anti-amyloids that were abandoned (for example, Verubecestat).
This one reduced amyloid an enormous amount ~90% with few side effects: problem was there was no cognitive benefit. This one was not included in the correlation plots because it was a BACE1 inhibitor and not an mab.

This is a good point about the COVID vaccines. It is extraordinary how rapidly these vaccines reached the market; it was ~10 months.
If we really put our minds to it, regulatory processes can be expedited. When there is enough pressure, when the economy is shuttered up, when there is a pandemic things can happen fast. Well, there is a pandemic an AD pandemic and it is important to realize that sometimes the circumstances dictate the response.

The newly disclosed clinical trial for aducan would seem to offer the financial workaround to make treatment affordable on a social scale. I had thought of the treatment plan more in terms of an endless wave of AD patients who would eternally present in the clinic and might ultimately completely bankrupt the medical system. The clinical trial posted to clinicaltrialsgov suggests a very different outcome. Treating cognitively normal people offers the possibility of entirely stopping progression across the full range of pre-clinical evidence.

The irony is that there might be not too much greed involved here but too little (with respect to those with clinical AD). Biogen pivoted immediately to the cognitively normal population who would benefit more from treatment because the neurodegeneration has not occurred yet, represent a much larger market, would have minimal risk of side effects and could be charged a life style medicine price that many would feel was highly reasonable. The overwhelming market opportunity is with those who are pre-disease. Considering how AD develops over many decades, it should not be overly surprising if in the future we are all designated as Alzheimer's patients: Alzheimer's- the musical.

In such a scenario, the primary focus would be directed at the population scale market. It is not totally beyond imagination that
with such a market definition, those with actual symptomatic dementia might then be offered highly discounted treatment. With the logic that the cognitively normal might simply boycott treatment if those with MCI/Early AD were not given reasonable access.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Julie G, I think the size of the check correlates with the extent of the due diligence. How many tens of millions of dollars of due diligence would a biotech firm conduct for a $380 million investment? If it were me, it would be a lot. That $380 million turned into $38 billion. With such an investment the background scientific investigations could be nearly endless; one could keep on checking until one were very very sure.

I am starting to see more clearly the logic that AD is a monocausal disease of amyloid. All of the rest of the features of AD are largely downstream consequences of amyloid. Amyloid dementia looks so complicated with degeneration of the hippocampi, reduced glucose uptake, inflammation etc. etc., yet stopping the cascade could stop all the rest that follows. This seems a profoundly powerful conception of the illness (notably which the thought leaders articulated decades ago). Alzheimer's might be a very simple illness to bring under control: stop amyloid.

I was reading some of the back posts about aducan and the post from broiler_x caught my attention. broiler noted that in the original research that discovered aducan, it was actually derived from a patient who experienced a reversal of AD. I had wondered about this question: What would capture your attention as being unusual enough to investigate further in AD? Would you seek out super-healthy cognitive super agers? Which AD patients would stand out? Clearly a patient with a reversal in AD would be the most prominent. This would be truly mysterious: AD patients by definition do not get better; if they get better one really most suspect that it is not AD. A true AD reversal is highly unusual. broiler noted that one of the first patients identified with natural aducan was such a reverser. (I am unable to locate the scientific literature that discusses this research). Certainly there is extreme selection bias involved, as in the phase 3 trials there were not many patients who had substantial cognitive reversals. Yet, in a non-clinical environment a reversal would be highly conspicuous. Any investigation that found that such a patient had no awareness of various potential strategies such as ketogenics, etc etc. that are discussed on this forum would generate additional interest from researchers. One might quickly narrow down the options that explain the benefit to naturally occurring aducan.

It must be remembered that no phase 2 trial was conducted with aducan. The phase 1 trial was such an overwhelming success that aducan went directly to phase 3. The high dose 103 cognitive benefits were almost improbably large: ~2 MMSE and 1.25 on CDR-sb.
The phase 3s were heavily weighted with MCI patients which have consistently shown reduced benefit to treatment. The benefits of 10 mg/kg dosing from the 103 was only discovered after the phase 3s were well underway so the trial protocols had to be adjusted while the trials were in progress which added a great deal of confusion to understanding the results.

Julie G, considering the approval of aducanumab for Alzheimer's Disease; the first approval since 2003 and the first treatment with disease modifying effect in AD, might this thread become a sticky? The discussion could continue on, though with this thread in a prominent place.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Julie G, on the question of safety, I am impressed by how potentially minimal ARIA might be for the epsilon 33s if extended titration dosing were explored. As I noted in a previous post, the 33s had only a 3.1% ARIA rate over a year of high dose monthly treatment in the phase 3 trials after the titration period along with a high dose treatment or two.

This is not overly surprising as the 33s are known not to have the extensive amyloid deposits seen in 34s and 44s. Exploring such extended titration would seem an obvious next step in the clinical research. For these 33 patients removing the concern of ARIA would likely be a big relief and also might help to reduce the financial burden involved in monitoring for such side effects.

epsilon 33s represent half of AD patients. It seems possible that with a year or two of lead-in titration ARIA could be nearly eliminated for 33s.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Dr. Aaron Kesselheim, a Harvard Medical School professor is the third resignation from FDA panel

https://childrenshealthdefense.org/defe ... 034097b363
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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buck3Maureen, thank you for your post.

Yes, the adcomm members are very impressive. I do not want to even speculate on what a reasonable estimate of their IQs might be; probably in the profoundly intelligent range. Many of the comments that they made at the adcomm and elsewhere are constructive and are not entirely in opposition to those who advocated for approval. Clearly, the winner of the argument would not be whoever threw the most chairs (as it is decided on TV); the discussion had to focus more on the evidence.

Nevertheless, We the People needed to win this one. Something needed to be done to alter the trajectory of the Alzheimer's pandemic. There needed to be an inflection point. Further escalation of the dementia crisis could have resulted in a society that was no longer viable. Mainstream society could not cope in a world with a one word dictionary.

In this first phase of a post-Alzheimer's world the benefits for mainstream society should become more obvious. The current management of Alzheimer's requires enormous resources. My US estimate had been $200 billion per year; apparently the update is closer to $400 B. The global financial burden must be at least $1 T. Over the next few years this burden could be greatly reduced. There is a very large financial U-turn that is about to happen. The people rowing in the wrong direction will start rowing in the right direction. It should not be entirely unexpected that other illness communities which we might persuade to help relieve of us of all these $400 B per year in unwanted resources could start to become strong dementia advocates; the faster we can work through the amyloid dementia cure roll-out the faster the resources can be transferred to help their loved ones.

In our experience, community resources were only actually needed (and accepted) when the dementia had progressed to a severe stage. Once ambulation is lost and a G-Tube was needed, fairly intense community support was required. Even with existing monotherapy aducan it is no longer obvious to me whether those with MCI will ever progress that far into care dependency. It is possible that we have already reached the dementia escape velocity; aducan and other potential future treatments might simply redefine the boundaries of extreme illness to be within the care potential of families (i.e., no community support might actually be needed).

For us even, at an MMSE of 0, we could still manage. [I did argue the 0 as our loved one did provide an answer about what country they were in; it was the wrong country, though I thought partial credit should have been awarded. An MMSE of 0.5?] All this argument about 0.39 CDR-sb ultimately seems largely futile. Another futile futility analysis? The fundamentally important question relates to the longer term care-giving needs. Preventing the progression to total care is the main cost driver in dementia. That right there is a $300 B per year budget item. More emphasis should have been placed on considering how aducan could impact that aspect of dementia. Yet, these features of the illnesses as measured by the ADCS-ADl and NPI ( aducan showed strong results in the phase 3s) were largely ignored in the discussion.
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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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This figure is from the Ganta clinical research
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6909550/

It clearly illustrates the very large amyloid reductions that occurred with treatment. The sub-figure on the bottom left does seem suspiciously similar, though, to the subfigure directly above it. As a common sense guess, removing all of that neurotoxic amyloid has to be a good thing. It might take time, though removal of amyloid could give the brain some chance of healing itself.

It also suggests to me the potential for AI to extract much more information from the brain scans. Why isn't there alpha-AD? Program a large supercomputer and see what it would learn from the massive datasets that exist. Just looking at the brain images above, I certainly wonder what a learning algorithm might find by carefully observing the patterns of amyloid removal. Instead of simply thinking about the absolute amount of amyloid removal, a computer program might see patterns in where the amyloid was removed and how this might relate to cognition. Some brain areas might respond especially well to amyloid removal. This might help to provide more accurate interpretations of the cognitive test scores vs SUVR changes. (The recent Biogen study is offering better access to patient level data for researchers. Open science! Why lock up the results where no one can analyze them?)

The FDA's lack of a clear definition of what stage of Alzheimer's Disease aducan should treat might then begin to be more comprehensible. None of the clinical research that I am aware of to date has treated with high dose into the moderate stage. All of the newest generation anti-amyloids such as aducan, leca, dona and ganta have shown dose relations in the MCI/Mild stage. The conviction that this new generation of strong anti-amyloids will not be effective in later stages is only based on past trials that only had minimal
centiloid lowering power. Perhaps treatment in moderate and severe stages with strong anti-amyloids will be effective. The aducan long term extensions do offer support for this suggestion. Patients in the long-term extension were treated for upwards of ~5 years. At this point they would have attained a diagnosis of moderate Alzheimer's. From previous figures on this thread, it appears that they were still benefiting from treatment even at this stage. The FDA is the dealer who knows everyone's hands. It would not seem to be wise to bet against the dealer. If the FDA believes that aducan should be applied in the treatment of Alzheimer's Disease (?) we should believe them. Possibly moderate to severe patients could benefit, though a more gradual titration would seem advisable.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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I have been thinking again about the ARIA side-effects that happen in the placebo. Upwards of 7% per year of the placebo experience ARIA. This is surprising. Is there really this ARIA disease that has up till now been unrecognized? Do 7% of those with substantial amyloid truly have falls, cognitive impairment from the micro-hemorrhages etc.? Do any medical handbooks even mention this as a diagnosable illness? Has there never been a comprehensive survey of the diseases that are present in the population, so that at least we would know what is out there? It can be quite surprising sometimes to appreciate the things that we don't know.

Apparently being treated with aducan reduces this risk as a side-effect as it removes the excess amyloid that can clog the brain's vascular system. After an 18 month treatment cycle of aducan, the rate of ARIA likely would be considerably reduced, while the placebo would then continue to have substantial ARIA risk over the long-term.

What now seems surprising to me is that the ARIA had not been chosen as an on label indication for the anti-amyloids. While ARIA is a significant disease, proving efficacy would be straight-forward: simply show that there is reduced ARIA risk. This was achieved in the phase 3 trials after only a few months. Such an on label indication would entirely avoid the question of efficacy in Alzheimer's. Yet, in time evidence might accumulate that such amyloid lowering had beneficial effects on amyloid neurodegeneration. For example,
neuroimaging might find that the hippocampi of those treated with anti-amyloids for ARIA prevention might not degenerate, etc..
Such a strategy that was not based on explicitly treating Alzheimer's might have ultimately been a much faster way to bring anti-amyloids to the market and to the patients that need them.

Yet, the big pharmas have worked the problems exactly the other way around. They have tried to solve the hard problem of showing efficacy after neurodegeneration has been ongoing for decades. Proving safety with low dose anti-amyloids for an ARIA on label indication in the pre-clinical AD phase would be easy. As we saw in the last few days now that the difficult part of the task has been achieved, a pivot is underway to dose in the healthy population. It would have been much easier to have started at the beginning and not the end.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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The FDA has recently posted additional background on aducan.

On page 41 of the main report, they report that brain amyloid reduction reached -0.33 (-0.3534, -0.3056) at week 132 into the long term extension for high dose 302. I interpret this as the FDA flexing; the LTE must now have substantially reduced p-values from the orginial analysis. Why not disclose these numbers?

The correlation regression that was endlessly referred to on thread suggests that this would move CDR-sb perhaps down to ~ -0.435 (though this was the regression only for the 78 week result; it could be larger at week 132, the placebo (historical) would have declined more.

On the same page of the FDA report it was noted that individual level correlations between CDR-sb and amyloid were weakish at 0.19 for the week 78 data. However, the correlation was stronger when week 106 and week 78 clinical endpoints were calculated. Would have also been helpful to include these numbers. This update highlights how the brain repair that could occur with anti-amyloids will take time and that it might be unrealistic to expect that all of the benefit will have been demonstrated within the 78 week treatment window of the phase 3s.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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CDR-sb Amyloid 4.gif
Correlation FDA Briefing.jpg
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