Julie G, thank you for your comment. Discussion about the reverse translation origins of aducan is almost absent in the popular discussion, yet it is of considerable importance in understanding the inherent strength of such a design strategy. I find much of the popular commentary to be narrowly constricted to a small set of topics; my impression is that many of the general commentators have almost no understanding of dementing illness.
What I think needs to be remembered is that Biogen paid $380 million for the intellectual property rights to aducan. I suspect that Biogen very carefully reviewed the possible confounds before writing the cheque. It is remarkable to realize that a natural experiment is occurring with aducan. Some people simply make it for themselves. One could imagine a great many possible tests of the natural effectiveness of aducan by merely observing outcomes in the wild. Even now such observations could be made. For example. there are genotype databases with tens of millions of people. It seems possible that 1 million epsilon 44s are genotyped in these databases. A random sample of these people might be contacted to see whether they were interested in being involved in research. Time for another correlation! Correlate their cognitive functioning with their titers of aducan (after adjusting for genotype etc.). Keep drawing samples until there is no one left to object. That would probably be me. When we reached about p< 0.0000000001, I think that would be sufficient, though perhaps not definitive supporting evidence.
With such a large dataset we could hide behind the law of large numbers. One might say well, this person might have had a super healthy diet, or this person might have been especially physically active etc.. That would be true, there can be confounds; oftentimes even science can confuse correlations with causes. Yet, with a big enough sample these objections no longer seem as plausible. Those who have naturally high anti-amyloid anti-bodies would not be aware of it. They are in a real sense completely randomized. With a trial patients know they are in a trial, such knowledge itself might distort the outcome. With a natural experiment, the participants would be unaware that they were actually living the experiment.
The research seems to indicate that essentially 100% of those 90 and above develop Alzheimer brain pathology (though not necessarily Alzheimer cognitive impairment). One expects that the strategy to locate those who were most protected was to simply choose extreme geriatric cognitive outliers. I have not yet been able to locate the supporting research for these claims.
The nature of the phase IV program continues to be unclear to me. The idea of a placebo controlled trial seems ethically wrong to me. It does seem to be a problem to overcome the need for a comparison. How can you show efficacy without a placebo? One suggestion is to use the AD patient registry. They have spent a great deal of money and effort establishing this resource, perhaps a trial could randomly draw patients from this registry and those selected could be assigned to treatment and their cognition trajectory could be compared against their decline as measured during their registry registration or perhaps against the decline of those still in the registry. This would not be a true placebo without treatment withheld.
Another idea, possibly even a better idea is to simply select a group of patients (from the registry?) and treat them all with high dose.
The question to be resolved is: Does the change in biomarker (i.e., amyloid) relate to cognitive changes. What is actually fairly interesting as we saw many hundreds of posts ago on this thread somewhere right near the start was that in the 103 study those who had more amyloid removal (the top 1 sd) did a great deal better cognitively than those who had less amyloid removal (the bottom 1 sd). Yet, these patients were all in the same treatment arm!!! Basically the dots in the correlation plots that were repeated endlessly on this thread really should not be thought of as points, they are more centroids of a data fog. What this means is that you could take a group of patients (hopefully more homogeneous than in the phase 3s) and just dose them up with high dose (better induction phase would be good). Some of these patients will simply naturally have more amyloid clearance than others. That just the way that it goes. Take this variation in amyloid clearance and see how it correlates with cognition changes. Perhaps for bonus marks one could then take some of those with less amyloid clearance and then see how they responded to adaptive dosing so that they were then in the +1sd amyloid group.
Tighten things up with an all American trial, tau imaging, mild AD, APOE+, iADRS, prespecified no rapid responders, 21 month trial with induction, full genome screening for AD genotypes. Possibly this could be a powerful approach to provide supporting evidence for aducan's efficacy and demonstrate that increased safety is feasible.
Celebration Thread! Biogen is going to the FDA with Aducan.
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.
https://pubmed.ncbi.nlm.nih.gov/32534594/
This is a good one to help understand the different cognitive tests available and their different characteristics. One of the first things to notice is how both the MMSE and CdR-sb are flat right up until ~5 years before disease onset. Catching the earlier changes might require another test such as the ADAS-cog 13. Perhaps this is one reason why ADAS-cog performed quite a bit better than MMSe and CDR-sb. With earlier patients, tests more suited to these patients might be needed. One other notable feature was how the ADCOMs was able to almost completely discriminate normal from dementia patients. Draw a horizontal line ~0.2. Below all the patients are normal; above the line all the patients are AD dementia. None of the others can do that (except the logical memory test is close). What is also notable is that actually distinguishing normal from MCI is much less precise than I would have guessed. They can tell who the mild AD patients are, though definitively establishing who is MCI does not appear to be possible. For example, about half of the MCI patients with ADCOMS could pass as normals. Basically if "normals" went for aducan treatment it would not be that easy to clearly differentiate them from MCI. Perhaps those who wanted "early" treatment could receive it because it really is not that easy to distinguish normal from not normal. Other studies though have reported that such determinations are possible. Yet, for epsilon 44s, many would have amyloid etc. and also pre-dementia neurodegeneration that happens years before onset.
The article's description of the neuropathology of AD is troubling. Hippocampal atrophy happens right at the start of amyloid accumulation? But that happens DECADES before AD onset -- for epsilon 44s that can be in the 40s! This might be why the FDA was so agnostic about the definition of "Alzheimer's disease". It is trying to open the conversation about amyloid positivity being a disease state. Amyloid is a biomarker for cognitive impairment.
"The model suggests that detectable memory dysfunction could occur up to three decades prior to the
onset of dementia due to AD (ADem). This is closely followed by changes in amyloid-β CSF levels and the first
cognitive decline, as assessed by sensitive measures. Hippocampal atrophy could be observed as early as the initial
amyloid-β accumulation. Brain hypometabolism starts later, about 14 years before onset, along with changes in the
levels of total and phosphorylated tau proteins."
This is a good one to help understand the different cognitive tests available and their different characteristics. One of the first things to notice is how both the MMSE and CdR-sb are flat right up until ~5 years before disease onset. Catching the earlier changes might require another test such as the ADAS-cog 13. Perhaps this is one reason why ADAS-cog performed quite a bit better than MMSe and CDR-sb. With earlier patients, tests more suited to these patients might be needed. One other notable feature was how the ADCOMs was able to almost completely discriminate normal from dementia patients. Draw a horizontal line ~0.2. Below all the patients are normal; above the line all the patients are AD dementia. None of the others can do that (except the logical memory test is close). What is also notable is that actually distinguishing normal from MCI is much less precise than I would have guessed. They can tell who the mild AD patients are, though definitively establishing who is MCI does not appear to be possible. For example, about half of the MCI patients with ADCOMS could pass as normals. Basically if "normals" went for aducan treatment it would not be that easy to clearly differentiate them from MCI. Perhaps those who wanted "early" treatment could receive it because it really is not that easy to distinguish normal from not normal. Other studies though have reported that such determinations are possible. Yet, for epsilon 44s, many would have amyloid etc. and also pre-dementia neurodegeneration that happens years before onset.
The article's description of the neuropathology of AD is troubling. Hippocampal atrophy happens right at the start of amyloid accumulation? But that happens DECADES before AD onset -- for epsilon 44s that can be in the 40s! This might be why the FDA was so agnostic about the definition of "Alzheimer's disease". It is trying to open the conversation about amyloid positivity being a disease state. Amyloid is a biomarker for cognitive impairment.
"The model suggests that detectable memory dysfunction could occur up to three decades prior to the
onset of dementia due to AD (ADem). This is closely followed by changes in amyloid-β CSF levels and the first
cognitive decline, as assessed by sensitive measures. Hippocampal atrophy could be observed as early as the initial
amyloid-β accumulation. Brain hypometabolism starts later, about 14 years before onset, along with changes in the
levels of total and phosphorylated tau proteins."
Re: Celebration Thread! Biogen is going to the FDA with Aducan.
broiler_x, the near unanimous negative opinion on the aducan decision is disappointing. Even some of the scientists associated with Biogen seem somewhat neutral or negative. My aim with this thread was to try and win the argument (fair and square) on the basis of ideas and logical reasoning. Consensus opinion did not accept this reasoning. There are a range of slogans and visual agitprop that could have effectively tilted the deck in aducan's favor, though I did not want to resort to non-rational arguments. I really wanted as much as possible to keep the debate civilized and focused on the research, even while a fair amount of the opinion from the other side often did not delve deeply into the many layers of the dataset.
I suspect that the largest factor involved in the counter-trend approval was the epsilon 44s. There are ~10 million 44s in America and they have high (near dominant) AD risk. They probably played a critical role. Such a large group of highly motivated people who know of their risk and have the cognitive ability to influence the political landscape in their favor almost certainly was decisive. It is basically an AIDS * 10 lobbying force.
The genotyping revolution has arrived and allowed us to peer into our genes and see decades into the future. This has never been possible before. Many 44s arrive on this forum in a state near total mental collapse: How are they going to cope with their job, their family and dementing illness? The focused energy of the 44s to create a future for themselves with the potential without dementing is quite probably what caused the approval. As is said on forum, they had skin in the game. The scientific community could be against it, the broad regulatory context could be against it; basically all the major institutional players could be against it, yet the socio-political force of 10 million people with near dominant Alzheimer's disease exercised their veto. They are the ones who face the prospect of earlish dementing illness, they have a lot more to lose than everyone else. Why not let those who are affected vote on their destiny instead of being told what to do by outsiders. Perhaps the political solution would be to simply enact such a partition and officially form dementia nation: The nation of and for the dementoids.
With most illnesses (even AD) there is a lack of effective socio-political lobbying. The near absence of any social voice for the trisomy 21 Down's syndrome kids is especially disturbing. Essentially children who develop amyloid dementia and no one is that interested?
It is only recently that I became aware of any clinical research for the kids. Considering that there is now a colossal amount of money floating around amyloids, helping them out would seem highly doable (with the caveats that could arise with the complexities of dementing illness superimposing upon intellectual disability).
Similar problem of collective coordination happens with 34s. Even with 50 million epsilon 34s, the group collective consciousness is fairly weak; as Marx would say 34s are fur sich (for themselves). This is true in my own experience. My 34 relatives actually were quite high performing across the age range -- one 34 family member in their mid 80s was paid by a memory clinics to demonstrate their cognitive ability. It is not easy to form a collectivist revolution under such conditions. Same with the 33 dominant dementia in the family. No one really wanted to admit it or talk about it, so we were all supposed to somehow pretend that it wasn't there.
The 44s are different. They could see how large their risk was and they saw how aducan might help them. While aducan treatment would be the most risky for the 44s, their risk of AD would also be the highest. Considering that many people consider Alzheimer's to be worse than cancer, many might consider the tradeoff of ARIA versus potential therapeutic effectiveness a good bargain. I find the risk involved troubling, though as I noted earlier in the thread, risk is deeply structured into the existing amyloid levels. For example, even placebo have a ~7% annual risk of ARIA. Doing nothing (while comforting) does not actually address this risk. Pretending that these risks are not present is not particularly helpful.
I suspect that the largest factor involved in the counter-trend approval was the epsilon 44s. There are ~10 million 44s in America and they have high (near dominant) AD risk. They probably played a critical role. Such a large group of highly motivated people who know of their risk and have the cognitive ability to influence the political landscape in their favor almost certainly was decisive. It is basically an AIDS * 10 lobbying force.
The genotyping revolution has arrived and allowed us to peer into our genes and see decades into the future. This has never been possible before. Many 44s arrive on this forum in a state near total mental collapse: How are they going to cope with their job, their family and dementing illness? The focused energy of the 44s to create a future for themselves with the potential without dementing is quite probably what caused the approval. As is said on forum, they had skin in the game. The scientific community could be against it, the broad regulatory context could be against it; basically all the major institutional players could be against it, yet the socio-political force of 10 million people with near dominant Alzheimer's disease exercised their veto. They are the ones who face the prospect of earlish dementing illness, they have a lot more to lose than everyone else. Why not let those who are affected vote on their destiny instead of being told what to do by outsiders. Perhaps the political solution would be to simply enact such a partition and officially form dementia nation: The nation of and for the dementoids.
With most illnesses (even AD) there is a lack of effective socio-political lobbying. The near absence of any social voice for the trisomy 21 Down's syndrome kids is especially disturbing. Essentially children who develop amyloid dementia and no one is that interested?
It is only recently that I became aware of any clinical research for the kids. Considering that there is now a colossal amount of money floating around amyloids, helping them out would seem highly doable (with the caveats that could arise with the complexities of dementing illness superimposing upon intellectual disability).
Similar problem of collective coordination happens with 34s. Even with 50 million epsilon 34s, the group collective consciousness is fairly weak; as Marx would say 34s are fur sich (for themselves). This is true in my own experience. My 34 relatives actually were quite high performing across the age range -- one 34 family member in their mid 80s was paid by a memory clinics to demonstrate their cognitive ability. It is not easy to form a collectivist revolution under such conditions. Same with the 33 dominant dementia in the family. No one really wanted to admit it or talk about it, so we were all supposed to somehow pretend that it wasn't there.
The 44s are different. They could see how large their risk was and they saw how aducan might help them. While aducan treatment would be the most risky for the 44s, their risk of AD would also be the highest. Considering that many people consider Alzheimer's to be worse than cancer, many might consider the tradeoff of ARIA versus potential therapeutic effectiveness a good bargain. I find the risk involved troubling, though as I noted earlier in the thread, risk is deeply structured into the existing amyloid levels. For example, even placebo have a ~7% annual risk of ARIA. Doing nothing (while comforting) does not actually address this risk. Pretending that these risks are not present is not particularly helpful.
Last edited by J11 on Sat Jun 26, 2021 12:12 pm, edited 1 time in total.
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floramaria
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.
. Hi J11, I realize you are talking about the population in general where avoidance is definitely an issue. That was certainly true in my family. For those of us here on ApoE4.Info, though, I don’t believe anyone considers doing nothing to be comforting. And even in the greater world beyond this community, I don’t think the choice is really between aducanumab and “pretending that these risks are not present”. There are other choices.J11 wrote: Doing nothing (while comforting) does not actually address this risk. Pretending that these risks are not present is not particularly helpful.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.
flora, this has been an overwhelmingly positive week for the Alzheimer's community. The approval of aducanumab put amyloid dementia at the center of the universe. It was euphoric.
A squadron of high capacity cargo planes flew past the Statue of Liberty ...
The FDA approves aducanumab for "Alzheimer's Disease".
... Wall Street achieved; payload doors open...
This is "intellectually insulting", a "disgrace", inter alia; "There is no cure for Alzheimer's"
... 100 billion US dollar falls from sky.
There is now.
Just a frenzy on the market.
Biotech companies have been clearly shown what they need to do to replicate the success.
If you want it to rain money, do that.
In a psychology course, I learned how to operantly condition mice to dance. Pavlov would not be overly impressed, ditto Skinner and neither would I, though overloading the nucleus accumbens with a massive dose of dopamine (by, for example, creating a torrential downpour of US currency) has a certain charming simplicity. Dancing bankers? Why study rates of extinction, schedules of reinforcement? Just drop the money. I suppose there are many others in difficult circumstances that would also be interested in such aerial maneuvers. However, the magic really only works when you are within the achievable near term proximal range. Some argued that aducanumab might have been somewhat short of the line when approved; from our vantage point now such an argument is no longer credible. $100 billion buys a whole bunch of research. There is also the question of the wallets of the dementia patient community. One clearly could wonder how much of the patient amyloid scans and other testing might be helpful for the collective research effort. There is an enormous amount of wealth now that will help advance Alzheimer's treatment.
Now that this market has clearly been revealed the basic science that often languishes for decades with little interest could be transformed almost immediately into large opportunities. For example, over the last few weeks a protein panel for Alzheimer's has been reported with 97% diagnostic accuracy in AD. Similar results have been published for years with not that much interest and until now no commercial potential. With aducanumab approval, potentially a billion dollar plus market moves into view. Patients might pay $5,000 for an amyloid PET, or perhaps much less for the protein panel. Without the approval there would have been no enthusiasm for the panel. If this were to go through the Chinese FDA and people could send samples there, such a panel could be on the market rapidly. Why exactly would such technology not be brought to market given its high accuracy? Even diagnostics can require elaborate and time consuming approval processes. With tens of millions of Alzheimer's patients now aware of a new approved treatment option, the AD diagnostics industry has suddenly become required.
The entirety of human civilization received an uplift this week with aducanumab's approval. I feel so blessed that with this approval I will never progress into dementia. This has not been true for any in my direct line of ancestors as far as records stretch. The earliest ancestor that I suspect was in the dementia line was transported as a teenager to the New World in the early 19th century on a charge of break and enter. Such was the teenage years of children of the demented at that time.
aducanumab will be an extremely safe and effective treatment for me which could be administered well before any the onset of neurodegeneration. With an appropriate treatment protocol the risk of ARIA or any other side-effect would approach zero. Treating early will mean that the treatment cost will likely be fairly modest. I am so grateful that my peer group will also be able to avoid dementing illness. I hope that my efforts spreading the word will help people investigate their risk even if they have no family history of AD. Family history is not a good yardstick to go by because epsilon 4 dementia can skip generations and sometimes only becomes revealed with an epsilon 44 family member. The polygenic nature of AD can also spontaneous introduce dementia into a family that might have no known family risk. It is important that everyone is aware of their AD risk and proactively manage the risk.
Society will be so much better. How can you possibly even have a society when upwards of 10 million people have some level of cognitive impairment from Alzheimer's? I am so excited to see what will happen over the next 5 years as treatment prevents people from progressing through to dementia. If we go far enough upstream, the entire conveyor belt of dementia could stop. The disease process begins decades before onset of symptoms: removing the amyloid cascade will be a large component of ending the pandemic.
A squadron of high capacity cargo planes flew past the Statue of Liberty ...
The FDA approves aducanumab for "Alzheimer's Disease".
... Wall Street achieved; payload doors open...
This is "intellectually insulting", a "disgrace", inter alia; "There is no cure for Alzheimer's"
... 100 billion US dollar falls from sky.
There is now.
Just a frenzy on the market.
Biotech companies have been clearly shown what they need to do to replicate the success.
If you want it to rain money, do that.
In a psychology course, I learned how to operantly condition mice to dance. Pavlov would not be overly impressed, ditto Skinner and neither would I, though overloading the nucleus accumbens with a massive dose of dopamine (by, for example, creating a torrential downpour of US currency) has a certain charming simplicity. Dancing bankers? Why study rates of extinction, schedules of reinforcement? Just drop the money. I suppose there are many others in difficult circumstances that would also be interested in such aerial maneuvers. However, the magic really only works when you are within the achievable near term proximal range. Some argued that aducanumab might have been somewhat short of the line when approved; from our vantage point now such an argument is no longer credible. $100 billion buys a whole bunch of research. There is also the question of the wallets of the dementia patient community. One clearly could wonder how much of the patient amyloid scans and other testing might be helpful for the collective research effort. There is an enormous amount of wealth now that will help advance Alzheimer's treatment.
Now that this market has clearly been revealed the basic science that often languishes for decades with little interest could be transformed almost immediately into large opportunities. For example, over the last few weeks a protein panel for Alzheimer's has been reported with 97% diagnostic accuracy in AD. Similar results have been published for years with not that much interest and until now no commercial potential. With aducanumab approval, potentially a billion dollar plus market moves into view. Patients might pay $5,000 for an amyloid PET, or perhaps much less for the protein panel. Without the approval there would have been no enthusiasm for the panel. If this were to go through the Chinese FDA and people could send samples there, such a panel could be on the market rapidly. Why exactly would such technology not be brought to market given its high accuracy? Even diagnostics can require elaborate and time consuming approval processes. With tens of millions of Alzheimer's patients now aware of a new approved treatment option, the AD diagnostics industry has suddenly become required.
The entirety of human civilization received an uplift this week with aducanumab's approval. I feel so blessed that with this approval I will never progress into dementia. This has not been true for any in my direct line of ancestors as far as records stretch. The earliest ancestor that I suspect was in the dementia line was transported as a teenager to the New World in the early 19th century on a charge of break and enter. Such was the teenage years of children of the demented at that time.
aducanumab will be an extremely safe and effective treatment for me which could be administered well before any the onset of neurodegeneration. With an appropriate treatment protocol the risk of ARIA or any other side-effect would approach zero. Treating early will mean that the treatment cost will likely be fairly modest. I am so grateful that my peer group will also be able to avoid dementing illness. I hope that my efforts spreading the word will help people investigate their risk even if they have no family history of AD. Family history is not a good yardstick to go by because epsilon 4 dementia can skip generations and sometimes only becomes revealed with an epsilon 44 family member. The polygenic nature of AD can also spontaneous introduce dementia into a family that might have no known family risk. It is important that everyone is aware of their AD risk and proactively manage the risk.
Society will be so much better. How can you possibly even have a society when upwards of 10 million people have some level of cognitive impairment from Alzheimer's? I am so excited to see what will happen over the next 5 years as treatment prevents people from progressing through to dementia. If we go far enough upstream, the entire conveyor belt of dementia could stop. The disease process begins decades before onset of symptoms: removing the amyloid cascade will be a large component of ending the pandemic.
Last edited by J11 on Sat Jun 12, 2021 6:13 pm, edited 6 times in total.
Re: Celebration Thread! Biogen is going to the FDA with Aducan.
J11: I am with you. This has been very interesting. Potential investors are counting their money . Perhaps now, contrary to all the experts opinion and dismay, new tratments will start poppng up, almost "out of nowhere" that can bring relief to millions of people with dementia. Some hope is essential here. Parallel that to the Covid-19 vaccines. They have been authorized for emergency use. Maybe we need to put all our energies in making Aduhelm affordable to every patient that needs it. Maybe the experts can influence Biogen to lower their prices? Biogen will cover their investment and more if millions of people with Mild AD have access to the drug. There are,as Floramaria put it in the previous post, other choices, with Aduhelm being one of the other options. Of course, this is just my opinion.
Re: Celebration Thread! Biogen is going to the FDA with Aducan.
Unfortunately, my friend, the size of the check doesn't correlate with the drug's effectiveness, but it may closely align with the company's desperation. I still think there's an enormous leap in logic to suggest that aducanumab = naturally occurring anti-amyloid antibodies, hence, those with dementia simply have an aducanumab deficiency. Aducanumab has never reversed dementia in any trial. In fact, in the first phase II trial, it performed worse than placebo. At best, after an ad-hoc analysis of a tinkered dataset, it was found to slow disease progression by 1/5 at a very high dose that causes significant side effects for 50% of E4 carriers. I hope to be proven wrong in the phase 4 trial, but we have nine long years to wait for that result...What I think needs to be remembered is that Biogen paid $380 million for the intellectual property rights to aducan. I suspect that Biogen very carefully reviewed the possible confounds before writing the cheque. It is remarkable to realize that a natural experiment is occurring with aducan. Some people simply make it for themselves. One could imagine a great many possible tests of the natural effectiveness of aducan by merely observing outcomes in the wild.
In the meantime, did you see that a third FDA advisor has quit over this approval? More here: https://www.statnews.com/2021/06/10/thi ... -decision/
Re: Celebration Thread! Biogen is going to the FDA with Aducan.
Just got better!
https://clinicaltrials.gov/ct2/show/NCT ... w=2&rank=1
Treating amyloid in the healthy before all of the neurodegeneration that happens for decades later would stop the entire dementia conveyor belt in its tracks. There would be no more dementia patients progressing along the entire pre-clinical spectrum of neuropathology. This would stop Alzheimer's along every point. Society would be radically transformed very quickly.
Will a phase IV trial even be necessary? Stopping the preclinical pathology would become obvious with typical neuroimaging over even the short term. Perhaps amyloid is not the biomarker that people will focus on but features such as hypocampal degeneration, PET FDG glucose, etc.. Cognitive endpoints can take years and years to evaluate; with biomarkers results can be much faster. It would be
difficult to prevent aducan dosing if it could be seen anecdotally to stop neurodegeneration.
Move to subcutaneous dosing in the healthy with single dose; 85 day observation period, 97 day trial; ARIA not even considered relevant in this context. Making these changes could unlock treatment for tens of millions of people. Time to call the cargo planes again? Population scale iv dosing for asymptomatics is not really plausible; there isn't enough infusion capacity. A pre-loaded subcutaneous injection into the bum would be a minimal skill procedure for a typical person. A 10 microgram/kg (~ 1 mg) dose of aducan based on the current pricing scheme would cost $5.
https://clinicaltrials.gov/ct2/show/NCT ... w=2&rank=1
Treating amyloid in the healthy before all of the neurodegeneration that happens for decades later would stop the entire dementia conveyor belt in its tracks. There would be no more dementia patients progressing along the entire pre-clinical spectrum of neuropathology. This would stop Alzheimer's along every point. Society would be radically transformed very quickly.
Will a phase IV trial even be necessary? Stopping the preclinical pathology would become obvious with typical neuroimaging over even the short term. Perhaps amyloid is not the biomarker that people will focus on but features such as hypocampal degeneration, PET FDG glucose, etc.. Cognitive endpoints can take years and years to evaluate; with biomarkers results can be much faster. It would be
difficult to prevent aducan dosing if it could be seen anecdotally to stop neurodegeneration.
Move to subcutaneous dosing in the healthy with single dose; 85 day observation period, 97 day trial; ARIA not even considered relevant in this context. Making these changes could unlock treatment for tens of millions of people. Time to call the cargo planes again? Population scale iv dosing for asymptomatics is not really plausible; there isn't enough infusion capacity. A pre-loaded subcutaneous injection into the bum would be a minimal skill procedure for a typical person. A 10 microgram/kg (~ 1 mg) dose of aducan based on the current pricing scheme would cost $5.
Re: Celebration Thread! Biogen is going to the FDA with Aducan.
Sorry everyone for not replying more promptly; summer laziness has arrived.
I want to return to a point from the above post. I realized that the phase 3 aducan trials had patients at a stage of dementia which did not have obvious specific features of neurodegeneration that were spared with treatment. There was amyloid, though amyloid can actually start to decrease in the later stages of illness. The degeneration process had been ongoing for decades before and there wasn't any obvious brain structure that had not already been damaged by the disease process.The brain had compensated and compensated, finally it was unable to compensate any more and this meant that apparent objective cognitive complaints were present.
With the phase 3s, there was no obvious degenerative process that the treated patients avoided that would capture public imagination.
Hippocampal shrinkage or brain glucose uptake reduction would be strongly recognized by the public as pathology that should intrinsically should be avoided even without cognitive test verification. Common sense tells us that having highly functioning hippocampi or sufficient brain glucose is critically important for proper brain function. Such common sense would likely even override opposing cognitive test results, as neuropathological evidence would likely be seen as more persuasive. Introducing clinically apparent biomarkers in this way would greatly simplify the process of establishing effectiveness. Perhaps moving to treating "cognitively normal"
people will allow for the introduction of such biomarkers
I want to return to a point from the above post. I realized that the phase 3 aducan trials had patients at a stage of dementia which did not have obvious specific features of neurodegeneration that were spared with treatment. There was amyloid, though amyloid can actually start to decrease in the later stages of illness. The degeneration process had been ongoing for decades before and there wasn't any obvious brain structure that had not already been damaged by the disease process.The brain had compensated and compensated, finally it was unable to compensate any more and this meant that apparent objective cognitive complaints were present.
With the phase 3s, there was no obvious degenerative process that the treated patients avoided that would capture public imagination.
Hippocampal shrinkage or brain glucose uptake reduction would be strongly recognized by the public as pathology that should intrinsically should be avoided even without cognitive test verification. Common sense tells us that having highly functioning hippocampi or sufficient brain glucose is critically important for proper brain function. Such common sense would likely even override opposing cognitive test results, as neuropathological evidence would likely be seen as more persuasive. Introducing clinically apparent biomarkers in this way would greatly simplify the process of establishing effectiveness. Perhaps moving to treating "cognitively normal"
people will allow for the introduction of such biomarkers
