tau terciles.GIF
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.
I am not sure about this one. If Trailblazer-2 only selected the entire intermediate subgroup, then it would be concealing the even better result with the lower tercile. I am not clear whether that would be something that would be done; it would be highly deceptive. The topline from the phase 2 was 22% slowing on CDR-sb, but this included a broad range of tau. Now the topline from the phase 3 Trailblazer-2 reported a 36% slowing on CDR-sb. Yet, this is still for the broadly defined intermediate third. The lower tercile had a 50% slowing on iADRS in the phase 2. I am not able to find clarification online on this point. All I see is that they selected for intermediate tau which is as we see above not really optimal.
Whoa! They say intermediate tau. Intermediate tau is not optimal selection if they are using the phase 2 result tau definitions. We can see above that the two figurets on the right with middle or high intermediate tau do not benefit.
Lilly press release:
"Participants in TRAILBLAZER-ALZ 2 were stratified by their level of the brain protein tau, a predictive biomarker for Alzheimer's disease progression. The primary analysis population (n=1182) for which the study was powered was comprised of people with an intermediate level of tau and clinical symptoms of Alzheimer's disease. In this population, the primary endpoint (iADRS) showed 35% slowing of decline (p<0.0001), and an important key secondary endpoint (Clinical Dementia Rating-Sum of Boxes, or CDR-SB) showed 36% slowing of decline (p<0.0001) over 18 months."
Whoa! They say intermediate tau. Intermediate tau is not optimal selection if they are using the phase 2 result tau definitions. We can see above that the two figurets on the right with middle or high intermediate tau do not benefit.
Lilly press release:
"Participants in TRAILBLAZER-ALZ 2 were stratified by their level of the brain protein tau, a predictive biomarker for Alzheimer's disease progression. The primary analysis population (n=1182) for which the study was powered was comprised of people with an intermediate level of tau and clinical symptoms of Alzheimer's disease. In this population, the primary endpoint (iADRS) showed 35% slowing of decline (p<0.0001), and an important key secondary endpoint (Clinical Dementia Rating-Sum of Boxes, or CDR-SB) showed 36% slowing of decline (p<0.0001) over 18 months."
Re: Celebration Thread! Biogen is going to the FDA with Aducan.
There is quite a bit to work through with the Trailblaazer-2 study. I am still unclear about the above selection question.
There is also this figure. What we see is that some of the patients in the phase 2 had quite a bit of amyloid at the start of the trial > 100 Centiloids and upwards to >150 and beyond. What I find of interest here is how this is another legacy feature of AD pathology that might not be true even in a year or two. Allowing amyloid levels to increase that high probably will soon not be seen as medically acceptable. Yet, these are the patients who now in the clinical trials probably have higher risk of ARIA. Carefully monitoring amyloid levels in patients will likely become a routine aspect of typical family medicine practice over even the near-medium term in a wide range of patient ages. It would probably be a good idea in mab clinical trials to recognize this fact and select patients who would be more typical 2-3 year ahead for those with <100 Centiloids.
We should also be looking out for the APOE 4+ results from the phase 3. The figure below suggests that e4+ should have a particularly good result. However, this would be at odds with the Clarity results were the e3+ did better and the e44s did not seem to have a strong showing (on CDR-sb at least)
The Lilly press release noted:
"Nearly half (47%) of the participants on donanemab (compared to 29% on placebo) had no clinical progression at 1 year (defined as no decline in CDR-SB)"
This represents another potential avenue of optimization. The 29% placebo patients who are non-decliners over a year can hardly be described as AD patients. When the decline phase starts in AD it is typically relentless. If another trial were done perhaps patients could be observed for a few months and then treatment could begin; this could be in the context of an AD patient registry. In this way one could first document the cognitive decline and then include patients in a trial. This perhaps would lead to an even stronger treatment effect.
I am also interested to see how Lecanemab's clinical development might be influenced by the Donanemab phase 3 result. Lecanemab likely would show a similar 35% benefit on CDR-sb if tau were to be selected. This would seem to be an easy empty net goal to score. Move the benefit from 27% to 35% while making a one time write-down on those patients who would be beyond optimal treatment.
There is also this figure. What we see is that some of the patients in the phase 2 had quite a bit of amyloid at the start of the trial > 100 Centiloids and upwards to >150 and beyond. What I find of interest here is how this is another legacy feature of AD pathology that might not be true even in a year or two. Allowing amyloid levels to increase that high probably will soon not be seen as medically acceptable. Yet, these are the patients who now in the clinical trials probably have higher risk of ARIA. Carefully monitoring amyloid levels in patients will likely become a routine aspect of typical family medicine practice over even the near-medium term in a wide range of patient ages. It would probably be a good idea in mab clinical trials to recognize this fact and select patients who would be more typical 2-3 year ahead for those with <100 Centiloids.
We should also be looking out for the APOE 4+ results from the phase 3. The figure below suggests that e4+ should have a particularly good result. However, this would be at odds with the Clarity results were the e3+ did better and the e44s did not seem to have a strong showing (on CDR-sb at least)
The Lilly press release noted:
"Nearly half (47%) of the participants on donanemab (compared to 29% on placebo) had no clinical progression at 1 year (defined as no decline in CDR-SB)"
This represents another potential avenue of optimization. The 29% placebo patients who are non-decliners over a year can hardly be described as AD patients. When the decline phase starts in AD it is typically relentless. If another trial were done perhaps patients could be observed for a few months and then treatment could begin; this could be in the context of an AD patient registry. In this way one could first document the cognitive decline and then include patients in a trial. This perhaps would lead to an even stronger treatment effect.
I am also interested to see how Lecanemab's clinical development might be influenced by the Donanemab phase 3 result. Lecanemab likely would show a similar 35% benefit on CDR-sb if tau were to be selected. This would seem to be an easy empty net goal to score. Move the benefit from 27% to 35% while making a one time write-down on those patients who would be beyond optimal treatment.
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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.
I have accumulated a fair number of backposts during my thread absence. I found the above of interest as it puts some perspective to all the sturm and drang that we have went (and are going) through in trying to think about AD clinical medicine at the start of the age of disease modification.
What we see is that at the earliest France would give early market access to Lecanemab by mid-2024. That is fairly astonishing. The entire treatment landscape could have been turned over a few times by mid-2024. It is possible that the concerns that we have now might have all but vanished in the next year. For example, worries about safety might be transformed over the next many months. The entire conversation about AD clinical medicine is rapidly evolving. Perhaps we will move to more subQ or oral dosing; and possibly combinations will already be on the market. When regulatory approval is that relaxed, then it would take away most of the conflict and drama that is part of most such processes when you are at the leading edge of change.
What we see is that at the earliest France would give early market access to Lecanemab by mid-2024. That is fairly astonishing. The entire treatment landscape could have been turned over a few times by mid-2024. It is possible that the concerns that we have now might have all but vanished in the next year. For example, worries about safety might be transformed over the next many months. The entire conversation about AD clinical medicine is rapidly evolving. Perhaps we will move to more subQ or oral dosing; and possibly combinations will already be on the market. When regulatory approval is that relaxed, then it would take away most of the conflict and drama that is part of most such processes when you are at the leading edge of change.
Re: Celebration Thread! Biogen is going to the FDA with Aducan.
So much great news!
The clinical progress is across so many other aspects of brain injury that we can see a convergence towards extremely powerful anti-dementing treatment.
One approach after clearing amyloid and addressing tau is to think in terms of neurorepair. I had been very unclear what the biology of repairing the central nervous system would look like. Apparently, there has been considerable background research on this question and a phase 1 in the context of AD with this approach is expected over the shortish term. There is so much very powerful research into the central nervous system broadly and it seems to have addressed fundamental aspects of biology that apply across multiple neuropathologies. The idea of reversing AD no longer seems an impossibility.
https://www.clinicaltrials.gov/ct2/show ... w=2&rank=1
The clinical progress is across so many other aspects of brain injury that we can see a convergence towards extremely powerful anti-dementing treatment.
One approach after clearing amyloid and addressing tau is to think in terms of neurorepair. I had been very unclear what the biology of repairing the central nervous system would look like. Apparently, there has been considerable background research on this question and a phase 1 in the context of AD with this approach is expected over the shortish term. There is so much very powerful research into the central nervous system broadly and it seems to have addressed fundamental aspects of biology that apply across multiple neuropathologies. The idea of reversing AD no longer seems an impossibility.
https://www.clinicaltrials.gov/ct2/show ... w=2&rank=1
Re: Celebration Thread! Biogen is going to the FDA with Aducan.
This is the url for the ADCOM for lecanemab. The webpage states that the related documents will be posted 2 days before the meeting. Considering how extremely important this meeting is for the AD community, I really think that they should be posted well in advance of that date to the extent that that is feasible. The companies behind Lecanemab presumably have the right to publicly disclose these documents at the time of their choosing. This could be helpful as such a disclosure could act as a beta version where they could discussed before the meeting and any mistakes or clarifications made before the meeting. I had not realized though it seems that at some of these meetings a lot of it is that all sorts of background issues are unclear to start and then they use the meeting to get the basics right. We could have a much more productive Leca ADCOM if everyone is fully informed before the meeting.
https://www.fda.gov/advisory-committees ... ee-meeting
https://www.fda.gov/advisory-committees ... ee-meeting
Re: Celebration Thread! Biogen is going to the FDA with Aducan.
We need to get into gear everyone as the ADCOM is approaching and we want everything to be all lined up ahead of time. Perhaps the APOE4 forum could make a collective statement to the ADCOM through the url above. Lecanemab is a very big moment for the AD community and some sort of position statement would seem in order, though I suppose the internal brawling would begin soon after any such statement were to be made. Notice in the url above that there will be a video simulcast of the ADCOM which given its importance is highly appreciated.
I want to start up this run for the finish line by expressing my deepest gratitude to the pharmaceutical companies that have developed these fantastic AD products. They have invested decades and decades into AD and considerable financial resources and it has finally paid off. However, when one is in the development stage it must have seemed that there was no light at the end of the tunnel. There was a highly consistent 100% failure rate in Alzheimer's clinical development for almost 20 years that must have put a damper on everyone's spirits. Yet, here we are now and the gold at the end of the rainbow is within sight.
For me personally, the financial benefits involved with the mab development is overwhelmingly positive (almost embarrassing so). I might not even need on label treatment while Lecanemab is under patent. So many tens of millions of others who might be at considerable risk (some including those with e44 or high risk polygenic risk or dominant risk) will also be in this atypical position of having the emergence of effective anti-dementings years before their expected age of onset. Many many people will receive benefit from these treatments at a generic price. We might wind up paying less for anti-dementing treatment than we paid for adult diapers while coping with clinical dementia. This does suggest to me that perhaps some sort of political deal could be arranged that could take AD drugs out of the CMS budget silo. The benefits for the broad community will be so large that it might be advantageous to make AD financing more visible. The thinking is that AD is a century scale medical breakthrough in which the community can unite and have a common purpose. Of course, the cost savings involved will be enormous.
Lecanemab in and of itself will be such a game changer for me personally and for my close family. My estimate as of now is that I will never progress to the severe dementia that has afflicted every generation in my family as far as the eye can see. My understanding of the anti-amyloid mabs is that they will serve as great preventative treatment. Stopping the accumulation of amyloid early will be a safe and effective approach to preventing the progression to further cognitive impairment.
In my family's form of dominant AD dementia we have seen it coming for years and years (even decades ahead) of official onset. The diagnosis of AD has not been a great mystery for us; the cognitive issues were self-apparently present long before the involvement of doctors. In fact, it has been more of a surprise when our family doctor was not sure of an AD diagnosis even nearly at the time of the official diagnosis. Everyone else in the family was at least a decade or more ahead of this.
The problem until this point has been that we had to wait and wait and watch for all these years and years as our loved ones progressed from slight but noticeable cognitive impairment, to MCI, to early AD, to moderate AD, to severe AD and then to complete dependence AD. AD has been our life.
We have been pretty much the most messed up people in town. While we pretended that we were somehow normal, from my perspective of today I really do not see how this was ever actually plausible. Essentially, my entire development has occurred within the context of family coping with various stages of dementing illness. I look forward to watching as the community re-unifies as the dementia life experience resolves through time.
Lecanemab is our ticket out. Given the nature of our dementia experience I do not think it would be realistic not to treat ahead of the official label. We are still unclear about the genetics involved, though full genome sequencing is now on the short term horizon. I want to go 100 times full genome sequencing on a family member's DNA with the family mutation when we move closer to the $100 genome. This might happen even over the next year or so. With an established DNA variant for dominant AD it would be then especially difficult to postpone treatment if one of the family had the variant and had cognitive impairment. The main genetic aspect of our AD has been e33 (with other genetic flavors present) dominant, so in this context early intervention possibly along the lines that I mentioned on thread of low dosing well before official onset would be safe and likely quite effective. I am somewhat unsure about what cognitive level AHEAD is using for inclusion. For us, cognitive impairment was self-apparent even in this so called pre-MCI stage.
I want to start up this run for the finish line by expressing my deepest gratitude to the pharmaceutical companies that have developed these fantastic AD products. They have invested decades and decades into AD and considerable financial resources and it has finally paid off. However, when one is in the development stage it must have seemed that there was no light at the end of the tunnel. There was a highly consistent 100% failure rate in Alzheimer's clinical development for almost 20 years that must have put a damper on everyone's spirits. Yet, here we are now and the gold at the end of the rainbow is within sight.
For me personally, the financial benefits involved with the mab development is overwhelmingly positive (almost embarrassing so). I might not even need on label treatment while Lecanemab is under patent. So many tens of millions of others who might be at considerable risk (some including those with e44 or high risk polygenic risk or dominant risk) will also be in this atypical position of having the emergence of effective anti-dementings years before their expected age of onset. Many many people will receive benefit from these treatments at a generic price. We might wind up paying less for anti-dementing treatment than we paid for adult diapers while coping with clinical dementia. This does suggest to me that perhaps some sort of political deal could be arranged that could take AD drugs out of the CMS budget silo. The benefits for the broad community will be so large that it might be advantageous to make AD financing more visible. The thinking is that AD is a century scale medical breakthrough in which the community can unite and have a common purpose. Of course, the cost savings involved will be enormous.
Lecanemab in and of itself will be such a game changer for me personally and for my close family. My estimate as of now is that I will never progress to the severe dementia that has afflicted every generation in my family as far as the eye can see. My understanding of the anti-amyloid mabs is that they will serve as great preventative treatment. Stopping the accumulation of amyloid early will be a safe and effective approach to preventing the progression to further cognitive impairment.
In my family's form of dominant AD dementia we have seen it coming for years and years (even decades ahead) of official onset. The diagnosis of AD has not been a great mystery for us; the cognitive issues were self-apparently present long before the involvement of doctors. In fact, it has been more of a surprise when our family doctor was not sure of an AD diagnosis even nearly at the time of the official diagnosis. Everyone else in the family was at least a decade or more ahead of this.
The problem until this point has been that we had to wait and wait and watch for all these years and years as our loved ones progressed from slight but noticeable cognitive impairment, to MCI, to early AD, to moderate AD, to severe AD and then to complete dependence AD. AD has been our life.
We have been pretty much the most messed up people in town. While we pretended that we were somehow normal, from my perspective of today I really do not see how this was ever actually plausible. Essentially, my entire development has occurred within the context of family coping with various stages of dementing illness. I look forward to watching as the community re-unifies as the dementia life experience resolves through time.
Lecanemab is our ticket out. Given the nature of our dementia experience I do not think it would be realistic not to treat ahead of the official label. We are still unclear about the genetics involved, though full genome sequencing is now on the short term horizon. I want to go 100 times full genome sequencing on a family member's DNA with the family mutation when we move closer to the $100 genome. This might happen even over the next year or so. With an established DNA variant for dominant AD it would be then especially difficult to postpone treatment if one of the family had the variant and had cognitive impairment. The main genetic aspect of our AD has been e33 (with other genetic flavors present) dominant, so in this context early intervention possibly along the lines that I mentioned on thread of low dosing well before official onset would be safe and likely quite effective. I am somewhat unsure about what cognitive level AHEAD is using for inclusion. For us, cognitive impairment was self-apparent even in this so called pre-MCI stage.
Re: Celebration Thread! Biogen is going to the FDA with Aducan.
Hope these treatments have a positive effect for your family over the coming years. No family should have to struggle with Alzheimer's and I appreciate your commitment to understanding and advocating for these solutions.J11 wrote:The problem until this point has been that we had to wait and wait and watch for all these years and years as our loved ones progressed from slight but noticeable cognitive impairment, to MCI, to early AD, to moderate AD, to severe AD and then to complete dependence AD. AD has been our life.
Re: Celebration Thread! Biogen is going to the FDA with Aducan.
Thank you for your deeply honest view of growing up in a family in which Alzheimer's and dementia has had such profound impact.J11 wrote: ↑Wed May 17, 2023 7:22 pm....In fact, it has been more of a surprise when our family doctor was not sure of an AD diagnosis even nearly at the time of the official diagnosis. Everyone else in the family was at least a decade or more ahead of this.
...We are still unclear about the genetics involved, though full genome sequencing is now on the short term horizon.... The main genetic aspect of our AD has been e33 (with other genetic flavors present) dominant, so in this context early intervention possibly along the lines that I mentioned on thread of low dosing well before official onset would be safe and likely quite effective. I am somewhat unsure about what cognitive level AHEAD is using for inclusion. For us, cognitive impairment was self-apparent even in this so called pre-MCI stage.
Although you are unlikely to know the ApoE status going back generations, if several have ApoE 3/3, it's possible that your family experienced multiple "hits", from vascular disease, exposure to pre-EPA environmental toxins in the same small town, other inflammatory processes and even psychosocial stressors that you don't have.
It's also possible that hey had other protein-misfolding diseases: "tauopathies", including Parkinson's, "LATE" ( limbic-predominant age-related TDP-43 encephalopathy, described here.
Here's a startling excerpt, with a happy caveat for people like you and me with many affected relatives:
These Lesser-Known Toxic Proteins Are Found in 60% of Alzheimer’s CasesMany Alzheimer’s brains featured four or more types of structural changes and protein aggregates. One individual may have amyloid plaques, tau tangles, alpha-synuclein plaques, signs of stroke, and Lewy bodies. Another individual with Alzheimer’s meanwhile may have a different combination of these toxic deposits. The researchers also found 35 different combinations of toxic protein deposits and structural changes in cognitively unimpaired individuals.
“A very interesting question is why some elderly individuals are resilient in the face of multiple neurodegenerative disease pathologies, being clinically normal despite having multiple brain pathologies,” Lee said. “Numerous factors are likely related to resilience including cognitive reserve which has been associated with educational attainment and other sociodemographic factors such as being minoritized or living in a deprived neighborhood.”
I've heard multiple researchers, including those leading the CLARITY trial, say that, like cancer, we will likely need a repetoire of prevention and treatment approaches. One of the best ways to advance knowledge is to have large data sets of people in patient registries and/or clinical trials. The AHEAD Clinical Trial is for people 55 and older with intermediate to elevated levels of amyloid beta plaques and cognition within normal limits. I'm in the trial, and may not score what I would have at age 20, but I am still well within WNL. Since they use composite assessments like ADAS-COG-13, you can still score "low" one a test of facial recognition, or memory for a paragraph, and be in the overall normal range. Your family might have had "subjective cognitive impairment" (SCI) seen in people with high levels of achievement and/or occupational challenge, who may be aware of subtle changes in their functioning a decade or more before any true "impairment".
4/4 and still an optimist!
