3 ms·

Unfortunately the evidence that targeting amyloid (e.g. Lecanemab and Donanemab) improves the symptoms of Alzheimer's disease is very weak. See the latest syste

by pcrh 6mo ago

Unfortunately the evidence that targeting amyloid (e.g. Lecanemab and Donanemab) improves the symptoms of Alzheimer's disease is very weak. See the latest systematic review [0]. This does not mean however that amyloid plays no role in the disease, the treatment may simply be too late. [0] https://www.cochrane.org/evidence/CD016297_are-medicines-anti-amyloid-monoclonal-antibodies-reduce-build-abnormal-proteins-brain-effective https://www.cochrane.org/evidence/CD016297_are-medicines-ant...

zosima 6mo ago
That systematic review is unfortunately severely flawed. They pooled the old anti-amyloid antibodies (which everybody agrees are inefficacious) and were never used outside clinical trials, with the new anti-amyloid antibodies, that does show modest efficacy in reducing the speed of progression. While these two classes of drugs target the same molecule, they are developed to target amyloid-beta in very different forms. Pooling all those drugs together, and then showing very weak effect, makes absolutely zero sense, and I hope and expect this review to be pulled soon.
- pcrh 6mo ago
  The point of systematic reviews is to be un-biased. So if their question is whether targeting Aβ amyloid is a valid approach they have to include the unsuccessful trails as well as those purported to be successful. As to the trials specifically for Lecanemab and Donanemab, the benefits are not claimed to be either strong or large, even by those who support it. The current support these receive is more aligned with the concept that an improved targeting of Aβ amyloid might improve outcomes. This remains to be demonstrated.
  - pfisherman 6mo ago
    I don’t quite follow the reasoning behind this being “unbiased”. Studies must be designed to answer specific research question. What is the question being asked by the study in question. If the question being asked is whether AB the right target (in humans), then it would need to consider other forms of human evidence, such as genetic evidence, alongside alternative explanations of failure — bad molecule, wrong isoform, bad cohort selection, etc.
    - pcrh 6mo ago
      The question asked in the Cochrane review linked to above is whether there is evidence that current treatments targeting amyloid provide relief. Their conclusion is that the effect is too small to be considered beneficial. Especially when considering the undoubted side-effects, which include edema and micro-bleeding in the brain. It doesn't ask whether amyloid is causative of the disease.
      - zosima 6mo ago
        I wonder. Because if that was the question, why would they include anti-amyloid treatments that were never approved and are not part of any current treatment regimen and dilute the real effect of the approved antibodies? (Not that the approved antibodies are a silver bullet, but clearly they have some positive effect.)
        pcrh 6mo ago
        The Cochrane review did not ask the question of whether Lecanemab (for example) worked, it asked the more general question of whether targeting amyloid worked. If targeting amyloid, generally, worked you might expect all approaches to targeting amyloid to show some efficacy. So they included all those for which clinical trials had been conducted. Obviously some treatments didn't pass the threshold required and so were not subsequently approved. If you only included successful trials you would bias the outcome. It's possible, of course, that some methods of targeting amyloid might work where others failed. But even those that claim success (Donanemab and Lecanemab) have a very modest benefit.
        zosima 6mo ago
        Yes, the new anti-amyloids are not a revolutionary therapy. But they do have a small but definite effect on disease-progression. (something which in a highly noisy indication like Alzheimer's may actually mean a lot more to the patients than it seems by looking at the data. E.g. donepezil and memantine have very modest effects too, but patients and caregivers are still surprisingly positive about them). And since these were developed using different methods and epitopes, it does not make sense to pool them together when doing a comparison. It's obvious that if you combine modestly beneficial compounds and compounds with zero beneficial effect then the mean effect will be worse than the modestly beneficial compounds. And when you do so just because they were aimed at the same molecular target, not even considering if anyone claims that the old, unapproved antibody-therapies, with no positive studies to support them, have any effect, what you are doing is somewhere between extreme ignorance and deception.
rustyhancock 6mo ago
Agreed, especially in some subpopulations. I think the strong case today is to research it's use in people with Dawn's syndrome (accelerated development Alzheimer's Disease due to 3 copies of the APP gene). Target it only to people with those 3 copies. It's legimate as people with DS have a hugely increased risk of AD. Their risk increase seems likely related specifically to Amyloid. Many with DS can consent to it. In general my completely gut feeling is that once we can target Tau we might find that targeting amyloid is needed to fully curtail progression.
- pcrh 6mo ago
  Agreed, using these anti-amyloid treatments at an early stage in people with a high risk of early onset Alzheimer's disease, such as those with Down's syndrome, is likely the most robust test available of the theory that Aβ amyloid is directly causative of this disease. Trials are currently ongoing. The results should start trickling out in a few years...

by pcrh 6mo ago

zosima 6mo ago

That systematic review is unfortunately severely flawed. They pooled the old anti-amyloid antibodies (which everybody agrees are inefficacious) and were never used outside clinical trials, with the new anti-amyloid antibodies, that does show modest efficacy in reducing the speed of progression. While these two classes of drugs target the same molecule, they are developed to target amyloid-beta in very different forms. Pooling all those drugs together, and then showing very weak effect, makes absolutely zero sense, and I hope and expect this review to be pulled soon.

pcrh 6mo ago
The point of systematic reviews is to be un-biased. So if their question is whether targeting Aβ amyloid is a valid approach they have to include the unsuccessful trails as well as those purported to be successful. As to the trials specifically for Lecanemab and Donanemab, the benefits are not claimed to be either strong or large, even by those who support it. The current support these receive is more aligned with the concept that an improved targeting of Aβ amyloid might improve outcomes. This remains to be demonstrated.
- pfisherman 6mo ago
  I don’t quite follow the reasoning behind this being “unbiased”. Studies must be designed to answer specific research question. What is the question being asked by the study in question. If the question being asked is whether AB the right target (in humans), then it would need to consider other forms of human evidence, such as genetic evidence, alongside alternative explanations of failure — bad molecule, wrong isoform, bad cohort selection, etc.
  - pcrh 6mo ago
    The question asked in the Cochrane review linked to above is whether there is evidence that current treatments targeting amyloid provide relief. Their conclusion is that the effect is too small to be considered beneficial. Especially when considering the undoubted side-effects, which include edema and micro-bleeding in the brain. It doesn't ask whether amyloid is causative of the disease.
    - zosima 6mo ago
      I wonder. Because if that was the question, why would they include anti-amyloid treatments that were never approved and are not part of any current treatment regimen and dilute the real effect of the approved antibodies? (Not that the approved antibodies are a silver bullet, but clearly they have some positive effect.)
      - pcrh 6mo ago
        The Cochrane review did not ask the question of whether Lecanemab (for example) worked, it asked the more general question of whether targeting amyloid worked. If targeting amyloid, generally, worked you might expect all approaches to targeting amyloid to show some efficacy. So they included all those for which clinical trials had been conducted. Obviously some treatments didn't pass the threshold required and so were not subsequently approved. If you only included successful trials you would bias the outcome. It's possible, of course, that some methods of targeting amyloid might work where others failed. But even those that claim success (Donanemab and Lecanemab) have a very modest benefit.
        zosima 6mo ago
        Yes, the new anti-amyloids are not a revolutionary therapy. But they do have a small but definite effect on disease-progression. (something which in a highly noisy indication like Alzheimer's may actually mean a lot more to the patients than it seems by looking at the data. E.g. donepezil and memantine have very modest effects too, but patients and caregivers are still surprisingly positive about them). And since these were developed using different methods and epitopes, it does not make sense to pool them together when doing a comparison. It's obvious that if you combine modestly beneficial compounds and compounds with zero beneficial effect then the mean effect will be worse than the modestly beneficial compounds. And when you do so just because they were aimed at the same molecular target, not even considering if anyone claims that the old, unapproved antibody-therapies, with no positive studies to support them, have any effect, what you are doing is somewhere between extreme ignorance and deception.

rustyhancock 6mo ago

Agreed, especially in some subpopulations. I think the strong case today is to research it's use in people with Dawn's syndrome (accelerated development Alzheimer's Disease due to 3 copies of the APP gene). Target it only to people with those 3 copies. It's legimate as people with DS have a hugely increased risk of AD. Their risk increase seems likely related specifically to Amyloid. Many with DS can consent to it. In general my completely gut feeling is that once we can target Tau we might find that targeting amyloid is needed to fully curtail progression.

pcrh 6mo ago
Agreed, using these anti-amyloid treatments at an early stage in people with a high risk of early onset Alzheimer's disease, such as those with Down's syndrome, is likely the most robust test available of the theory that Aβ amyloid is directly causative of this disease. Trials are currently ongoing. The results should start trickling out in a few years...