5 ms·

That systematic review is unfortunately severely flawed. They pooled the old anti-amyloid antibodies (which everybody agrees are inefficacious) and were never u

• pcrh 5mo 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 5mo 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 5mo 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 5mo 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 5mo 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.
          • pfisherman 5mo ago
            No you would not expect all efforts to target AB to work. You can have the right target and the wrong molecule. Look at GLP1s as an example. Multiple pharma companies tried GLP1 receptor agonists for more than a decade and it was not until recently that Novo and Lilly got them to work.
            • pcrh 5mo ago
              The first GLP-1 receptor agonist to enter clinical trials was exenatide by Amylin Pharmaceuticals. It worked from the get go.
              • zosima 5mo ago
                But has only weak/moderate effect on weight loss compared to semaglutide, tirzepatide and retatrutide. Alzheimer is a lot more difficult to measure than weight and amyloid-beta in the brain obviously significantly harder to target than the GLP-1 receptor in the body. Also, a review pooling together all GLP-1's (including those that failed in development) and concluding that they as a class have only moderate or weak effect on weight loss, would obviously be badly misleading.