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Derek Lowe's comments on the reboot were understandably a bit skeptical: > [W]hile the new larger EMERGE data do look like there’s a dose-responsive effect in

Derek Lowe's comments on the reboot were understandably a bit skeptical: > [W]hile the new larger EMERGE data do look like there’s a dose-responsive effect in the primary measurement (the CDR-SB scale) and three secondary dementia scores, the ENGAGE data actually show worse than placebo for CDR-SB at the higher dose (see slide 19 in Biogen’s presentation). They’re also worse than placebo in the MMSE scoring, but both the ADAS-Cog13 and the ADAS-ADL-MCI scales show apparent dose-responsive improvement. I have no idea why four different dementia rating systems should give such different results, and to a first approximation, no one else seems to have a good idea, either. So we’ve got the EMERGE/ENGAGE difference to explain (you’ve seen Biogen’s explanation, higher dosing later in the trial), and the variable results within the ENGAGE trial itself. And who are these high-dose patients in the ENGAGE study that Biogen says line up with the EMERGE trial? Ed Silverman at Stat quotes an analyst saying that it looks like fewer than 100 patients out of the whole set. That reminds me a bit of Biogen and Eisai’s tease of “We’re seeing positive data!” during the clinical trials, which also turned out to be based on a smaller number of patients than one would want when making a call on Alzheimer’s efficacy.[1] He's written a fair amount about Alzheimer's,[2] and it's been an informative and useful commentary (at least for me). [1] https://blogs.sciencemag.org/pipeline/archives/2019/10/23/the-return-of-aducanumab https://blogs.sciencemag.org/pipeline/archives/2019/10/23/th... [2] https://search.sciencemag.org/?searchTerm=Lowe https://search.sciencemag.org/?searchTerm=Lowe alzheimers&order=tfidf&limit=textFields&pageSize=10&&

zosima 7y ago
Different dementia rating scales may give different results because the study is underpowered for the effect, and/or Aducanumab is only effective in a subset of patients. There is something to suggest that the latter is the case. The MMSE score usually becomes low relatively late in dementia. The questions are easily solvable for most non-affected people [1] and the cognitive impairment must be quite severe for a significant drop. ADAS-COG on the other hand is more sensitive, especially in early disease [2]. It would be plausible then that patients in an early dementia stage treated with a higher dose, respond, while patients in a later disease stage can not be treated using Aducanumab. (Maybe it even has a paradoxical detrimental effect in late-stage dementia, who knows?) I would hope that they dig down in the data and find an objectively identifiable subpopulation where there appears to be significant effect, and rerun a phase III trial on that subgroup. Even if they only can treat a subset of Alzheimer patients, that's a very significant breakthrough. [1] https://www.bgs.org.uk/sites/default/files/content/attachment/2018-07-05/mini-mental_state_exam.pdf https://www.bgs.org.uk/sites/default/files/content/attachmen... [2] https://www.ncbi.nlm.nih.gov/pubmed/12079572 https://www.ncbi.nlm.nih.gov/pubmed/12079572
- Dylan16807 7y ago
  > Different dementia rating scales may give different results because the study is underpowered for the effect, and/or Aducanumab is only effective in a subset of patients. Though if a couple thousand people is underpowered for the effect, that's not a great sign for the drug.

zosima 7y ago

Different dementia rating scales may give different results because the study is underpowered for the effect, and/or Aducanumab is only effective in a subset of patients. There is something to suggest that the latter is the case. The MMSE score usually becomes low relatively late in dementia. The questions are easily solvable for most non-affected people [1] and the cognitive impairment must be quite severe for a significant drop. ADAS-COG on the other hand is more sensitive, especially in early disease [2]. It would be plausible then that patients in an early dementia stage treated with a higher dose, respond, while patients in a later disease stage can not be treated using Aducanumab. (Maybe it even has a paradoxical detrimental effect in late-stage dementia, who knows?) I would hope that they dig down in the data and find an objectively identifiable subpopulation where there appears to be significant effect, and rerun a phase III trial on that subgroup. Even if they only can treat a subset of Alzheimer patients, that's a very significant breakthrough. [1] https://www.bgs.org.uk/sites/default/files/content/attachment/2018-07-05/mini-mental_state_exam.pdf https://www.bgs.org.uk/sites/default/files/content/attachmen... [2] https://www.ncbi.nlm.nih.gov/pubmed/12079572 https://www.ncbi.nlm.nih.gov/pubmed/12079572

Dylan16807 7y ago
> Different dementia rating scales may give different results because the study is underpowered for the effect, and/or Aducanumab is only effective in a subset of patients. Though if a couple thousand people is underpowered for the effect, that's not a great sign for the drug.