Egan MF, Kost J, Voss T, Mukai Y, Aisen PS, Cummings JL, Tariot PN, Vellas B, van Dyck CH, Boada M, Zhang Y, Li W, Furtek C, Mahoney E, Harper Mozley L, Mo Y, Sur C, Michelson D. Randomized Trial of Verubecestat for Prodromal Alzheimer's Disease. N Engl J Med. 2019 Apr 11;380(15):1408-1420. PubMed.

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Comments

  1. There really is no way to spin this that avoids the conclusion that these findings weaken, if not falsify, the hypothesis that Aβ production produces Alzheimer’s disease. If there were no effect, there might be some wiggle room left. The fact is that, just like the γ-secretase trials, people get worse; and it looks to be dose-dependent. Can we please redirect our priorities? Sooner rather than later?

    View all comments by Karl Herrup

  2. I side with the closing comments of David Knopman: "To be blunt, Aβ lowering seems to be an ineffective approach, and it is time to focus on other targets to move therapeutics for Alzheimer’s disease forward." We do need a fresh start and also to consider combination therapies and cost-effective multi-arm clinical trials.

    References:

    Knopman DS. Lowering of Amyloid-Beta by β-Secretase Inhibitors - Some Informative Failures. N Engl J Med. 2019 Apr 11;380(15):1476-1478. PubMed.

    View all comments by Stefano Sensi

  3. Not discoursing on the amyloid hypothesis ... However, I do believe one shouldn't forget the alternative BACE1-amyloidolytic activity when attempting to use BACE1-inhibitors in the clinic (Liu et al., 2002; Shi et al., 2003; Kimura et al., 2016).

    References:

    Liu K, Doms RW, Lee VM. Glu11 site cleavage and N-terminally truncated A beta production upon BACE overexpression. Biochemistry. 2002 Mar 5;41(9):3128-36. PubMed.

    Shi XP, Tugusheva K, Bruce JE, Lucka A, Wu GX, Chen-Dodson E, Price E, Li Y, Xu M, Huang Q, Sardana MK, Hazuda DJ. Beta-secretase cleavage at amino acid residue 34 in the amyloid beta peptide is dependent upon gamma-secretase activity. J Biol Chem. 2003 Jun 6;278(23):21286-94. PubMed.

    Kimura A, Hata S, Suzuki T. Alternative Selection of β-Site APP-Cleaving Enzyme 1 (BACE1) Cleavage Sites in Amyloid β-Protein Precursor (APP) Harboring Protective and Pathogenic Mutations within the Aβ Sequence. J Biol Chem. 2016 Nov 11;291(46):24041-24053. Epub 2016 Sep 29 PubMed.

    View all comments by Carla Bento

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