. The BACE1 inhibitor verubecestat (MK-8931) reduces CNS β-amyloid in animal models and in Alzheimer's disease patients. Sci Transl Med. 2016 Nov 2;8(363):363ra150. PubMed.


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  1. It is great for the whole field that the Merck group publishes their preclinical and Phase I data. The results look very promising for the ongoing Phase 3 trials. A very interesting finding is that a potential side effect—the fur depigmentation—only occurred in rodents, but not in the non-human primates, suggesting that this side effect (resulting from BACE2 inhibition) may not be a concern for humans. As such, the regular dermatology testing may no longer be required for future clinical trials. However, this needs to be carefully monitored in the ongoing clinical trials, which will also provide other key outcomes, such as insights into how safe BACE inhibitors are upon long-term treatment and how efficiently they slow cognitive decline in patients. The latter point will inform us about whether BACE inhibition can still be effective at the onset of symptoms or whether they are likely to be even more effective as a preventive treatment. The recent data on aducanumab—although acting through a different mechanism—gives hope that amyloid reduction at the onset of symptoms may still be effective.

    View all comments by Stefan Lichtenthaler
  2. This study demonstrates that verubecestat is a potent, selective, brain-penetrating BACE1 inhibitor with excellent pharmacokinetic properties. The compound also appears to be safe by a number of measures, avoiding some of the toxic effects seen with genetic knockout or other pharmacological inhibitors. Ongoing late-stage clinical trials with verubecestat, both in mild to moderate AD and in prodromal AD subjects, are therefore well-justified and should provide an important test of Aβ as a therapeutic target for AD. The primary concern, however, is that even the prodromal phase may be too late. Amyloid deposition can begin up to 25 years before the onset of symptoms, and it is not yet clear if and when the disease process becomes Aβ-independent and primarily tau-driven. Thus, there are no guarantees that verubecestat will show clear efficacy in these trials.

    View all comments by Michael Wolfe
  3. First of all, I would like to express my respect for the tremendous amount of work performed by Kennedy et al. Protease inhibitors have proven to be effective and safe medications. ACE inhibitors for hypertension are a good example, although they are being replaced by angiotensin receptor blockers.

    MK-8931 potently inhibits both BACE1 and BACE2 without major side effects. The authors also show that the inhibitor reduces sAPPβ in vivo (in animals and humans). Why do BACE inhibitors show much fewer side effects than γ-secretase inhibitors? This is probably because there exists essentially no alternative enzyme for γ-secretase, while at least one, α-secretase, can substitute for the β-secretases (BACE1 and BACE2).

    The above explains why the selective BACE inhibitors do not exhibit major side effects up to a few months. My only concern is about the α-secretase product(s), Aβ17-40/42, which is extremely amyloidogenic in vitro. I am aware, because I have synthetized these peptides by my own hand. Normally, Aβ17-40/42 is not abundant in AD brain (Saido et al., 1996; Iwatsubo et al., 1996). Although the reason for this remains elusive, it is possible that Aβ17-40/42 is easier to catabolize than Aβ1-40/42 in vivo.

    Quantification of sAPPα in the paper would have given an estimate of Aβ17-40/42 production. If MK-8931 causes overproduction and accumulation of Aβ17-40/42 in vivo, pathological consequences might emerge after some years of treatment in people. I suggest that the authors examine the effect of MK-8931 on our single NL-F App knock-in mice (Saito et al.,  2014), which show extensive pathology at six months without overexpressing APP. We probably are the only ones who possess Aβ17-40/42-specific antibodies, extremely difficult to generate, and are willing to help in this context.


    . Amino- and carboxyl-terminal heterogeneity of beta-amyloid peptides deposited in human brain. Neurosci Lett. 1996 Sep 13;215(3):173-6. PubMed.

    . Full-length amyloid-beta (1-42(43)) and amino-terminally modified and truncated amyloid-beta 42(43) deposit in diffuse plaques. Am J Pathol. 1996 Dec;149(6):1823-30. PubMed.

    . Single App knock-in mouse models of Alzheimer's disease. Nat Neurosci. 2014 May;17(5):661-3. Epub 2014 Apr 13 PubMed.

    View all comments by Takaomi Saido

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This paper appears in the following:


  1. Paper Alert: Verubecestat Preclinical and Phase 1 Data Published


  1. Verubecestat