Supplementary Materials

Supplementary Material for:

The BACE1 inhibitor verubecestat (MK-8931) reduces CNS β-amyloid in animal models and in Alzheimer's disease patients

Matthew E. Kennedy,* Andrew W. Stamford,* Xia Chen, Kathleen Cox, Jared N. Cumming, Marissa F. Dockendorf, Michael Egan, Larry Ereshefsky, Robert A. Hodgson, Lynn A. Hyde, Stanford Jhee, Huub J. Kleijn, Reshma Kuvelkar, Wei Li, Britta A. Mattson, Hong Mei, John Palcza, Jack D. Scott, Michael Tanen, Matthew D. Troyer, Jack L. Tseng, Julie A. Stone, Eric M. Parker*, Mark S. Forman*

*Corresponding author. Email: matthew.kennedy{at}merck.com (M.E.K.); andy.stamford1{at}gmail.com (A.W.S.); ericmcparker{at}comcast.net (E.M.P.); mark.forman{at}merck.com (M.S.F.)

Published 2 November 2016, Sci. Transl. Med. 8, 363ra150 (2016)
DOI: 10.1126/scitranslmed.aad9704

This PDF file includes:

  • Materials and Methods
  • Fig. S1. Time course of total plasma (closed circles), brain (open circles), and CSF (stars) concentrations of verubecestat after oral administration of a single dose to rats.
  • Fig. S2. Effect of oral administration of a single dose of verubecestat on CSF sAPPβ concentrations in cisterna magna–cannulated cynomolgus monkeys.
  • Fig. S3. Chronic (9-month) oral administration of verubecestat reduces CSF and cortical Aβ40, Aβ42, and sAPPβ in cynomolgus monkeys.
  • Fig. S4. Chronic (3-month) oral administration of verubecestat reduces cortical Aβ40 in rats.
  • Fig. S5. Chronic verubecestat treatment causes fur hypopigmentation in Dutch belted rabbits.
  • Fig. S6. Single doses of verubecestat reduce plasma Aβ40 after oral administration to healthy nonelderly adults.
  • Fig. S7. Multiple doses of verubecestat reduce plasma Aβ40 after oral administration to healthy nonelderly adults.
  • Fig. S8. Schematic of the amyloid dynamics model.
  • Fig. S9. Model-based representation of verubecestat effects on CSF Aβ40, Aβ42, and sAPPβ in the three phase 1 studies.
  • Table S1. Activity of verubecestat at additional targets.
  • Table S2. Total plasma, CSF, and brain concentrations of verubecestat after acute oral administration to rats.
  • Table S3. Total plasma, CSF, and brain concentrations of verubecestat after acute oral administration to cynomolgus monkeys.
  • Table S4. Total plasma, CSF, and brain concentrations of verubecestat after chronic oral administration to cynomolgus monkeys.
  • Table S5. Total plasma and brain concentrations of verubecestat after chronic oral administration to rats.
  • Table S6. Animal PK properties of verubecestat.
  • Table S7. Serum glucose concentrations after chronic treatment of rats with verubecestat for 6 months.
  • Table S8. Serum glucose concentrations after chronic treatment of monkeys with verubecestat for 9 months.
  • Table S9. PK of verubecestat after single-dose administration to healthy nonelderly adults (experiment shown in Fig. 4).
  • Table S10. PK of verubecestat after multiple-dose administration to healthy nonelderly adults (day 14) (experiment shown in Fig. 5).
  • Table S11. PK of verubecestat after multiple-dose administration to patients with AD (day 7) (experiment shown in Fig. 6).
  • Table S12. Number (%) of healthy nonelderly adults with adverse events after administration of single oral doses of verubecestat.
  • Table S13. Number (%) of healthy nonelderly adults with adverse events in the multiple-dose study after once-daily oral administration of verubecestat for 14 days.
  • Table S14. Number (%) of AD patients with adverse events after once-daily oral administration of verubecestat for 7 days.
  • Table S15. Model-based estimates of verubecestat effects on de novo brain production of Aβ40, Aβ42, and sAPPβ in humans.

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Other Supplementary Material for this manuscript includes the following:

  • Protocols (.pdf format).

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