Clinical Drug Investigation

, Volume 32, Issue 11, pp 761–769

Effects of Single Doses of Avagacestat (BMS-708163) on Cerebrospinal Fluid Aβ Levels in Healthy Young Men

  • Gary Tong
  • Lorna Castaneda
  • Jun-Sheng Wang
  • Oleksandr Sverdlov
  • Shu-Pang Huang
  • Randy Slemmon
  • Huidong Gu
  • Oi Wong
  • Hewei Li
  • Robert M. Berman
  • Christina Smith
  • Charles Albright
  • Randy C. Dockens
Original Research Article

Abstract

Background

The concentration of amyloid β (Aβ) peptides in cerebrospinal fluid (CSF) is a biomarker for Alzheimer’s disease (AD) pathology, and has been used to evaluate the effectiveness of γ-secretase inhibition. Avagacestat is a selective γ-secretase inhibitor in development for the treatment of AD. The primary objective of this study was to assess the effects of single oral doses of avagacestat on the CSF Aβ concentrations in healthy male subjects. Secondary objectives included single-dose pharmacokinetics in CSF and plasma, safety and tolerability.

Methods

This was a double-blind, placebo-controlled, randomized, single-dose study. Healthy male subjects were assigned to one of three sequential avagacestat dose panels (50, 200 and 400 mg) or placebo as single oral doses.

Results

34 subjects were enrolled. Administration of a single dose of 200 or 400 mg of avagacestat resulted in a marked decrease in CSF Aβ1–38, Aβ1–40 and Aβ1–42 concentrations vs placebo; with smaller decreases observed in the 50 mg dose group. Avagacestat was quickly absorbed into the systemic circulation, with a mean time to reach maximum plasma concentration (tmax) of approximately 1–2 h, and a CSF tmax of approximately 3 h. Adverse events were uncommon and occurred with similar frequency in the placebo and avagacestat groups.

Conclusion

Avagacestat was safe, well tolerated, and resulted in a notable decrease in CSF Aβ concentrations, suggestive of γ-secretase inhibition. The results warrant further clinical study in patients with AD.

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Copyright information

© Springer International Publishing Switzerland 2012

Authors and Affiliations

  • Gary Tong
    • 1
  • Lorna Castaneda
    • 1
  • Jun-Sheng Wang
    • 1
  • Oleksandr Sverdlov
    • 2
  • Shu-Pang Huang
    • 2
  • Randy Slemmon
    • 3
  • Huidong Gu
    • 4
  • Oi Wong
    • 4
  • Hewei Li
    • 5
  • Robert M. Berman
    • 6
  • Christina Smith
    • 7
  • Charles Albright
    • 7
  • Randy C. Dockens
    • 1
  1. 1.Discovery Medicine and Clinical PharmacologyBristol-Myers Squibb, HopewellPrincetonUSA
  2. 2.Global Biometric SciencesBristol-Myers SquibbPrincetonUSA
  3. 3.Biomarkers GroupBristol-Myers SquibbWallingfordUSA
  4. 4.Bioanalytical SciencesBristol-Myers SquibbPrincetonUSA
  5. 5.Safety ReportingBristol-Myers SquibbHopewellUSA
  6. 6.Global Clinical ResearchBristol-Myers SquibbWallingfordUSA
  7. 7.Research and DevelopmentBristol-Myers SquibbPrincetonUSA

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