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

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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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Acknowledgments

This study was supported by Bristol-Myers Squibb. The authors would like to acknowledge the writing and editorial support of Brian Atkinson, PhD, Bristol-Myers Squibb.

Conflicts of interest

All authors are employees of Bristol-Myers Squibb.

Author information

Authors and Affiliations

  1. Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb, Hopewell, PO Box 5400, Princeton, NJ, 08543, USA

    Gary Tong, Lorna Castaneda, Jun-Sheng Wang & Randy C. Dockens

  2. Global Biometric Sciences, Bristol-Myers Squibb, Princeton, NJ, USA

    Oleksandr Sverdlov & Shu-Pang Huang

  3. Biomarkers Group, Bristol-Myers Squibb, Wallingford, CT, USA

    Randy Slemmon

  4. Bioanalytical Sciences, Bristol-Myers Squibb, Princeton, NJ, USA

    Huidong Gu & Oi Wong

  5. Safety Reporting, Bristol-Myers Squibb, Hopewell, NJ, USA

    Hewei Li

  6. Global Clinical Research, Bristol-Myers Squibb, Wallingford, NJ, USA

    Robert M. Berman

  7. Research and Development, Bristol-Myers Squibb, Princeton, NJ, USA

    Christina Smith & Charles Albright

Authors
  1. Gary Tong
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  2. Lorna Castaneda
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  13. Randy C. Dockens
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Corresponding author

Correspondence to Gary Tong.

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Tong, G., Castaneda, L., Wang, JS. et al. Effects of Single Doses of Avagacestat (BMS-708163) on Cerebrospinal Fluid Aβ Levels in Healthy Young Men. Clin Drug Investig 32, 761–769 (2012). https://doi.org/10.1007/s40261-012-0006-4

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