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Elenbecestat and Compound 89 Potently Inhibit BACE1 but Not BACE2 When Subchronically Dosed in Non-Human Primates.

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Area of Science:

  • Neuroscience
  • Pharmacology
  • Biochemistry

Background:

  • Beta-secretase 1 (BACE1) is a key target for Alzheimer's disease (AD) drug development, catalyzing amyloid-beta (Aβ) generation.
  • Clinical trials of BACE1 inhibitors have faced setbacks due to cognitive side effects, potentially linked to off-target inhibition of the BACE1 homolog, BACE2.
  • VCAM-1 is a proposed cerebrospinal fluid (CSF) biomarker for BACE2 activity, but its in vivo validation is lacking.

Purpose of the Study:

  • To evaluate VCAM-1 as a pharmacodynamic biomarker for BACE2 target engagement in vivo.
  • To assess the in vivo BACE1 and BACE2 inhibitory profiles of novel and existing BACE inhibitors.
  • To investigate the mechanism behind cognitive side effects observed in BACE1 inhibitor trials.

Main Methods:

  • Subchronic dosing of BACE inhibitors (compound 89, elenbecestat, verubecestat) in non-human primates.
  • Cerebrospinal fluid (CSF) pharmacoproteomic analysis to measure substrate levels.
  • Quantification of BACE1 and BACE2 substrates, including VCAM-1, to assess target engagement.

Main Results:

  • Compound 89 and elenbecestat selectively inhibited BACE1, evidenced by reduced BACE1 substrates without affecting VCAM-1 levels.
  • Verubecestat, a dual BACE1/BACE2 inhibitor, reduced both BACE1 and BACE2 substrates (VCAM-1).
  • These findings support VCAM-1's utility as a biomarker for BACE2 inhibition.

Conclusions:

  • VCAM-1 is a suitable pharmacodynamic biomarker for assessing BACE2 target engagement in CSF.
  • Selective BACE1 inhibition can be achieved without affecting BACE2, potentially mitigating cognitive side effects.
  • Understanding BACE1/BACE2 selectivity is crucial for developing safer and more effective Alzheimer's disease therapeutics.