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

## TL;DR

This study shows that two BACE1 inhibitors, elenbecestat and compound 89, do not inhibit BACE2 in non-human primates, supporting VCAM-1 as a biomarker for BACE2 activity.

## Contribution

The study validates VCAM-1 as a pharmacodynamic biomarker for BACE2 inhibition in cerebrospinal fluid during subchronic dosing.

## Key findings

- Elenbecestat and compound 89 inhibit BACE1 but not BACE2 in non-human primates.
- VCAM-1 levels in CSF remain unchanged with BACE1 inhibition, indicating it is a specific biomarker for BACE2.
- Verubecestat inhibits both BACE1 and BACE2, reducing substrates of both enzymes.

## Abstract

The β‐secretase BACE1 (β‐site amyloid precursor (APP) cleaving enzyme 1) is a major drug target for Alzheimer's disease (AD), as it catalyzes the first step in amyloid β (Aβ) generation, but has additional substrates and functions, in particular in the brain. Several advanced clinical trials with BACE1 inhibitors were stopped because of an adverse event, a mild cognitive worsening. The underlying mechanism is not yet known but may result from co‐inhibition of the BACE1‐homolog BACE2. While a cerebrospinal fluid (CSF) biomarker for measuring BACE2 activity is not yet established, VCAM‐1 has been suggested as such a biomarker, but has not yet been tested upon prolonged dosing in vivo. Using CSF pharmacoproteomics and a subchronic dosing paradigm in non‐human primates, we demonstrate that compound 89, a BACE inhibitor not yet tested in humans, and the clinically tested drug elenbecestat inhibit BACE1 in vivo, with little or no effect on BACE2, as seen with a reduction of substrates of BACE1, but not of the BACE2 substrate VCAM‐1. As a control, verubecestat, which inhibits both BACE2 and BACE1, reduced CSF abundance of BACE1 substrates as well as of VCAM‐1. This study demonstrates the suitability of VCAM‐1 as a pharmacodynamic biomarker for measuring BACE2 target engagement in CSF.