Drug Discovery 2021 After the Storm: Re-connect, Re-invent, Re-imagine

Plasma LOXL2 target engagement by GB2064, a high affinity, small-molecule LOXL2 inhibitor, in a phase 1 healthy subject study.


J Roper1; A Santani2; G Bains2; R Slack1
1 Galecto, Inc., UK;  2 PharmAkea, Inc., UK


GB2064 is a high affinity, selective, pseudo-irreversible, small-molecule inhibitor of LOXL2, a secreted glycoprotein that crosslinks extracellular matrix (ECM) collagens & elastin contributing to the stiffness & loss of function of fibrotic organs, that is currently being developed for myelofibrosis. In this study we describe the target engagement (TE) of plasma LOXL2 by GB2064 in a phase 1 healthy subject study using an exploratory assay with ferrite beads chemically coupled to a LOXL2 inhibitor to capture only free/unbound LOXL2. A single-centre, randomised, placebo-controlled study was completed to assess safety, tolerability, & PK/PD of GB2064 in 78 healthy subjects. Single doses (150 to 2500 mg) & multiple doses of GB2064 (150 to 2000 mg QD or 1000 mg BID) for 7 days were found to be safe & well tolerated with no appreciable accumulation in plasma & steady state attained within 1-2 days. When dosed orally GB2064 bound circulating plasma LOXL2 & inhibited the capture of LOXL2 by inhibitor-coupled beads. At 2 h post-dosing, binding to LOXL2, defined as TE, increased in a dose-related fashion with near maximal target engagement observed at doses at or above 750 mg. The in vivo IC50 (905 nM) for LOXL2 binding/TE was shown to be very comparable to that determined in vitro in human blood (715 nM). TE was comparable between identical dosing groups in SAD & MAD & within dosing groups on Day 1 & 7. The consistency of these data illustrates the reproducibility of this exploratory assay & validation for future use in phase 2 clinical studies.

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