FIGURE 3.

Inhibition of human lysyl oxidase‐like 2 (LOXL2) enzymatic activity by PXS‐5338 in clinical trials. (A) LOXL2 protein concentration in human serum is fairly constant over 24 h. Protein concentrations normalised to pre‐dose levels are plotted over time in healthy subjects treated with different doses (placebo, 100, 200 and 400 mg) of PXS‐5338. Mean ± SD with n = 6/time point. Phase 1 study with healthy male volunteers, ANZCTR ACTRN12617001444370. Legend of (A) also applies to (B) and (C). (B) Dose‐dependent inhibition of LOXL2 in plasma following a single oral dose of 100, 200 mg or 400 mg PXS‐5338. PXS‐5878/Simoa® platform used to measure the residual activity. Mean ± SD with n = 6/time point. (C) Pharmacokinetic (PK) profile of PXS‐5338 in healthy human males. The long‐lasting inhibition of LOXL2 activity by PXS‐5338 is driven by the prolonged compound half‐life in humans, with the irreversible nature of inhibition not significantly contributing to pharmacodynamics owing to the fast rate of de novo protein synthesis. (D) Correlation between LOXL2 protein concentration versus % inhibition. Activity data normalised to pre‐dose value. The calculated (correlation between LOXL2 protein concentration versus % inhibition) IC₅₀ of 24 nM is in excellent agreement with IC₅₀ values of 35 and 37 nM generated using recombinant and native human LOXL2, respectively; n = 210.