Translational pharmacokinetic and pharmacodynamic modelling of the anti-ADAMTS-5 NANOBODY (M6495) using the neo-epitope ARGS as a biomarker.

M6495 is a first-in-class NANOBODY molecule and an inhibitor of ADAMTS-5, with the potential to be a disease modifying osteoarthritis drug. In order to investigate the PK/PD (pharmacokinetic and pharmacodynamic) properties of M6495, a single dose study was performed in cynomolgus monkeys with doses up to 6 mg/kg, with the goal of understanding the PK/PD properties of M6495. The neo-epitope ARGS (Alanine-Arginine-Glycine-Serine) generated by cleavage of aggrecan by ADAMTS-5 was used as a target-engagement biomarker. A long-lasting dose-dependent decrease in serum ARGS could be observed after a single dose of M6495 in cynomolgus monkeys. The serum biomarker ARGS decreased to levels below the limit of quantification of the assay in animals which received doses of M6495 of 6 mg/kg and higher, indicating a strong inhibition of ADAMTS-5. Data from the single-dose PK/PD study was combined with data from a multiple dose study, and a non-linear mixed effects model was used to explore the relationship between plasma concentrations of M6495 and the reduction of serum ARGS. The model was subsequently used to inform the clinical phase 1 study design and was successful in predicting the human clinical pharmacokinetics and pharmacodynamics of M6495. In addition to having enabled a Phase 1 trial with M6495, this is the first PK/PD model describing the pharmacodynamics of the neo-epitope ARGS after ADAMTS5 inhibition. It is expected that in the future, this model can be used or adapted to explore the PK/PD relationship between M6495 serum concentrations and the ARGS serum biomarker.