Pharmacokinetics and pharmacodynamics of PEGylated truncated human cystathionine beta-synthase for treatment of homocystinuria

Aims: PEGylated human truncated cystathionine beta-synthase, lacking the C-terminal regulatory domain (PEGCBS),
is a promising preclinical candidate for enzyme replacement therapy in homocystinuria (HCU). It was
designed to function as a metabolic sink to decrease the severely elevated plasma and tissue homocysteine
concentrations. In this communication, we evaluated pharmacokinetics (PK), pharmacodynamics (PD) and subchronic
toxicity of PEG-CBS in homocystinuric mice, wild type rats and monkeys to estimate the minimum
human efficacious dose for clinical trials.
Main methods: Animal models received single or multiple doses of PEG-CBS. Activity of PEG-CBS and sulfur
amino acid metabolites were determined in plasma and used to determine PK and PD.
Key findings: The plasma half-lives of PEG-CBS after a single subcutaneous (SC) injection were approximately 20,
44 and 73 h in mouse, rat and monkey, respectively. The SC administration of PEG-CBS resulted in a significant
improvement or full correction of metabolic imbalance in both blood and tissues of homocystinuric mice. The PD
of PEG-CBS in mouse was dose-dependent, but less than dose-proportional, with the maximal efficacy achieved
at 8 mg/kg. PEG-CBS was well-tolerated in mice and monkeys, but resulted in dose-dependent minimal-tomoderate
inflammation at the injection sites and vacuolated macrophages in rats. Allometric scaling of animal
data was linear and the estimated human efficacious dose was determined as 0.66 mg/kg administered once a
week.
Significance: These results provide critical preclinical data for the design of first-in-human PEG-CBS clinical trial.