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

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