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

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journal contribution

posted on 2019-03-08, 22:50 authored by Tomas Majtan, Erez M. Bublil, Insun Park, Erland Arning, Teodoro Bottiglieri, Frank Glavin, Jan P. Kraus

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.

History

16SDG30040000

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