Vestronidase alfa

Mucopolysaccharidosis VII is a lysosomal storage disorder characterized by the deficiency of betaglucuronidase (GUS) that results in glycosaminoglycans (GAGs) accumulation in cells throughout the body leading to multisystem tissue and organ damage.

Vestronidase alfa is a recombinant form of human GUS and is intended to provide exogenous GUS enzyme for uptake into cellular lysosomes and subsequent catabolism of accumulated GAGs in affected tissues.

The pharmacokinetics of vestronidase alfa were evaluated in a total of 19 MPS VII patients including 15 paediatric patients and 4 adults from 3 clinical trials. After repeated dosing of 4 mg/kg every other week, the maximal serum concentration (C_max) was 20.0 ± 8.1 µg/mL (mean ± s.d.; range: 6.6 to 34.9 µg/mL) and the area under the concentration-time curve from time zero to the last measurable concentration (AUC_0-t) was 57.4 ± 23.9 µg*h/mL (mean ± s.d.; range: 18.8 to 97.0 µg*h/mL). The pharmacokinetics of vestronidase alfa are time independent with repeat dosing. The limited pharmacokinetic data at steady state suggest dose proportional increase in exposure of vestronidase alfa over the dose range of 1 – 4 mg/kg every other week.

Distribution

After repeated dosing of 4 mg/kg every other week in MPS VII patients, the mean ± standard deviation the total volume of distribution (V_ss) was 0.26 ± 0.13 L/kg (range: 0.10 to 0.60 L/kg).

Biotransformation

Vestronidase alfa is a recombinant human enzyme and is therefore eliminated by proteolytic degradation into small peptides and amino acids.

Elimination

After repeated dosing of 4 mg/kg every other week in MPS VII patients, the mean ± standard deviation of the total clearance (CL) was 0.079 ± 0.045 L/h/kg (range: 0.038 to 0.20 L/h/kg); the mean ± standard deviation of the elimination half-life (t_1/2) was 2.6 ± 0.6 hours (range: 0.9 to 3.6 hours).

Excretion

No excretion studies have been conducted in humans. Vestronidase alfa is not expected to be eliminated through renal or faecal excretion.

Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single-dose toxicity in rats, repeated dose toxicity in MPS VII mice and juvenile monkeys, or fertility and embryo-foetal development in rats or rabbits. Studies on pre- and postnatal development have not been performed.

Genotoxicity studies and carcinogenicity studies have not been performed with vestronidase alfa. Based on mechanism of action, rhGUS is not expected to be tumorigenic.