Pharmacokinetic and Pharmacodynamic Modeling to Optimize the Dose of Vestronidase Alfa, an Enzyme Replacement Therapy for Treatment of Patients with Mucopolysaccharidosis Type VII: Results from Three Trials

Abstract

Introduction: Mucopolysaccharidosis type VII (MPS VII, Sly Syndrome) is a progressive, debilitating, ultra-rare lysosomal storage disorder caused by the deficiency of β-glucuronidase (GUS), an enzyme required for breakdown of glycosaminoglycans (GAGs). Vestronidase alfa, a recombinant human GUS, is an enzyme replacement therapy approved in the US and EU for the treatment of MPS VII.

Methods: The pharmacokinetics (PK) and pharmacodynamics (PD) of vestronidase alfa were evaluated in 23 adult and pediatric subjects with MPS VII enrolled in phase I-III clinical trials to optimize the clinical dosing regimen of vestronidase alfa. The serum concentration-time profiles were adequately described by a two-compartment population PK model incorporating subjects' body weight as the only significant covariate.

Results: Model-based simulations predicted a substantially decreased time duration of serum exposures exceeding the level of Kuptake (the in vitro determined vestronidase alfa concentration corresponding to 50% maximum rate of cellular uptake) for 4 or 8 mg/kg once every 4 weeks dosing, compared with 4 mg/kg once every other week (QOW) dosing by intravenous infusion, suggesting that given the same total monthly dose, the QOW dosing frequency should result in more efficient delivery to the GUS-deficient tissue cells, and therefore superior treatment efficacy. A standard inhibitory maximal effect model reasonably explained the observed pharmacological PD responses of reduction in urinary GAGs from pretreatment baseline, which appeared to have reached the plateau of maximal effect at the 4 mg/kg QOW dose.

Conclusion: The modeling results, together with the clinical evidence of safety and efficacy, supported the recommended 4 mg/kg QOW dosing regimen of vestronidase alfa for pediatric and adult patients with MPS VII.

Clinical trial registration: NCT01856218, NCT02418455, NCT02230566.

Conflict of interest statement

Ethics approval

Study protocols for all procedures performed in studies involving human participants were reviewed and approved by Institutional Review Boards at each investigational site, and conducted in accordance with principles in the Declaration of Helsinki and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Good Clinical Practice guidelines.

Conflict of interest

Yulan Qi, Wenjie Song, and Christine Haller were employees of Ultragenyx Pharmaceutical Inc. at the time of the study. Kathleen McKeever, Julie Taylor, and Jack Shi are employees of Ultragenyx Pharmaceutical Inc. Simon A. Jones has been an investigator and consultant for Ultragenyx Pharmaceutical Inc.

Informed consent

Each participant or his/her legally authorized representative provided written informed consent before entering the study, in compliance with the applicable local regulations.

Figures

Fig. 1

Design of the studies included in the analysis: a study 1 (phase I/II); b study 2 (phase II); and c study 3 (phase III). IV intravenous, QOW every other week

Fig. 2

Diagnostic plots of the final population pharmacokinetic model. a Observed vs. population predicted concentrations. b Observed vs. individual predicted concentrations. c CWRES vs. observed concentrations. d CWRES vs. time. CWRES conditional weighted residuals

Fig. 3

Visual predictive check for the final model. Open symbols are observed data, solid gray line is the median observed concentration, dashed gray lines are the upper and lower 95% observed intervals, solid black line is the median of the simulated data, and dashed black lines are the upper and lower 95th percentiles of the simulated data

Fig. 4

Population prediction (solid line) and observations (symbols) for the relationship between vestronidase alfa exposure and percentage change from baseline in subjects with mucopolysaccharidosis type VII. a Urinary chondroitin sulfate. b Urinary dermatan sulfate. AUC area under the concentration-time curve, QOW every other week, uCS urinary chondroitin sulfate, uDS urinary dermatan sulfate