Enzyme replacement therapy for mucopolysaccharidosis VI: Growth and pubertal development in patients treated with recombinant human N-acetylgalactosamine 4-sulfatase

Abstract

BACKGROUND AND METHODS: Growth failure is characteristic of untreated mucopolysaccharidosis type VI (MPS VI: Maroteaux-Lamy syndrome). Growth was studied in fifty-six MPS VI patients (5 to 29 years old) prior to and for up to 240 weeks of weekly infusions of recombinant human arylsulfatase B (rhASB) at 1 mg/kg during Phase 1/2, Phase 2, Phase 3 or Phase 3 Extension clinical trials. Height, weight, and Tanner stage data were collected. Pooled data were analyzed to determine mean height increase by treatment week, growth impacts of pubertal status, baseline urinary GAG, and age at treatment initiation. Growth rate for approximately 2 years prior to and following treatment initiation was analyzed using longitudinal modeling. RESULTS: Mean height increased by 2.9 cm after 48 weeks and 4.3 cm after 96 weeks on enzyme replacement therapy (ERT). Growth on ERT was not correlated with baseline urinary GAG. Patients under 16 years of age showed greatest increases in height on treatment. Model results based on pooled data showed significant improvement in growth rate during 96 weeks of ERT when compared to the equivalent pretreatment time period. Delayed pubertal onset or progression was noted in 10 patients entering the clinical trials; all of whom showed progression of at least one Tanner stage during 2 years on ERT, and 6 of whom (60%) completed puberty. CONCLUSION: Analysis of mean height by treatment week and longitudinal modeling demonstrate significant increase in height and growth rate in MPS VI patients receiving long-term ERT. This impact was greatest in patients aged below 16 years. Height increase may result from bone growth and/or reduction in joint contractures. Bone growth and resolution of delayed puberty may be related to improvements in general health, bone cell health, nutrition, endocrine gland function and reduced inflammation.

Fig. 1

Height, observed mean overall and by pubertal status at initiation of ERT. Each point represents the mean height (cm) for the group of patients observed at number of weeks on ERT indicated by x-axis. Asterisks (*) denote p-values < 0.05 at week 96 compared to baseline.

Fig. 2

Height, observed mean by GAG level and by age category at initiation of ERT. Each point represents the mean height (cm) for the group of patients observed at number of weeks on ERT indicated by x-axis. Asterisks (*) denote p-values < 0.05 at week 96 compared to baseline.

Fig. 3

Observed height over two years, with fitted regression line. Each symbol/color combination represents a single patient’s height measurement at the time indicated on the x-axis. In this figure, each dot represents an actual measurement. Time 0 is the time of initiation of ERT.

Fig. 4

Modeled rates of growth over one year compared to WHO growth charts. Each hatched bar represents the normal range of rates of growth by year of age. The bottom of the box represents the 1st percentile; the top represents the 99th percentile. Each dot shows an individual patient’s Tanner score at time of initiation of ERT and the rate of growth pre- and post- initiation of ERT. For patients without a pre-ERT measurement, the baseline values were imputed by a longitudinal model (see text). (Reference for normal rates: http://www.who.int/childgrowth/standards/en/).