Pharmacokinetic profile of recombinant human N‐acetylgalactosamine 4‐sulphatase enzyme replacement therapy in patients with mucopolysaccharidosis VI (Maroteaux–Lamy syndrome): a phase I/II study

Abstract

Aim: Mucopolysaccharidosis VI (Maroteaux–Lamy syndrome) is a lysosomal storage disease caused by a deficiency of the enzyme N‐acetylgalactosamine 4‐sulphatase (ASB). Enzyme replacement therapy with recombinant human ASB (rhASB) has been studied in a randomized, double‐blind, two‐dose (0.2 and 1.0 mg/kg/week) phase I/II study (n=7) followed by an open‐label single dose (1.0 mg/kg/week) extension study. We report the pharmacokinetic profile of rhASB and the impact of antibody development. Methods: Pharmacokinetic analysis was performed at weeks 1, 2, 12, 24, 83, 84 and 96. Infusions were administered over 4 hours using a ramp‐up protocol. Plasma ASB and rhASB antibody concentrations and urine glycosaminoglycan (GAG) concentrations were determined. Results: The area under the plasma concentration–time curve (AUC0−t) for the high‐dose group increased from week 1 to week 2, but remained unchanged at weeks 12 and 24. A large difference in mean AUC0−t was observed between the low‐ and high‐dose groups. Pharmacokinetic results at weeks 83, 84 and 96 were similar to those at week 24. Six patients developed antibodies to rhASB. One patient developed high antibody levels in combination with a high ASB concentration, while a second patient also developed high antibody levels with undetectable ASB concentrations. Antibodies from the second patient blocked detection of ASB. By week 72, antibody levels had decreased in all patients. The high‐dose rhASB produced a more rapid and greater percentage reduction in urinary GAG concentrations than the lower dose (70% versus 55% at 24 weeks). Antibody levels did not appear to influence urinary GAG concentrations. Conclusion: Pharmacokinetic parameters appear to be independent of the duration of treatment and are not linear between the 0.2 and 1.0 mg/kg/week doses. Antibodies to rhASB develop in most patients, but their concentration decreases over time. Antibody formation may influence pharmacokinetic parameters during the early phases of treatment, although it appears to have limited impact on biochemical efficacy.

Lysosomal storage diseases: Diagnostic confirmation and management of presymptomatic individuals

“…Although visceromegaly in MPS VI is not as prominent as other types of MPS, the five (50%) patients with hepatomegaly in the 48-week open-label phase II trial demonstrated reduction in liver size, with four demonstrating normal age-weight adjusted liver size. 298 In the same study, the three patients with the most severe abnormalities in nocturnal pulse oximetry experienced improvement in average oxygen saturation and decrease in time spent below 90% saturation. In the 24-week phase III doubleblind, randomized, placebo-controlled study, the rhASB group demonstrated a significant improvement in the 12-minute walk test distance compared with the placebo group.…”

“…Results of clinical trials for recombinant human arylsulfatase B (rhASB, Naglazyme; Biomarin Corporation, Novato, CA) have been published. [297][298][299] The 1 mg/kg/week dose produced a greater reduction in urinary GAG excretion compared with the 0.2 mg/kg/week dose. Although visceromegaly in MPS VI is not as prominent as other types of MPS, the five (50%) patients with hepatomegaly in the 48-week open-label phase II trial demonstrated reduction in liver size, with four demonstrating normal age-weight adjusted liver size.…”

Mucopolysaccharidosis I, II, and VI: brief review and guidelines for treatment

“…ERT became a reality approved for clinical use in 2003 for MPS I, in 2005 for MPS VI, and in 2006 for MPS II (Kakkis et al , 2001a,b; Wraith et al , 2004, 2007; Harmatz et al , 2005a,b, 2008; Wraith, 2005; Muenzer et al , 2006, 2007; Sifuentes et al , 2007; Clarke, 2008; Clarke et al , 2009; Giugliani et al , 2009). …”

“…Phase I/II - The study by Harmatz et al (2005b) was performed in six patients, using two different doses of the drug, 1 mg/kg and 0.2 mg/kg, given in weekly infusions during 48 weeks.…”

Natural history and galsulfase treatment in mucopolysaccharidosis VI (MPS VI, Maroteaux–Lamy syndrome)—10‐year follow‐up of patients who previously participated in an MPS VI survey study

“…International management guidelines for MPS VI recommend galsulfase ERT as the first-line therapy for treating MPS VI patients [Giugliani et al, 2007]. Three clinical trials, including a randomized double-blind placebo-controlled Phase 3 trial, showed improved endurance based on increased 12-minute walk test (12MWT) and 3-minute stair-climb (3MSC) measurements, and decreased urinary GAGs, demonstrating efficacy of galsulfase in the MPS VI patients [Harmatz et al, 2006; Harmatz et al, 2005a; Harmatz et al, 2005b; Harmatz et al, 2004]. An analysis of pooled data from the clinical trial program showed improvement in pulmonary function tests and growth velocity in patients (n=56, mean age approximately 12 years, range 5 to 29 years) who received ERT for up to 240 weeks [Decker et al, 2010; Harmatz et al, 2010].…”