Mechanism of Action

Mucopolysaccharide storage disorders are caused by the deficiency of specific lysosomal enzymes required for the catabolism of glycosaminoglycans (GAG). Mucopolysaccharidosis I (MPS I) is characterized by the deficiency of α-L-iduronidase, a lysosomal hydrolase which catalyses the hydrolysis of terminal oc-L-iduronic acid residues of dermatan sulfate and heparan sulfate. Reduced or absent α-L-iduronidase activity results in the accumulation of the GAG substrates, dermatan sulfate and heparan sulfate, throughout the body and leads to widespread cellular, tissue, and organ dysfunction.

The rationale of ALDURAZYME therapy in MPS I is to provide exogenous enzyme for uptake into lysosomes and increase the catabolism of GAG. ALDURAZYME uptake by cells into lysosomes is most likely mediated by the mannose-6-phosphate-terminated oligosaccharide chains of laronidase binding to specific mannose-6-phosphate receptors.

Because many proteins in the blood are restricted from entry into the central nervous system by the blood brain barrier, effects of intravenously administered ALDURAZYME on cells within the central nervous system (CNS) cannot be inferred from activity in sites outside the CNS. The ability of ALDURAZYME to cross the blood brain barrier has not been evaluated in animal models or in clinical trials.

Pharmacokinetics

The pharmacokinetics of laronidase were evaluated in 12 patients with MPS I who received 0.58 mg/kg of ALDURAZYME as a 4 hour infusion. After the 1st, 12th and 26th weekly infusions, the mean maximum plasma concentrations (Cmax) ranged from 1.2 to 1.7 mcg/mL for the 3 time points. The mean area under the plasma concentration-time curve (AUC_∞) ranged from 4.5 to 6.9 mcg • hour/mL. The mean volume of distribution (Vz) ranged from 0.24 to 0.6 L/kg. Mean plasma clearance (CL) ranged from 1.7 to 2.7 mL/min/kg, and the mean elimination half-life (t_½) ranged from 1.5 to 3.6 hours.

Effects of Antibodies

Most patients who received once-weekly infusions of ALDURAZYME developed antibodies to laronidase by week 12. Between weeks 1 and 12, increases in plasma clearance of laronidase were observed in some patients which appeared to be proportional to the antibody titer. At week 26, plasma clearance of laronidase was comparable to that at week 1, in spite of the continued and, in some cases, increased titers of antibodies.

Clinical Studies

ALDURAZYME was studied in a randomized, placebo-controlled clinical trial of 45 MPS I patients of whom 1 patient was clinically assessed as having the Hurler form, 37 Hurler-Scheie, and 7 Scheie. All patients had a baseline forced vital capacity (FVC) less than or equal to 77% of predicted. Patients received ALDURAZYME at 0.58 mg/kg or placebo once-weekly for 26 weeks. All patients were treated with antipyretics and antihistamines prior to each infusion.

The primary efficacy outcome assessments were FVC and distance walked in 6 minutes (6-minute walk test, 6MWT). After 26 weeks, patients treated with ALDURAZYME showed improvement in FVC and in 6MWT compared to placebo-treated patients (see Table 1).

Table 1: Primary Efficacy Outcomes

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