Aldurazyme (Laronidase) - Description and Clinical Pharmacology

DESCRIPTION

ALDURAZYME^® (laronidase) is a polymorphic variant of the human enzyme, (alpha)-L-iduronidase that is produced by recombinant DNA technology in a Chinese hamster ovary cell line. (alpha)-L-iduronidase (glycosaminoglycan (alpha)-L-iduronohydrolase, EC 3.2.1.76) is a lysosomal hydrolase that catalyses the hydrolysis of terminal (alpha)-L-iduronic acid residues of dermatan sulfate and heparan sulfate.

Laronidase is a glycoprotein with a molecular weight of approximately 83 kD. The predicted amino acid sequence of the recombinant form, as well as the nucleotide sequence that encodes it, are identical to a polymorphic form of human (alpha)-L-iduronidase. The recombinant protein is comprised of 628 amino acids after cleavage of the N-terminus and contains 6 N-linked oligosaccharide modification sites. Two oligosaccharide chains terminate in mannose-6-phosphate sugars. ALDURAZYME has a specific activity of approximately 172 U/mg.

ALDURAZYME, for intravenous infusion, is supplied as a sterile, nonpyrogenic, colorless to pale yellow, clear to slightly opalescent solution that must be diluted prior to administration in 0.9% Sodium Chloride Injection, USP containing 0.1% Albumin (Human). The solution in each vial contains a nominal laronidase concentration of 0.58 mg/mL and a pH of approximately 5.5. The extractable volume of 5.0 mL from each vial provides 2.9 mg laronidase, 43.9 mg sodium chloride, 63.5 mg sodium phosphate monobasic monohydrate, 10.7 mg sodium phosphate dibasic heptahydrate, and 0.05 mg polysorbate 80. ALDURAZYME does not contain preservatives; vials are for single use only.

CLINICAL PHARMACOLOGY

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 (alpha)-L-iduronidase, a lysosomal hydrolase which catalyses the hydrolysis of terminal (alpha)-L-iduronic acid residues of dermatan sulfate and heparan sulfate. Reduced or absent (alpha)-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 1^st, 12^th and 26^th weekly infusions, the mean maximum plasma concentrations (C_max) ranged from 1.2 to 1.7 mcg/mL for the 3 time points. The mean area under the plasma concentration-time curve (AUC_(infinity)) ranged from 4.5 to 6.9 mcg·hour/mL. The mean volume of distribution (V_z) 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_1/2) 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).

Evaluations of bioactivity were changes in liver size and urinary GAG levels. Liver size and urinary GAG levels decreased in patients treated with ALDURAZYME compared to patients treated with placebo. No subject in the group receiving ALDURAZYME reached the normal range for urinary GAG levels during this 6-month study.

All 45 patients received open-label ALDURAZYME for 36 weeks following the double-blind period. Maintenance of mean FVC and an additional increase in mean 6MWT distance were observed compared to the start of the open-label period among patients who were initially randomized to and then continued to receive ALDURAZYME. Among patients who had been initially randomized to placebo, improvements from baseline in mean FVC and 6MWT distance were observed compared to the start of the open-label period.