Aldurazyme Mechanism of Action

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 α-L-iduronidase, a lysosomal hydrolase which catalyses the hydrolysis of terminal α-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 (CNS) by the blood brain barrier, effects of intravenously administered ALDURAZYME on cells within the 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 studies.
Pharmacodynamics: The pharmacodynamic effect of ALDURAZYME was assessed by reductions in urinary GAG levels. The responsiveness of urinary GAG to dosage alterations of ALDURAZYME is unknown, and the relationship of urinary GAG to other measures of clinical response has also not been established (see Clinical Studies as follows).
Clinical Studies: Clinical Studies in Patients 6 Years and Older: Study 1 (NCT00912925) was a randomized, double-blind, placebo-controlled study in 45 patients with MPS I, including 1 patient with the Hurler form, 37 patients with Hurler-Scheie form, and 7 patients with Scheie form of MPS I. Among the 45 patients who completed Study 1, 22 (49%) were male and 23 (51%) were female ranging in age from 6 to 43 years with a mean age of 15.5 years. Thirty seven (82%) were White, 2 (4%) were Asian, 6 (13%) were Other and no patients were Black or African American. For ethnicity, 4 (9%) were Hispanic. All patients had a baseline percent predicted forced vital capacity (FVC) less than or equal to 77%. Patients received ALDURAZYME intravenously at 0.58 mg/kg of body weight once weekly or placebo once weekly for 26 weeks. All 45 randomized patients completed the study.
The primary efficacy outcome assessments were percent predicted FVC and distance walked in 6 minutes (6-minute walk test). After 26 weeks, patients treated with ALDURAZYME showed improvement in percent predicted FVC and in 6-minute walk test compared to placebo-treated patients (see Table 1).

Click on icon to see table/diagram/image

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 patient in the group receiving ALDURAZYME reached the normal range for urinary GAG levels during this 6-month study.
Study 2 (NCT00146770) was a 182-week, open-label, uncontrolled extension study of all 45 patients who completed Study 1. Patients received ALDURAZYME intravenously at 0.58 mg/kg body weight once weekly. Forty (89%) patients completed the study through Week 182. Five (11%) patients, all of whom received placebo in Study 1 and subsequently received Aldurazyme in Study 2 discontinued prematurely. Of these, 2 patients discontinued due to an adverse event, 2 patients due to patient wishes, and 1 patient due to pregnancy. For patients treated with ALDURAZYME, the mean increase in 6-minute walk test distance was maintained for an additional 182 weeks through completion of Study 2.
At the end of Study 2, the decrease in mean urinary GAG was similar to the decrease in urinary GAG reported in ALDURAZYME treated patients at the end of Study 1. The relationship of urinary GAG to other measures of clinical response has not been established.
Clinical Studies in Patients 6 Years and Younger: Study 3 (NCT00146757) was a 52-week, open-label, uncontrolled clinical study in 20 patients with MPS I, including 16 patients (80%) with the Hurler form and 4 patients (20%) with the Hurler-Scheie form. Among the 20 patients who participated in Study 3, 12 (60%) were male and 8 (40%) were female ranging in age from 6 months to 5 years old with a mean age of 2.9 years. Eighteen (90%) were White, 1 (5%) were Black or African American and 1 (5%) were Other. A total of 18 patients completed the study. All 20 patients received ALDURAZYME intravenously at 0.58 mg/kg of body weight once weekly for 26 weeks. After 26 weeks of treatment, 16 patients continued to receive 0.58 mg/kg of body weight once weekly through Week 52, and 4 patients received 1.16 mg/kg of body weight once weekly from Week 26 through Week 52.
Reduction in mean urinary GAG was demonstrated at Week 13 and was maintained through Week 52. No patient receiving ALDURAZYME reached the normal range for urinary GAG levels during this 52-week study. Changes in urinary GAG levels in children 6 years and younger were similar to changes reported in older patients in Studies 1 and 2 (6 through 43 years old). The relationship of urinary GAG to other measures of clinical response has not been established.
Pharmacokinetics: The pharmacokinetics of laronidase were evaluated in 6-year-old or older patients (N=10 to 12) with MPS I who received 0.58 mg/kg of body weight once weekly of ALDURAZYME as a 4-hour infusion in the placebo-controlled clinical study (Study 1). 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_∞) ranged from 4.5 to 6.9 mcg·hour/mL. The mean volume of distribution (V_z) ranged from 0.24 to 0.60 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.
The pharmacokinetics of laronidase were evaluated in 6-year-old or younger patients (N=7 to 9) with MPS I disease who received 0.58 mg/kg of body weight once weekly of ALDURAZYME as a 4-hour infusion in the open label clinical study (Study 3). After the 26th infusion, the 95% confidence interval of the geometric mean values of PK parameters ranged from 0.6 to 1.6 mcg/mL for the maximum plasma concentrations (C_max), from 1.3 to 4.4 mcg·hour/mL for area under the plasma concentration-time curve (AUC_∞), from 0.12 to 0.56 L/kg for volume of distribution (V_z), from 2.2 to 7.7 mL/min/kg for plasma clearance (CL), and from 0.3 to 1.9 hours for elimination half-life (t_½).
Immunogenicity: The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described as follows with the incidence of ADA in other studies, including those of ALDURAZYME or of other laronidase products.
In clinical studies 1, 2, 3 (see Clinical Studies as previously mentioned) and a dose-ranging clinical study that enrolled 8 patients between 3 to 17 years old who received once weekly intravenous doses of 0.58 mg/kg of ALDURAZYME, 70 of 73 (96%) of ALDURAZYME-treated patients developed IgG anti-laronidase antibodies (referred to as ADA). The 3 patients who did not develop ADA were patients with Hurler-Scheie forms of MPS I. In the 70 patients who developed ADA, the onset of ADA positivity in most patients occurred within 2 months after starting ALDURAZYME treatment. ADA titers peaked at approximately 4 months and generally declined over time. Higher ADA titers were observed in patients with Hurler forms of MPS I. Neutralizing antibodies that inhibited cellular uptake of laronidase were detected in 38 of 70 (54%) patients who developed ADA. Neutralizing antibodies that inhibited laronidase enzyme activity were detected in 1 of 70 (1.4%) patients who developed ADA.
Anti-Drug Antibody Effects on Pharmacokinetics: In Study 1, in some ALDURAZYME-treated patients who developed ADA the plasma clearance of laronidase at Week 12 was higher than that at Week 1, and patients with higher ADA titer had higher clearance. At Week 26, plasma clearance of laronidase was comparable to that at Week 1.
Anti-Drug Antibody Effects on Pharmacodynamics: Among the 70 ALDURAZYME-treated patients who developed ADA described as previously mentioned, patients with lower ADA titers tended to have greater than 50% reduction in urinary GAG (uGAG) levels at Week 26, while patients with higher ADA titers tended to have less than 50% reduction in uGAG levels. This correlation was observed in patients with Hurler-Scheie or Scheie form of MPS I. There was no clear correlation in patients with Hurler form of MPS I because these patients had high ADA titers and variable urinary GAG reductions.
In post-marketing studies, an inverse correlation between percent uGAG reduction and ADA titer was observed in ALDURAZYME-treated patients who developed ADA. Patients with sustained ADA titers were more likely to have high ADA titers and tended to have less reduction in uGAG.
Anti-Drug Antibody Effects on Efficacy and Safety: In clinical studies, no correlation was demonstrated between the presence of ADA and therapeutic response for FVC or 6MWT.
In Study 1 and Study 2, 9 ALDURAZYME-treated patients who experienced severe infusion-associated reactions were tested for laronidase-specific IgE antibodies. One of the 9 patients tested positive for laronidase-specific IgE antibodies.
In the MPS I Registry, laronidase-specific IgE and IgG antibodies were evaluated in 10 ALDURAZYME-treated patients who had suspected hypersensitivity reactions and had an immunogenicity sample collected within seven days of event onset (see Adverse Reactions). Of the 10 patients, 9 tested positive for laronidase-specific IgE and/or IgG antibodies and 1 patient tested negative for both IgE and IgG antibodies.
In the postmarketing setting, five ALDURAZYME-treated patients who experienced anaphylaxis had ADA results available within seven days of event onset. Of these 5 patients, 3 patients tested positive for laronidase-specific IgE and/or IgG antibodies and in the other 2 patients, IgE antibodies were not detected and IgG antibody results were not reported.
Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Animal studies to evaluate the mutagenic and carcinogenic potential of laronidase have not been conducted.
Laronidase at intravenous doses up to 3.6 mg/kg (6.2 times the recommended human dose) was found to have no effect on the fertility and reproductive performance of male and female rats.