ALDURAZYME Concentrate for solution for infusion Ref.[9232] Active ingredients: Laronidase

Pharmacotherapeutic group: Enzymes
ATC code: A16AB05

MPS I disease

Mucopolysaccharide storage disorders are caused by the deficiency of specific lysosomal enzymes required for the catabolism of glycosaminoglycans (GAGs). MPS I is a heterogeneous and multisystemic disorder characterised by the deficiency of α-L-iduronidase, a lysosomal hydrolase which catalyses the hydrolysis of terminal α-L-iduronic residues of dermatan sulfate and heparan sulfate. Reduced or absent α-L-iduronidase activity results in the accumulation of the GAGs, dermatan sulfate and heparan sulfate in many cell types and tissues.

Mechanism of action

The rationale for enzyme replacement therapy is to restore a level of enzymatic activity sufficient to hydrolyse the accumulated substrate and to prevent further accumulation. After intravenous infusion, laronidase is rapidly removed from the circulation and taken up by cells into lysosomes, most likely via mannose-6 phosphate receptors.

Purified laronidase is a glycoprotein with a molecular weight of approximately 83 kDa. Laronidase is comprised of 628 amino acids after cleavage of the N-terminus. The molecule contains 6 N-linked oligosaccharide modifications sites.

Clinical efficacy and safety

Three clinical trials were performed with Aldurazyme to assess its efficacy and safety. One clinical study focussed mainly on assessing the effect of Aldurazyme on the systemic manifestations of MPS I such as poor endurance, restrictive lung disease, upper airway obstruction, reduced joint range of motion, hepatomegaly and visual impairment. One study mainly assessed the safety and pharmacokinetics of Aldurazyme in patients less than 5 years old, but some efficacy measurements were included as well. The third study was conducted to evaluate the pharmacodynamics and safety of different dose regimens of Aldurazyme. To date there are no clinical data that demonstrate any benefit on the neurological manifestations of the disorder.

The safety and efficacy of Aldurazyme was assessed in a randomised, double-blind, placebo controlled, Phase 3 Study of 45 patients, ranging in age from 6 to 43 years. Although patients representing the full range of the disease spectrum were enrolled, the majority of the patients were of the intermediate phenotype, with only one patient exhibiting the severe phenotype. Patients were enrolled with a Forced Vital Capacity (FVC) less than 80% of the predicted value and had to be able to stand for 6 minutes and to walk 5 meters. Patients received either 100 U/kg of Aldurazyme or placebo every week for a total of 26 weeks. The primary efficacy endpoints were changes in percent of predicted normal FVC and absolute distance travelled in the six-minute walk test (6MWT). All patients subsequently enrolled in an open label extension study where they all received 100 U/kg of Aldurazyme every week for an additional 3.5 years (182 weeks).

Following 26 weeks of therapy, Aldurazyme-treated patients showed improved respiratory function and walking ability as compared to placebo as indicated below.

The open label extension study showed improvement and/or maintenance of these effects up to 208 weeks in the Aldurazyme/Aldurazyme group and 182 weeks in the Placebo/Aldurazyme group as indicated in the table below.

¹ The decrease in percent predicted FVC is not clinically significant over this timeframe, and absolute lung volumes continued to increase commensurate with changes in height in growing paediatric patients.
² Both groups exceeded the minimal clinically important difference (-0.24).

Of the 26 patients with abnormal liver volumes at pre-treatment baseline, 22 (85%) achieved a normal liver size by the end of the study. There was a rapid reduction in the excretion of urinary GAG (µg/mg creatinine) within the first 4 weeks, which was maintained through the remainder of the study. Urinary GAG levels decreased by 77% and 66% in the Placebo/Aldurazyme and Aldurazyme/Aldurazyme groups, respectively; at the end of the study one-third of the patients (15 of 45) had reached normal urinary GAG levels.

To address the heterogeneity in disease manifestation across patients, using a composite endpoint that summed up clinically significant changes across five efficacy variables (percent predicted normal FVC, 6MWT distance, shoulder flexion range of motion, AHI, and visual acuity) the global response was an improvement in 26 patients (58%), no change in 10 patients (22%), and a deterioration in 9 patients (20%).

A Phase 2 open-label, 1-year study was conducted that mainly assessed the safety and pharmacokinetics of Aldurazyme in 20 patients less than 5 years of age at the time of enrolment (16 patients with the severe phenotype and 4 with the intermediate phenotype). The patients were scheduled to receive Aldurazyme 100 U/kg weekly infusions for a total duration of 52 weeks. Four patients underwent dosage increases to 200 U/kg for the last 26 weeks because of elevated urinary GAG levels at Week 22.

Eighteen patients completed the study. Aldurazyme was well tolerated at both dosages. The mean urinary GAG level declined by 50% at Week 13 and was reduced by 61% at the end of the study. Upon study completion, all patients showed reductions in liver size and 50% (9/18) had normal liver size. The proportion of patients with mild left ventricular hypertrophy decreased from 53% (10/19) to 17% (3/18), and mean left ventricular mass normalized for body surface area decreased by 0.9 Z-Score (n=17). Several patients showed an increase in height (n=7) and weight (n=3) for age Z-score. The younger patients with the severe phenotype (<2.5 years) and all 4 patients with the intermediate phenotype exhibited a normal rate of mental development, whereas the older patients with a severe phenotype made limited or no gains in cognition.

A phase 4 study was conducted to evaluate the pharmacodynamic effects on urinary GAGs, liver volume, and 6MWT, of different Aldurazyme dose regimens. In this 26-week open label study, 33 MPS I patients received 1 of 4 dose regimens of Aldurazyme: 100 U/kg IV every week (recommended dose), 200 U/kg IV every week, 200 U/kg IV every 2 weeks; or 300 U/kg IV every 2 weeks. No definite benefit was shown with the higher doses over the recommended dose. The 200 U/kg IV every 2 weeks regimen may be an acceptable alternative for patients with difficulty receiving weekly infusions; however, there is no evidence that the long term clinical efficacy of these two dose regimens is equivalent.