Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Other alimentary tract and metabolism products, enzymes, ATC code: A16AB08


Mucopolysaccharide storage disorders are caused by the deficiency of specific lysosomal enzymes required for the catabolism of glycosaminoglycans (GAGs). MPS VI is a heterogeneous and multisystemic disorder characterized by the deficiency of N-acetylgalactoasamine 4-sulfatase, a lysosomal hydrolase which catalyses the hydrolysis of sulfate moiety of the glycosaminoglycan, dermatan sulfate. Reduced or absent N-acetylgalactosamine 4-sulfatase activity results in the accumulation of dermatan sulfate in many cell types and tissues.

The rationale for enzyme replacement therapy is to restore a level of enzymatic activity sufficient to hydrolyze the accumulated substrate and to prevent further accumulation.

Purified galsulfase, a recombinant form of human N-acetylgalactosamine 4-sulfatase, is a glycoprotein with a molecular weight of approximately 56 kD. Galsulfase is comprised of 495 amino acids after cleavage of the N-terminus. The molecule contains 6 N-linked oligosaccharide modification sites.
After intravenous infusion, galsulfase is rapidly removed from the circulation and taken up by cells into lysosomes, most likely via mannose-6 phosphate receptors.

The three clinical studies performed with Naglazyme focused on assessing the systemic manifestations of MPS VI such as endurance, joint mobility, joint pain and stiffness, upper airway obstruction, manual dexterity and visual acuity.

The safety and efficacy of Naglazyme was assessed in a randomised, double blind, placebo controlled, Phase 3 study of 39 MPS VI patients, ranging in age from 5 to 29 years. The majority of the patients presented with short stature, impaired endurance, and musculoskeletal symptoms. Patients who could walk more than 5 meters (m) but less than 250 m in 6 minutes of a 12 Minute Walk test or less than 400 m at the 12 minute time point at baseline were enrolled in the study.

Patients received either 1 mg/kg of galsulfase or placebo every week for a total of 24 weeks. The primary efficacy endpoint was the numbers of meters walked in 12 minutes at Week 24 compared to the number of meters walked at baseline. The secondary efficacy endpoints were the rate of stairs climbed in three minutes and the urinary glycosaminoglycan excretion of treated patients compared to placebo at Week 24. Thirty-eight patients subsequently enrolled in an Open Label extension study where they received 1 mg/kg of galsulfase every week.

Following 24 weeks of therapy, Naglazyme-treated patients experienced a 92 ± 40 m improvement in the distance walked in 12 minutes relative to placebo-treated patients (p = 0.025). Treated patients experienced a 5.7 stair per minute improvement in the 3 Minute Stair Climb relative to placebo-treated patients. Treated patients also experienced a mean decrease in urinary glycosaminoglycan excretion of 238 ± 17.8 μg/mg creatinine (± Standard Error [SE]) following 24 weeks of treatment relative to placebo-treated patients. GAG results approached the normal range for age in the Naglazyme treatment group.

In an additional Phase 4, randomised, two-dose level study, four MPS VI patients <1 year of age were treated at 1 or 2 mg/kg/week for 53 to 153 weeks.

Although limited by the very small number of patients that were enrolled, the conclusions that can be drawn from this study are the following:

Treatment with Naglazyme showed improvement, or lack of worsening, of facial dysmorphism. It did not prevent the progression of skeletal dysplasia and development of hernias and did not prevent the progression of corneal clouding. Growth rate remained normal over this limited follow-up period.
Improved hearing was noted in at least one ear for all four subjects. Urinary GAG levels decreased by more than 70%, consistent with results in older patients.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
The pharmacokinetics of galsulfase were evaluated in 13 patients with MPS VI who received 1 mg/kg of galsulfase as a 4 hour infusion. After 24 weeks of treatment the mean (± Standard Deviation [SD]) maximum plasma concentration (Cmax) was 2,357 (± 1,560) ng/ml and the mean (± SD) area under the plasma concentration-time curve (AUC0-t) was 5,860 (± 4,184) h × ng/ml. The mean (± SD) volume of distribution (Vz) was 316 (± 752) ml/kg and the mean (± SD) plasma clearance (CL) was 7.9 (± 14.7) ml/min/kg. The mean (± SD) elimination half-life (t1/2) was 22.8 (± 10.7) minutes at Week 24.

Pharmacokinetic parameters in Phase 1 patients have remained stable over the long term (through at least 194 weeks).

Galsulfase is a protein and is expected to be metabolically degraded through peptide hydrolysis.
Consequently, impaired liver function is not expected to affect the pharmacokinetics of galsulfase in a clinically significant way. Renal elimination of galsulfase is considered a minor pathway for clearance (see section 4.2).