"Today, the U.S. Food and Drug Administration approved Kanuma (sebelipase alfa) as the first treatment for patients with a rare disease known as lysosomal acid lipase (LAL) deficiency.
Patients with LAL deficiency (also known as Wolman disea"...
Mechanism Of Action
Mucopolysaccharide storage disorders are caused by the deficiency of specific lysosomal enzymes required for the catabolism of GAG. MPS VI is characterized by the absence or marked reduction in N–acetylgalactosamine 4-sulfatase. The sulfatase activity deficiency results in the accumulation of the GAG substrate, dermatan sulfate, throughout the body. This accumulation leads to widespread cellular, tissue, and organ dysfunction. NAGLAZYME is intended to provide an exogenous enzyme that will be taken up into lysosomes and increase the catabolism of GAG. Galsulfase uptake by cells into lysosomes is most likely mediated by the binding of mannose-6-phosphate-terminated oligosaccharide chains of galsulfase to specific mannose-6-phosphate receptors.
The responsiveness of urinary GAG to dosage alterations of NAGLAZYME is unknown, and the relationship of urinary GAG to other measures of clinical response has not been established. No association was observed between antibody development and urinary GAG levels [see ADVERSE REACTIONS].
The pharmacokinetic parameters of galsulfase were evaluated in 13 patients with MPS VI who received 1 mg /kg of NAGLAZYME as a weekly 4-hour infusion for 24 weeks. The pharmacokinetic parameters at Week 1 and Week 24 are shown in Table 2.
Table 2: Pharmacokinetic Parameters (Median, Range)
|Pharmacokinetic Parameter||Week 1||Week 24|
|Cmax (mcg/mL)||0.8 (0.4 to 1.3)||1.5 (0.2 to 5.5)|
|AUC0-t (hr•mcg/mL)*||2.3 (1.0 to 3.5)||4.3 (0.3 to 14.2)|
|Vz (mL/kg)||103 (56 to 323)||69 (59 to 2,799)|
|CL (mL/kg/min)||7.2 (4.7 to 10.5)||3.7 (1.1 to 55.9)|
|Half-life (min)||9 (6 to 21)||26 (8 to 40)|
|* Area under the plasma galsulfase concentration-time curve from start of infusion to 60 minutes post infusion.|
Galsulfase pharmacokinetic parameters listed in Table 2 require cautious interpretation because of large assay variability. Development of anti-galsulfase antibodies appears to affect galsulfase pharmacokinetics, however, the data are limited.
A total of 56 patients with MPS VI, ages 5 years to 29 years, were enrolled in four clinical studies. The majority of patients had severe manifestations of the disease as evidenced by poor performance on a test of physical endurance.
In the randomized, double-blind, multicenter, placebo-controlled clinical trial, 38 patients with MPS VI received 1 mg/kg NAGLAZYME or placebo, once-weekly for 24 weeks. The patients' ages ranged from 5 to 29 years. Enrollment was restricted to patients with a 12-minute walk distance of 5 to 400 meters. All patients were treated with antihistamines prior to each infusion.
The NAGLAZYME-treated group showed greater mean increases in the distance walked in 12 minutes (12-minute walk test, 12-MWT) and in the rate of stair climbing in a 3-minute stair climb test, compared with the placebo group (Table 3).
Table 3: Results from Placebo-Controlled Clinical
|NAGLAZYME||Placebo||NAGLAZYME vs. Placebo|
|Baseline||Week 24||Change||Baseline||Week 24||Change||Difference in Changes|
|Results from the 12-Minute Walk Test (Meters)|
|Mean ± SD Median||227 ± 170||336 ± 227||109 ± 154||381 ± 202||399 ± 217||26 ± 122||83 ± 45†|
|Median||210||316||48||365||373||34||92 ± 40‡
(p = 0.025)‡§
|Percentiles (25th, 75th)||90, 330||125, 483||7, 183||256, 560||204, 573||-3, 89|
|Results from 3-Minute Stair Climb Test (Stairs/Minute)|
|Mean± SD||19.4 ± 12.9||26.9 ± 16.8||7.4 ± 9.9||31.0 ± 18.1||32.6 ± 19.6||2.7 ± 6.9||4.7 ±2.8†|
|Median||16.7||22.8||5.2||24.7||29.0||4.3||5.7 ± 2.9‡
(p = 0.053)‡§
|Percentiles (25th, 75th)||10.0, 26.3||14.8, 33.0||2.2, 9.9||18.1, 51.5||14.2, 57.9||1.0, 6.2|
|* One patient in the placebo group dropped out after 4
weeks of infusion
† Observed mean of NAGLAZYME - Placebo ± SE
‡ Model-based mean of NAGLAZYME - Placebo ± SE, adjusted for baseline
§ p-value based on the model-based mean difference
Following the 24-week placebo-controlled study period, 38 patients received open-label NAGLAZYME for 72 weeks. Among the 19 patients who were initially randomized to NAGLAZYME and who continued to receive treatment for 72 weeks (total of 96 weeks), increases in the 12-MWT distance and in the rate of stair climbing were observed compared to the start of the open-label period (mean [ ± SD] change): 72 ± 116 meters and 5.6 ± 10.6 stairs/minute, respectively). Among the 19 patients who were randomized initially to placebo for 24 weeks, and then crossed over to treatment with NAGLAZYME, the increases after 72 weeks of NAGLAZYME treatment compared to the start of the open-label period, (mean [ ± SD] change): were 118 ± 127 meters and 11.1 ± 10.0 stairs/minute, for the 12-MWT and the rate of stair climbing, respectively.
Bioactivity was evaluated with urinary GAG concentration. Overall, 95% of patients showed at least a 50% reduction in urinary GAG levels after 72 weeks of treatment with NAGLAZYME. No patient receiving NAGLAZYME reached the normal range for urinary GAG levels [see Pharmacodynamics].
In an additional open-label extension study, patients receiving NAGLAZYME showed maintenance of initial improvement in endurance for approximately 240 weeks.
Last reviewed on RxList: 12/1/2014
This monograph has been modified to include the generic and brand name in many instances.
Additional Naglazyme Information
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