August 24, 2016
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"The U.S. Food and Drug Administration yesterday approved Ruconest, the first recombinant C1-Esterase Inhibitor product for the treatment of acute attacks in adult and adolescent patients with hereditary angioedema (HAE).

Hereditary angioede"...




Mechanism Of Action

Mucopolysaccharidoses comprise a group of lysosomal storage disorders caused by the deficiency of specific lysosomal enzymes required for the catabolism of glycosaminoglycans (GAG). Mucopolysaccharidosis IVA (MPS IVA, Morquio A Syndrome) is characterized by the absence or marked reduction in N-acetylgalactosamine-6-sulfatase activity. The sulfatase activity deficiency results in the accumulation of the GAG substrates, KS and C6S, in the lysosomal compartment of cells throughout the body. The accumulation leads to widespread cellular, tissue, and organ dysfunction. Vimizim is intended to provide the exogenous enzyme N-acetylgalactosamine-6-sulfatase that will be taken up into the lysosomes and increase the catabolism of the GAGs KS and C6S. Elosulfase alfa uptake by cells into lysosomes is mediated by the binding of mannose-6-phosphate-terminated oligosaccharide chains of elosulfase alfa to mannose-6-phosphate receptors.

In the absence of an animal disease model that recapitulates the human disease phenotype, elosulfase alfa pharmacological activity was evaluated using human primary chondrocytes from two MPS IVA patients. Treatment of MPS IVA chondrocytes with elosulfase alfa induced clearance of KS lysosomal storage from the chondrocytes.


The pharmacodynamic effect of Vimizim was assessed by reductions in urinary KS levels. The relationship of urinary KS to other measures of clinical response has not been established [see Clinical Studies]. No association was observed between antibody development and urinary KS levels.


The pharmacokinetics of elosulfase alfa were evaluated in 23 patients with MPS IVA who received intravenous infusions of Vimizim 2 mg/kg once weekly, over approximately 4 hours, for 22 weeks. Eleven patients were aged 5 to 11 years, six were aged 12 to 17 years, and six were aged 18 to 41 years. Table 2 summarizes the pharmacokinetic parameters at Week 0 and Week 22. Mean AUC0-t and Cmax increased to 2.8- and 2.9-fold, respectively, at Week 22 compared to Week 0. Mean t½increased from 7.5 min at Week 0 to 35.9 min at Week 22. These changes are likely related to the development of neutralizing antibodies in all patients.

Table 2: Pharmacokinetic Parameters

Pharmacokinetic Parameter Week 0
(N = 22)* Mean (SD)
Week 22
(N = 22)* Mean (SD)
AUC0-t, min x μg/mL† 238 (100) 577 (416)
Cmax, μg/mL‡ 1.49 (0.534) 4.04 (3.24)
Tmax, min§ 172 (75.3) 202 ( 90.8)
CL, mL/min/kg¶ 10.0 (3.73)# 7.08 (13.0)♠
Vdss, mL/kg♥ 396 (316) ♦ 650 (1842) ♠
t½, min♣ 7.52 (5.48) # 35.9 (21.5)♠
* The pharmacokinetics of elosulfase alfa was evaluated in 23 individual patients. However, 1 patient was not tested at Week 0 and another patient was not tested at Week 22.
†AUC0-t, area under the plasma concentration-time curve from time zero to the time of last measurable concentration;
‡Cmax, observed maximum plasma concentration;
§ Tmax, time from zero to maximum plasma concentration;
¶CL, total clearance of drug after intravenous administration;
#N = 15;
♠N = 20
♥Vdss, apparent volume of distribution at steady-state;
♦N = 14;
♣ t½, elimination half-life

Clinical Studies

The safety and efficacy of Vimizim were assessed in a 24-week, randomized, double-blind, placebo-controlled clinical trial of 176 patients with MPS IVA. The age of patients ranged from 5 to 57 years. The majority of the patients (82%) presented with a medical history of musculoskeletal conditions, which includes knee deformity (52%), kyphosis (31%), hip dysplasia (22%), prior spinal fusion surgery (22%) and arthralgia (20%). At baseline, all enrolled patients could walk more than 30 meters (m) but less than 325 m in six minutes.

Patients received Vimizim 2 mg/kg once per week (n=58), Vimizim 2 mg/kg once every other week (n=59), or placebo (n=59).

The primary endpoint was the change from baseline in the distance walked in six minutes (six minute walk test, 6-MWT) at Week 24. The other endpoints included changes from baseline in the rate of stair climbing in three minutes (three-minute stair climb test, 3-MSCT) and changes from baseline in urine KS levels at Week 24. The treatment effect in the distance walked in 6 minutes, compared to placebo, was 22.5 m (CI95, 4.0, 40.9; p=0.0174) in patients who received Vimizim 2 mg/kg once per week. There was no difference in the rate of stair climbing between patients who received Vimizim 2 mg/kg once per week and those who received placebo. Patients who received Vimizim 2 mg/kg once every other week performed similarly in the 6-MWT and 3-MSCT as those who received placebo. The reduction in urinary KS levels from baseline, a measure of pharmacodynamic effect, was greater in the Vimizim treatment groups compared to placebo. The relationship between urinary KS and other measures of clinical response has not been established.

Table 3: Results from Placebo-Controlled Clinical Trial

  Vimizim 2 mg/kg once per week Placebo Vimizim vs. Placebo
Baseline Week 24 Change Baseline Week 24 Change Mean Difference in Changes
N 58 57* 57 59 59 59  
Six-Minute Walk Test (Meters)
Mean ± SD 203.9± 76.32 243.3± 83.53 36.5± 58.49 211.9± 69.88 225.4± 83.22 13.5± 50.63 23.0† (CI95, 2.9, 43.1)
Median 216.5 251 20 228.9 229.4 9.9 22.5‡ (CI95, 4.0, 40.9) (p = 0.0174)‡,§
Min, Max 42.4, 321.5 52.0, 399.9 -57.8, 228.7 36.2, 312.2 50.6, 501.0 -99.2, 220.5
* One patient in the Vimizim group dropped out after 1 infusion
† Observed Vimizim mean change – Placebo mean change
‡ ANCOVA Model-based Vimizim mean change – Placebo mean change, adjusted for baseline 6MWT categories (less than or equal to 200 meters, greater than 200 meters) and age groups (5-11, 12-18, 19 or older)
§ p-value based on the model-based difference in means

Extension Trial

Patients who participated in the placebo-controlled trial were eligible to continue treatment in an open-label extension trial. One hundred seventy-three of 176 patients enrolled in the extension trial in which patients received Vimizim 2 mg/kg once per week (n=86) or Vimizim 2 mg/kg once every other week (n=87). In patients who continued to receive Vimizim 2 mg/kg once per week for another 48 weeks (for a total of 72-week exposure), walking ability showed no further improvement beyond the first 24 weeks of treatment in the placebo-controlled trial.

Last reviewed on RxList: 2/27/2014
This monograph has been modified to include the generic and brand name in many instances.

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