Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Other alimentary tract and metabolism products, enzymes. ATC code: A16AB12.

Mechanism of action

Mucopolysaccharidoses comprises a group of lysosomal storage disorders caused by the deficiency of specific lysosomal enzymes required for the catabolism of glycosaminoglycans (GAG). MPS IVA 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 chondroitin 6 sulphate (C6S), in the lysosomal compartment of cells throughout the body. The accumulation leads to widespread cellular, tissue, and organ dysfunction. Elosulfase alfa 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. Enzyme uptake by cells into lysosomes is mediated 
by cation independent mannose-6-phosphate receptors leading to restored GALNS activity and clearance of KS and C6S.

Clinical efficacy and safety
Clinical studies performed with Vimizim assessed the impact of treatment on the systemic manifestations of MPS IVA in various domains including endurance, respiratory function, growth velocity, and mobility, as well as urine KS.

A total of 235 patients with MPS IVA were enrolled and exposed to Vimizim in six clinical studies.

The safety and efficacy of Vimizim was assessed in a randomised, double-blind, placebo-controlled, Phase 3 clinical study of 176 patients with MPS IVA, ranging in age from 5 to 57 years. The majority of the patients presented with short stature, impaired endurance, and musculoskeletal symptoms.
Patients who could walk more than 30 meters (m) but less than 325 m in a 6 Minute Walk Test (MWT) at baseline were enrolled in the study.

Patients received elosulfase alfa 2 mg/kg every week (n=58) or 2 mg/kg every other week (n=59), or placebo (n=59) for a total of 24 weeks. All patients were treated with antihistamines prior to each infusion. The primary endpoint was the change from baseline in the 6 MWT distance compared to placebo at Week 24. The secondary endpoints were the change from baseline in the 3 Minute Stair Climb Test (MSCT) and urine KS levels at Week 24. A total of 173 patients subsequently enrolled in an extension study in which patients received 2 mg/kg of elosulfase alfa every week or 2 mg/kg every other week, and then all were switched to 2 mg/kg every week upon availability of the Week 24 results.

The primary and secondary endpoints were evaluated at Week 24 (see Table 3). The modelled treatment effect in the distance walked in 6 minutes, compared to placebo, was 22.5 m (CI95, 4.0, 40.9; p=0.0174) for the 2 mg/kg per week regimen. The modelled treatment effect in stairs climbed per minute, compared to placebo, was 1.1 stairs/minute (CI95, -2.1, 4.4; p=0.4935) for the 2 mg/kg per week regimen. The modelled treatment effect for the percent change in urine KS, compared to placebo, was -40.7 % (CI95, -49.0, -32.4; p<0.0001) for the 2 mg/kg per week regimen. The difference was greatest between the placebo group and the weekly treatment group for all endpoints. The results from the every other week regimen in the distance walked in 6 minutes or in stairs climbed per minute were comparable to placebo.

Table 3: Results from placebo-controlled clinical study at 2 mg per kg per week 
Vimizim                             Placebo
Vimizim vs.
placebo
Baseline Week 24       Change        Baseline   Week 24   Change
N       58          57*       57            59         59        59      Difference in changes 6-Minute walk test (meters)
Mean     203.9       243.3      36.5        211.9        225.4    13.5 ± SD    ±76.32      ±83.53     ±58.49       ±69.88      ±83.22   ±50.63 

Model-based mean‡            22.5
(95%CI)            (CI95, 4.0, 40.9) p-value             (p = 0.0174)
3-Minute stair climb test (stairs/minute)


Mean       29.6        34.9        4.8        30.0           33.6      3.6 ± SD      ±16.44      ± 18.39     ± 8.06     ± 14.05        ± 18.36   ± 8.51 

Model-based mean‡          1.1
(95%CI)         (CI95, -2.1, 4.4) p-value         (p = 0.4935)
* One patient in the Vimizim group dropped out after 1 infusion
‡
Model-based mean of Vimizim versus placebo, adjusted for baseline

In additional extension studies, patients receiving elosulfase alfa 2 mg/kg every week, showed maintenance of initial improvement in endurance and sustained reduction of urinary KS up to 156 weeks.

Paediatric population

It is important to initiate treatment as early as possible.
The majority of patients who received Vimizim during clinical studies were in the paediatric and adolescent age range (5 to 17 years). In an open-label study, 15 paediatric patients with MPS IVA under the age of 5 years (9 months to <5 years) received 2 mg/kg of Vimizim once a week for 52 weeks. Patients continued a long-term follow-up observational study for at least another 52 weeks, for a total of 104 weeks. Safety and pharmacodynamic results in these patients are consistent with results observed in the first 52 weeks (see section 4.8). The baseline mean (±SD) normalised standing height z-score was - 1.6 (±1.61). After the first 52 weeks of treatment the normalised standing height z-score was -1.9 (±1.62). At Week 104 mean (±SD) normalised standing height z-score was -3.1 (± 1.13).

The European Medicines Agency has deferred the obligation to submit the results of studies with Vimizim in one or more subsets of the paediatric population in MPS IVA. See section 4.2 for information on paediatric use.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties


The pharmacokinetic parameters of elosulfase alfa were evaluated in 23 patients with MPS IVA who received weekly intravenous infusions of 2 mg/kg of elosulfase alfa over approximately 4 hours for 22 weeks and the parameters at Week 0 and Week 22 were compared. At Week 22, the mean AUC0-t and Cmax increased by 181 % and 192 % respectively, when compared to Week 0.

Table 4: Pharmacokinetic properties
Week 0                                     Week 22
Pharmacokinetic parameter             Mean (SD)                                   Mean (SD) AUC0-t, minute • µg/ml*                 238 (100)                                   577 (416) Cmax, µg/ml†                          1.49 (0.534)                                 4.04 (3.24) CL, ml/minute/kg‡                      10.0 (3.73)                                 7.08 (13.0) t1/2, minute§                          7.52 (5.48)                                 35.9 (21.5) Tmax, minute¶                          172 (75.3)                                  202 ( 90.8) *
AUC0-t, area under the plasma concentration-time curve from time zero to the time of last measurable concentration;
†
Cmax, observed maximum plasma concentration;
‡
CL, total clearance of elosulfase alfa after intravenous administration; § t1/2, elimination half-life;
¶
Tmax, time from zero to maximum plasma concentration

Biotransformation

Elosulfase alfa 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 elosulfase alfa.
Elimination

Renal elimination of elosulfase alfa is considered a minor pathway for clearance. Mean half-life (t1/2) increased from 7.52 minutes at Week 0 to 35.9 minutes at Week 22. Male and female patients had comparable elosulfase alfa clearance, and clearance did not trend with age or weight at week 22.
Impact of antibodies on elosulfase alfa pharmacokinetics was assessed. No association was apparent between the total antibody titre and elosulfase clearance. However, patients with positive neutralizing antibodies responses had decreased total clearance (CL) values and prolonged t 1/2. Despite the alteration of the pharmacokinetics profile, presence of neutralizing antibodies did not affect pharmacodynamics, efficacy, or safety of the patients who were treated with elosulfase alfa. No accumulation of elosulfase alfa in plasma was evident following weekly dosing.