VIMIZIM Concentrate solution for injection Ref.[10278] Active ingredients: Elosulfase alfa

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 (14)]. 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 AUC_0‑t and C_max increased to 2.8- and 2.9-fold, respectively, at Week 22 compared to Week 0. Mean t_1/2 increased 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:

* 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.
^† AUC_0-t, area under the plasma concentration-time curve from time zero to the time of last measurable concentration;
^‡ C_max, observed maximum plasma concentration;
^§ T_max, time from zero to maximum plasma concentration;
^¶ CL, total clearance of drug after intravenous administration;
^# N = 15;
^♠ N = 20
^♥ V_dss, apparent volume of distribution at steady-state;
^♦ N = 14;
^♣ t_1/2, elimination half-life

Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with elosulfase alfa. Based on the mechanism of action, elosulfase alfa is not expected to be tumorigenic. Daily intravenous administration of elosulfase alfa in rats at doses up to 20 mg/kg (55 times the human steady-state AUC in male rats and 33 times the human steady-state AUC in female rats at the recommended human weekly dose) had no effects on fertility or reproductive performance.

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:

* 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.