ELAPRASE Concentrate for solution for infusion Ref.[9221] Active ingredients: Idursulfase

Pharmacotherapeutic group: Other alimentary tract and metabolism products – enzymes
ATC code: A16AB09

Mechanism of action

Hunter syndrome is an X-linked disease caused by insufficient levels of the lysosomal enzyme iduronate-2-sulfatase. Iduronate-2-sulfatase functions to catabolize the glycosaminoglycans (GAG) dermatan sulfate and heparan sulfate by cleavage of oligosaccharide-linked sulfate moieties. Due to the missing or defective iduronate-2-sulfatase enzyme in patients with Hunter syndrome, glycosaminoglycans progressively accumulate in the cells, leading to cellular engorgement, organomegaly, tissue destruction, and organ system dysfunction.

Idursulfase is a purified form of the lysosomal enzyme iduronate-2-sulfatase, produced in a human cell line providing a human glycosylation profile, which is analogous to the naturally occurring enzyme. Idursulfase is secreted as a 525 amino acid glycoprotein and contains 8 N-linked glycosylation sites that are occupied by complex, hybrid, and high-mannose type oligosaccharide chains. Idursulfase has a molecular weight of approximately 76 kD.

Treatment of Hunter syndrome patients with intravenous idursulfase provides exogenous enzyme for uptake into cellular lysosomes. Mannose-6-phosphate (M6P) residues on the oligosaccharide chains allow specific binding of the enzyme to the M6P receptors on the cell surface, leading to cellular internalization of the enzyme, targeting to intracellular lysosomes and subsequent catabolism of accumulated GAG.

Clinical efficacy and safety

The safety and efficacy of Elaprase has been shown in three clinical studies: two randomised, placebo-controlled clinical studies (TKT008 and TKT024) in adults and children above the age of 5 years and one open-label, safety study (HGT-ELA-038) in children between the age of 16 months and 7.5 years.

A total of 108 male Hunter syndrome patients with a broad spectrum of symptoms were enrolled in the two randomized, placebo-controlled clinical studies, 106 continued treatment in two open-label, extension studies.

Study TKT024

In a 52-week, randomized, double-blind, placebo-controlled clinical study, 96 patients between the ages of 5 and 31 years received Elaprase 0.5 mg/kg every week (n=32) or 0.5 mg/kg every other week (n=32), or placebo (n=32). The study included patients with a documented deficiency in iduronate-2-sulfatase enzyme activity, a percent predicted FVC <80%, and a broad spectrum of disease severity.

The primary efficacy endpoint was a two-component composite score based on the sum of the ranks of the change from baseline to the end of the study in the distance walked during six minutes (6-minute walk test or 6MWT) as a measure of endurance, and % predicted forced vital capacity (FVC) as a measure of pulmonary function. This endpoint differed significantly from placebo for patients treated weekly (p=0.0049).

Additional clinical benefit analyses were performed on individual components of the primary endpoint composite score, absolute changes in FVC, changes in urine GAG levels, liver and spleen volumes, measurement of forced expiratory volume in 1 second (FEV₁), and changes in left ventricular mass (LVM). The results are presented in Table 2.

Table 2. Results from pivotal clinical study at 0.5 mg/kg per week (Study TKT024):

A total of 11 of 31 (36%) patients in the weekly treatment group versus 5 of 31 (16%) patients in the placebo group had an increase in FEV₁ of at least 0.2 l at or before the end of the study, indicating a dose-related improvement in airway obstruction. The patients in the weekly treatment group experienced a clinically significant 15% mean improvement in FEV₁ at the end of the study.

Urine GAG levels were normalized below the upper limit of normal (defined as 126.6 μg GAG/mg creatinine) in 50% of the patients receiving weekly treatment.

Of the 25 patients with abnormally large livers at baseline in the weekly treatment group, 80% (20 patients) had reductions in liver volume to within the normal range by the end of the study.

Of the 9 patients in the weekly treatment group with abnormally large spleens at baseline, 3 had spleen volumes that normalized by the end of the study.

Approximately half of the patients in the weekly treatment group (15 of 32; 47%) had left ventricular hypertrophy at baseline, defined as LVM index 103 g/m². Of these 6 (40%) had normalised LVM by the end of the study. All patients received weekly idursulfase up to 3.2 years in an extension to this study (TKT024EXT).

Among patients who were originally randomised to weekly idursulfase in TKT024, mean maximum improvement in distance walked during six minutes occurred at Month 20 and mean percent predicted FVC peaked at Month 16.

Among all patients, statistically significant mean increases from treatment baseline (TKT024 baseline for TKT024 idursulfase patients and Week 53 baseline for TKT024 placebo patients) were seen in the distance walked 6MWT at the majority of time points tested, with significant mean and percent increases ranging from 13.7m to 41.5m (maximum at Month 20) and from 6.4% to 13.3% (maximum at Month 24) respectively. At most time points tested, patients who were from the original TKT024 weekly treatment group improved their walking distance to a greater extent that patients in the other 2 treatment groups.

Among all patients, mean % predicted FVC was significantly increased at Month 16, although by Month 36, it was similar to the baseline. Patients with the most severe pulmonary impairment at baseline (as measured by % predicted FVC) tended to show the least improvement.

Statistically significant increases from treatment baseline in absolute FVC volume were seen at most visits for all treatment groups combined and for each of the prior TKT024 treatment groups. Mean changes from 0.07 l to 0.31 l and percent ranged from 6.3% to 25.5% (maximum at Month 30). The mean and percent changes from treatment baseline were greatest in the group of patients from the TKT024 study who had received the weekly dosing, across all time points.

At their final visit 21/31 patients in the TKT024 Weekly group, 24/32 in the TKT024 EOW group and 18/31 patients in the TKT024 placebo group had final normalised urine GAG levels that were below the upper limit of normal. Changes in urinary GAG levels were the earliest signs of clinical improvement with idursulfase treatment and the greatest decreases in urinary GAG were seen within the first 4 months of treatment in all treatment groups; changes from Month 4 to 36 were small. The higher the urinary GAG levels at baseline, the greater the magnitude of decreases in urinary GAG with idursulfase treatment.

The decreases in liver and spleen volumes observed at the end of study TKT024 (week 53) were maintained during the extension study (TKT024EXT) in all patients regardless of the prior treatment they had been assigned. Liver volume normalised by Month 24 for 73% (52 out of 71) of patients with hepatomegaly at baseline. In addition, mean liver volume decreased to a near maximum extent by Month 8 in all patients previously treated, with a slight increase observed at Month 36. The decreases in mean liver volume were seen regardless of age, disease severity, IgG antibody status or neutralising antibody status. Spleen volume normalised by Months 12 and 24 for 9.7% of patients in the TKT024 Weekly group with splenomegaly.

Mean cardiac LVMI remained stable over 36 months of idursulfase treatment within each TKT024 treatment group.

In a post-hoc analysis of immunogenicity in studies TKT024 and TKT024EXT (see section 4.8), patients were shown to have either the mis-sense mutation or the frameshift/nonsense mutation. After 105 weeks of exposure to idursulfase, neither antibody status nor genotype affected reductions in liver and spleen size or distance walked in the 6-minute walk test or forced vital capacity measurements. Patients who tested antibody-positive displayed less reduction in urinary output of glycosaminoglycans than antibody-negative patients. The longer-term effects of antibody development on clinical outcomes have not been established.

Study HGT-ELA-038

This was an open-label, multicenter, single-arm study of idursulfase infusions in male Hunter syndrome patients between the age of 16 months and 7.5 years.

Idursulfase treatment resulted in up to 60% reduction in urine output of glycosaminoglycans and in reductions of liver and spleen size: results were comparable to those found in study TKT024. Reductions were evident by week 18 and were maintained to week 53. Patients who developed a high titre of antibodies displayed less response to idursulfase as assessed by urine output of glycosaminoglycans and by liver and spleen size.

Analyses of genotypes of patients in study HGT-ELA-038

Patients were classified into the following groups: missense (13), complete deletion/large rearrangement (8), and frameshift/splice site mutations (5). One patient was unclassified/unclassifiable.

The complete deletion/large rearrangement genotype was most commonly associated with development of high titre of antibodies and neutralising antibodies to idursulfase and was most likely to display a muted response to the medicinal product. It was not possible, however, to accurately predict individual clinical outcome based on antibody response or genotype.

No clinical data exist demonstrating a benefit on the neurological manifestations of the disorder.

This medicinal product has been authorised under “exceptional circumstances”. This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product.

The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.