Elaprase - Scientific Information
|Condition:||Mucopolysaccharidosis Type II|
|Form:||Liquid solution, Intravenous (IV)|
|Ingredients:||idursulfase, polysorbate 20, sodium chloride, sodium phosphate dibasic heptahydrate, sodium phosphate monobasic monohydrate, water for injection|
|Molecular formula and molecular mass:|
|Idursulfase is a glycoprotein with a molecular weight of approximately 76 kilodaltons, consisting of 525 amino acids.|
|This molecule consists of 525 amino acids. Idursulfase is human iduronate-2-sulfatase manufactured by recombinant DNA technology in a continuous human cell line. The amino acid sequence of idursulfase, determined by sequencing of cDNA in the Master Cell Bank and Working Cell Bank and confirmed by peptide mass mapping and Nterminal sequencing, is illustrated below. The 8 sites of N-linked glycosylation are noted.|
Amino Acid Sequence of Idursulfase
ELAPRASE (idursulfase) is a clear to slightly opalescent, colorless solution. As supplied,
ELAPRASE has a pH of approximately 6.
Study Demographics and Trial Design
|Study #||Trial design||Dosage, route of
|0.5 mg/kg idursulfase weekly or every other week or placebo, intravenous infusion, 52 weeks of infusions||n=96||14 years
(5 – 31 years)
|TKT024EXT||Phase II/III multicenter, singlearm, open-label extension study of TKT024||0.5 mg/kg idursulfase weekly, intravenous infusion, 156 weeks of infusion||n=94||15 years*
|HGT-ELA-038||Open-label, multicenter, single-arm study||0.5 mg/kg idursulfase weekly, intravenous infusion, 52 weeks of infusion||n=28||4 years
*Age at first infusion of 0.5 mg/kg weekly idursulfase
The safety and efficacy of ELAPRASE were evaluated in a randomized, double-blind, placebo controlled clinical study of 96 patients with Hunter syndrome. The study included patients with a documented deficiency in iduronate-2-sulfatase enzyme activity who had a percent predicted forced vital capacity (%-predicted FVC) less than 80%. Patients who were unable to perform the appropriate pulmonary function testing or those who could not follow protocol instructions were excluded from the study. Patients received ELAPRASE 0.5 mg/kg every week (n=32), ELAPRASE 0.5 mg/kg every other week (n=32), or placebo (n=32). The study duration was 53 weeks.
The primary efficacy outcome assessment in the 53-week placebo-controlled study was a two-component composite score based on the sum of the ranks of the change from baseline to Week 53 in distance walked during a six-minute walk test (6-MWT) and the ranks of the change in %-predicted FVC. This two-component composite primary endpoint differed statistically significantly between the three groups, and the difference was greatest between the placebo group and the weekly treatment group (weekly ELAPRASE vs. placebo, p=0.0049).
Additional clinical benefit analyses were performed on individual components of the primary endpoint composite score (6-MWT and %-predicted FVC, see Table 2), and on FVC absolute volume, urine GAG levels, liver and spleen volumes (see Table 3), and measurement of forced expiratory volume in 1 second (FEV1), and left ventricular mass (LVM).
The analyses of the components of the composite score demonstrated that, for the 6-MWT, the weekly ELAPRASE group mean adjusted difference in meters walk from baseline to Week 53 was 35 meters compared to placebo (p=0.0131).
The change in %-predicted FVC in the weekly group was 4.3% greater compared to placebo, however this was not statistically significant.
|n||Baseline||Week 53 Change||Adjusted
|Total Distance Walked in 6MWT (m)|
|ELAPRASE Weekly||32||391.63 (19.10)||44.28 (12.31)||36.95 (10.89)|
|Placebo||32||392.47 (18.72)||7.28 (9.46)||1.86 (11.84)|
|Difference||35.09 (13.69)||7.66, 62.52||0.0131|
|Forced Vital Capacity (% of Predicted)|
|ELAPRASE Weekly||32||55.30 (2.80)||3.45 (1.77)||1.29 (1.73)|
|Placebo||32||55.57 (2.18)||0.75 (1.70)||-2.99 (1.85)|
|Difference||4.28 (2.27)||-0.27, 8.83||0.0650|
|n||Baseline||Week 53 Change||Adjusted
|Forced Vital Capacity Absolute Volume (L)|
|32||1.19(0.10)||0.22 (0.05)||0.18 (0.04)|
|Placebo||32||1.09 (0.09)||0.06 (0.03)||-0.01 (0.04)|
|Difference||0.19 (0.06)||0.08, 0.30||0.0011|
|Normalized Urine GAG (μg/mg creatinine)|
|ELAPRASE Weekly||32||325.59(25.79)||-189.23 (25.76)||-224.90 (22.10)|
|Placebo||32||419.40(34.37)||18.16 (29.94)||50.63 (21.29)|
|Difference||-275.54 (30.10)||-335.82, -215.25||<0.0001|
|Liver Volume (cc)a|
|ELAPRASE Weekly||31||1262.30(49.83)||-25.34% (1.57)||-25.61% (1.66)|
|Placebo||30||1197.78(47.81)||-0.85% (1.60)||-0.44 % (1.62)|
|Difference||25.16% (2.19)||-29.56%, -20.77%||<0.0001|
|Spleen Volume (cc)a|
|ELAPRASE Weekly||31||316.18 (39.46)||-25.05% (2.36)||-25.12% (3.48)|
|Placebo||30||287.49(29.96)||7.21% (4.15)||8.10% (3.62)|
|Difference||-33.22% (4.79)||-42.82%, -23.61%||<0.0001|
a ANCOVA analysis was based upon percentage change from baseline
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 ELAPRASE weekly.
Of the 25 patients with abnormally large livers at baseline in the ELAPRASE weekly 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 ELAPRASE weekly group with abnormally large spleens at baseline, 3 had spleen volumes that normalized by the end of the study.
A total of 11 of 31 (36%) patients in the ELAPRASE weekly group versus 5 of 31 (16%) patients in the placebo group had an increase in FEV1 of at least 200 cc at or before the end of the study, indicating an improvement in airway obstruction. The patients in the weekly ELAPRASE treated group experienced a clinically significant 15% mean improvement in FEV1 at the end of the study.
Approximately half of the patients in the ELAPRASE weekly group (15 of 32; 47%) had left ventricular hypertrophy at baseline, defined as LVM index >103 g/m2. Of these, 6 patients (40%) had normalized LVM by the end of the study.
TKT024 Extension Study
Patients who participated in the controlled study were eligible to continue treatment in an open label extension study. 94 patients enrolled and received ELAPRASE 0.5mg/kg weekly.
Statistically significant improvements from baseline in mean and percent increases in distance walked in the 6-MWT ranged from 13.7 (SE 4.76) to 41.5 (SE 9.55) meters and from 6.4% (SE 2.71) to 11.7% (SE 2.96), respectively (maximum at Month 20). Patients who were treated with weekly ELAPRASE in the controlled study generally improved their walking distance to a greater extent than patients in the other treatment groups.
Statistically significant increases from baseline in absolute FVC volume ranged from 0.07 L (SE 0.018) to 0.31 L (SE 0.059) and percent changes ranged from 6.32% (SE 1.317) to 25.47% (SE 4.129) (maximum at Month 30). The mean and percent changes from treatment baseline were greatest in patients who initiated therapy with weekly ELAPRASE. Percentage predicted FVC remained stable in all Hunter syndrome patients treated for 2 to 3 years with idursulfase 0.5 mg/kg weekly.
Reductions in mean urine GAG levels were maintained in patients initially treated with weekly ELAPRASE, and those initially treated every other week experienced further mean reductions. At the completion of the extension study, mean urine GAG levels fell below the upper limit of normal in patients who initiated treatment with ELAPRASE and were near normal in those who were initially in the placebo group and later switched to enzyme therapy. Change in the urine GAG levels was the earliest sign of clinical improvement with ELAPRASE treatment and the greatest decreases in urine GAG were seen in the first 4 months of treatment. In those patients whose urine GAG levels fell to within the normal range, this fall was regardless of patient age, disease severity at baseline, and residual iduronate-2-sulfatase activity category. The higher the urine GAG levels at baseline, the greater the magnitude of decreases in urine GAG with treatment.
The decrease in liver and spleen volumes at Week 53 was maintained during the extension study in all patients regardless of prior TKT024 treatment assignment. Seventy one out of 94 patients had hepatomegaly at baseline. Liver volume normalized by Month 24 for 73% (52 out of 71) of these patients. In addition, mean liver volume decreased to a near maximum extent by Month 8 in all TKT024 treatment groups, increasing slightly from this nadir at Month 36. Decreases in mean liver volume were seen regardless of age, disease severity, antibody status, or neutralizing antibody status. For the study population as a whole, mean spleen volume also decreased rapidly after the initiation of idursulfase and remained well below mean baseline volume for the duration of the extension study.
An open-label, multicenter, single-arm study was conducted to assess the safety of ELAPRASE infusions for male patients with Hunter syndrome who were 1.4 to 7.5 years-old. In addition, the study evaluated efficacy, clinical outcomes, and ELAPRASE pharmacokinetics in this patient population.
All patient groups experienced a decrease in urine uGAG levels, liver size and spleen volume after initiation of ELAPRASE treatment. Patients with the complete deletion/large rearrangement genotype had a less pronounced decrease in uGAG levels than patients with the missense mutation genotype. In the patients with the complete deletion/large rearrangement genotype the initial response was followed by an increase in the liver size to approximately baseline values at 53 weeks and spleen volume also increased but remained below baseline values at 53 weeks. Patients with frameshift/splice genotype had the least pronounced response to ELAPRASE. These genotype-based results are consistent with the antibody-based analysis, which showed that patients with antibodies and neutralizing antibodies had a slightly less pronounced decrease in uGAG, liver size and spleen volume. However, individual patients with a complete deletion/large rearrangement genotype and high titer antibodies experienced a therapeutic response similar or better than some patients with a missense mutation genotype and no antibody response.
Comparative Bioavailability Studies
No comparative bioavailability studies have been performed with ELAPRASE.
An animal model of Hunter syndrome, the iduronate-2-sulfatase knockout (IKO) mouse, exhibits many of the physical characteristics of Hunter syndrome seen in humans, including coarse features, skeletal defects (including thickened digits), hepatomegaly, and a reduced lifespan. Elevated glycosaminoglycan (GAG) levels are observed in urine and tissues throughout the body and widespread cellular vacuolization is observed histopathologically. The IKO model was used to evaluate the dose levels and dose regimen of idursulfase required to degrade stored GAG in this animal model.
A series of pharmacodynamic studies was conducted in which idursulfase was administered IV at weekly intervals to IKO mice. The doses of idursulfase ranged from 0.1 to 5.0 mg/kg. These studies established that idursulfase caused a reduction in urinary and tissue (liver, spleen, kidney and heart) GAG, indicating that idursulfase was active, reached target organs and was likely taken up into the lysosomes where catabolism of excess GAG occurs. From these studies it was determined that doses as low as 0.1 mg/kg resulted in a measurable pharmacodynamic effect.
Another set of pharmacodynamic studies was performed to establish dose frequency. IKO mice were administered weekly, every other week, or monthly IV injections of idursulfase. Clear reductions in urinary and tissue GAG were observed after dosing regimens ranging from 8 weeks to approximately 6 months. Long-term administration (12 and 24 weeks) of 1 mg/kg idursulfase administered weekly and every other week were both effective in reducing tissue GAG concentrations in various tissues, and were more effective than monthly dosing.
Idursulfase was detected in all organs and tissues examined in a 125I-radiolabeled rat biodistribution study. Tissue half-lives were similar for the major organs and were approximately 1 to 2 days for liver, kidney, heart, spleen, and bone (including marrow). The accumulation and retention of idursulfase in these organs and tissues is consistent with the distribution of M6P receptors in tissues and organs in mammals.
Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single dose toxicity, repeated dose toxicity, and male fertility. Genotoxic and carcinogenic potential are not expected. No reproductive toxicity studies in female animals have been performed. It is not known whether idursulfase crosses the placenta.
Acute Toxicity Studies
The acute toxicity of idursulfase was evaluated in rats and cynomolgus monkeys. Doses of up to 20 mg/kg body weight for both species, representing 40 times the recommended dose in humans, have been tested without any adverse toxicity.
Repeat-dose Toxicity Studies
A 6-month, repeat-dose toxicity study was conducted in cynomolgus monkeys at doses up to 0.5, 2.5, and 12.5 mg/kg body weight/week. A no adverse effect level of at least 12.5 mg/kg body weight idursulfase was established since there were no adverse, treatment-related findings observed at any dose level tested (a dose of 25 times the recommended dose in humans).
Reproduction and Teratology
A male fertility study was performed in rats at doses up to 5 mg/kg body weight, twice weekly or 10 times the human dose. There was no evidence of impaired male fertility at any dose level tested. Hence, the NOAEL was determined to be at least 5 mg/kg body weight/dose. No reproductive toxicity studies in female animals have been performed. It is not known whether idursulfase crosses the placenta.
Mutagenicity and Carcinogenicity Studies
No animal studies have been conducted to assess the mutagenic, genotoxic, and carcinogenic potential for idursulfase. This is consistent with the ICH guideline S1A, “Guidelines on the Need for Carcinogenicity Studies of Pharmaceuticals.” As a purified form of the naturally occurring enzyme iduronate-2-sulfatase, such potential is not expected for idursulfase.