Gaucher disease is an autosomal recessive disorder caused by mutations in the human glucocerebrosidase gene, which results in a reduced activity of the lysosomal enzyme glucocerebrosidase. Glucocerebrosidase catalyzes the conversion of the sphingolipid glucocerebroside into glucose and ceramide. The enzymatic deficiency results in accumulation of substrate glucocerebroside primarily in the lysosomal compartment of macrophages, giving rise to foam cells or "Gaucher cells," which accumulate in the liver, spleen and bone marrow.
ELELYSO, an enzyme replacement therapy, is a recombinant analog of human lysosomal glucocerebrosidase that catalyzes the hydrolysis of glucocerebroside to glucose and ceramide, reducing the amount of accumulated glucocerebroside. ELELYSO uptake into cellular lysosomes is mediated by binding of ELELYSO mannose oligosaccharide chains to specific mannose receptors on the cell surface leading to internalization and subsequent transport to the lysosomes.
Pharmacokinetics of taliglucerase alfa were evaluated in 38 patients (29 adult and 9 pediatric patients) who received intravenous infusions of ELELYSO 30 units/kg (50% of the recommended dosage) or 60 units/kg (the recommended dosage) [see Dosage and Administration (2.1)] every other week. The pharmacokinetic parameters in adult and pediatric patients are summarized in Table 3.
In adult Type 1 Gaucher disease patients treated with ELELYSO 30 units/kg (50% of the recommended dosage) or 60 units/kg (the recommended dosage) [see Dosage and Administration (2.1)] (N=29) every other week as initial therapy, pharmacokinetics were determined with the first dose and at Week 38 of treatment. The pharmacokinetics of taliglucerase alfa appeared to be nonlinear with a greater than dose-proportional increase in exposure at the doses studied.
No significant accumulation or change in taliglucerase alfa pharmacokinetics over time from Weeks 1 to 38 was observed with repeated dosages of 30 units/kg (50% of the recommended dosage) or 60 units/kg (the recommended dosage) [see Dosage and Administration (2.1)] every other week. Based on the limited data, there were no significant pharmacokinetic differences between male and female patients in this study.
The pharmacokinetics of taliglucerase alfa were evaluated in 9 pediatric patients 4 to 17 years of age with Type 1 Gaucher disease who were treated with ELELYSO for 10 to 27 months. Six of the 9 patients were treatment-naïve, and 3 patients were switched from imiglucerase. In both the 30 units/kg (50% of the recommended dosage) and 60 units/kg (the recommended dosage) [see Dosage and Administration (2.1)] dose groups, clearance values in pediatric patients were similar to those in adult patients. AUC values in pediatric patients were lower than AUC values in adult patients, due to weight-based dosing of taliglucerase alfa and lower body weights in pediatric patients.
| Pediatric Patients (N=9) Median (Range) | Adult Patients at Week 38 (N=29) Median (Range) | |||
|---|---|---|---|---|
30 units/kg* | 60 units/kg | 30 units/kg* | 60 units/kg | |
Age (years) | 15 (10, 17) | 11 (4, 16) | 35 (19, 74) | 33 (19, 58) |
Weight (kg) | 44.3 (22.8, 71.0) | 28.6 (16.5, 50.4) | 72.5 (51.5, 99.5) | 73.5 (58.5, 87.0)† |
AUC0–∞ (ng*h/mL)‡ | 1416 (535, 1969) | 2984 (1606, 4273) | 2007 (1007, 10092) | 6459 (2548, 21020)† |
T1/2 (min) | 37.1 (22.5, 56.8) | 32.5 (18.0, 42.9) | 18.9 (9.20, 57.9) | 28.7 (11.3, 104)† |
CL (L/h) | 30.5 (17.4, 37.8) | 15.8 (11.7, 24.9) | 30.5 (6.79, 68.0) | 18.5 (6.20, 37.9)† |
Vss (L) | 14.9 (10.1, 35.6) | 8.80 (3.75, 21.4) | 11.7 (2.3, 22.7) | 10.7 (1.4, 18.5)† |
The observed incidence of ADA (including neutralizing antibodies [Nab]) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of ELELYSO or of other taliglucerase alfa products.
Anti-Drug Antibodies
In Trials 1, 2, and 3, a greater portion of ELELYSO-treated patients who developed ADA had hypersensitivity reactions compared to those who did not develop ADA [see Adverse Reactions (6.1) and Warnings and Precautions (5.1)].
In Trial 1 (treatment-naïve adults with Gaucher disease) [see Clinical Studies (14.1)], 17 (53%) of 32 ELELYSO-treated patients developed ADA. Additionally 2 (6%) patients tested positive for ADA at baseline prior to ELELYSO treatment.
In Trial 2 (treatment-naïve pediatric patients with Gaucher disease) [see Clinical Studies (14.1)], 2 (22%) of 9 Type 1 Gaucher disease ELELYSO-treated patients developed ADA. Additionally, 1 patient was ADA-positive prior to initiation of ELELYSO.
In Trial 3 (switched from imiglucerase to ELELYSO), of 31 ELELYSO-treated patients (26 adult and 5 pediatric patients) [see Clinical Studies (14.2)], 6 adults (23% of adult patients) developed ADA and no pediatric patient developed ADA. Additionally, 3 (10%) patients were ADA positive prior to initiation of ELELYSO.
There is insufficient information to characterize the ADA response to ELELYSO and the effects of ADA on pharmacokinetics, pharmacodynamics, or effectiveness of taliglucerase alfa products.
Neutralizing Antibodies
In Trials 1, 2 and 3 with a total number of 72 patients, 30 of the 31 ELELYSO-treated adult and pediatric patients who developed ADA or tested positive for ADA at baseline were evaluated for neutralizing activity of the ADA in the mannose receptor binding and enzyme activity assays.
Although the effectiveness was numerically lower (less spleen and liver volume reduction) in ELELYSO-treated patients who developed Nab compared to those that did not develop Nab, the data were not sufficient to fully assess whether the observed Nab reduces effectiveness.
Other Antibodies
Nine (29%) of the 31 ELELYSO-treated adult and pediatric patients who developed ADA during treatment or tested positive for ADA at baseline also developed antibodies against plant-specific glycans in ELELYSO.
Gaucher disease is an autosomal recessive disorder caused by mutations in the human glucocerebrosidase gene, which results in a reduced activity of the lysosomal enzyme glucocerebrosidase. Glucocerebrosidase catalyzes the conversion of the sphingolipid glucocerebroside into glucose and ceramide. The enzymatic deficiency results in accumulation of substrate glucocerebroside primarily in the lysosomal compartment of macrophages, giving rise to foam cells or "Gaucher cells," which accumulate in the liver, spleen and bone marrow.
ELELYSO, an enzyme replacement therapy, is a recombinant analog of human lysosomal glucocerebrosidase that catalyzes the hydrolysis of glucocerebroside to glucose and ceramide, reducing the amount of accumulated glucocerebroside. ELELYSO uptake into cellular lysosomes is mediated by binding of ELELYSO mannose oligosaccharide chains to specific mannose receptors on the cell surface leading to internalization and subsequent transport to the lysosomes.
Pharmacokinetics of taliglucerase alfa were evaluated in 38 patients (29 adult and 9 pediatric patients) who received intravenous infusions of ELELYSO 30 units/kg (50% of the recommended dosage) or 60 units/kg (the recommended dosage) [see Dosage and Administration (2.1)] every other week. The pharmacokinetic parameters in adult and pediatric patients are summarized in Table 3.
In adult Type 1 Gaucher disease patients treated with ELELYSO 30 units/kg (50% of the recommended dosage) or 60 units/kg (the recommended dosage) [see Dosage and Administration (2.1)] (N=29) every other week as initial therapy, pharmacokinetics were determined with the first dose and at Week 38 of treatment. The pharmacokinetics of taliglucerase alfa appeared to be nonlinear with a greater than dose-proportional increase in exposure at the doses studied.
No significant accumulation or change in taliglucerase alfa pharmacokinetics over time from Weeks 1 to 38 was observed with repeated dosages of 30 units/kg (50% of the recommended dosage) or 60 units/kg (the recommended dosage) [see Dosage and Administration (2.1)] every other week. Based on the limited data, there were no significant pharmacokinetic differences between male and female patients in this study.
The pharmacokinetics of taliglucerase alfa were evaluated in 9 pediatric patients 4 to 17 years of age with Type 1 Gaucher disease who were treated with ELELYSO for 10 to 27 months. Six of the 9 patients were treatment-naïve, and 3 patients were switched from imiglucerase. In both the 30 units/kg (50% of the recommended dosage) and 60 units/kg (the recommended dosage) [see Dosage and Administration (2.1)] dose groups, clearance values in pediatric patients were similar to those in adult patients. AUC values in pediatric patients were lower than AUC values in adult patients, due to weight-based dosing of taliglucerase alfa and lower body weights in pediatric patients.
| Pediatric Patients (N=9) Median (Range) | Adult Patients at Week 38 (N=29) Median (Range) | |||
|---|---|---|---|---|
30 units/kg* | 60 units/kg | 30 units/kg* | 60 units/kg | |
Age (years) | 15 (10, 17) | 11 (4, 16) | 35 (19, 74) | 33 (19, 58) |
Weight (kg) | 44.3 (22.8, 71.0) | 28.6 (16.5, 50.4) | 72.5 (51.5, 99.5) | 73.5 (58.5, 87.0)† |
AUC0–∞ (ng*h/mL)‡ | 1416 (535, 1969) | 2984 (1606, 4273) | 2007 (1007, 10092) | 6459 (2548, 21020)† |
T1/2 (min) | 37.1 (22.5, 56.8) | 32.5 (18.0, 42.9) | 18.9 (9.20, 57.9) | 28.7 (11.3, 104)† |
CL (L/h) | 30.5 (17.4, 37.8) | 15.8 (11.7, 24.9) | 30.5 (6.79, 68.0) | 18.5 (6.20, 37.9)† |
Vss (L) | 14.9 (10.1, 35.6) | 8.80 (3.75, 21.4) | 11.7 (2.3, 22.7) | 10.7 (1.4, 18.5)† |
The observed incidence of ADA (including neutralizing antibodies [Nab]) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of ELELYSO or of other taliglucerase alfa products.
Anti-Drug Antibodies
In Trials 1, 2, and 3, a greater portion of ELELYSO-treated patients who developed ADA had hypersensitivity reactions compared to those who did not develop ADA [see Adverse Reactions (6.1) and Warnings and Precautions (5.1)].
In Trial 1 (treatment-naïve adults with Gaucher disease) [see Clinical Studies (14.1)], 17 (53%) of 32 ELELYSO-treated patients developed ADA. Additionally 2 (6%) patients tested positive for ADA at baseline prior to ELELYSO treatment.
In Trial 2 (treatment-naïve pediatric patients with Gaucher disease) [see Clinical Studies (14.1)], 2 (22%) of 9 Type 1 Gaucher disease ELELYSO-treated patients developed ADA. Additionally, 1 patient was ADA-positive prior to initiation of ELELYSO.
In Trial 3 (switched from imiglucerase to ELELYSO), of 31 ELELYSO-treated patients (26 adult and 5 pediatric patients) [see Clinical Studies (14.2)], 6 adults (23% of adult patients) developed ADA and no pediatric patient developed ADA. Additionally, 3 (10%) patients were ADA positive prior to initiation of ELELYSO.
There is insufficient information to characterize the ADA response to ELELYSO and the effects of ADA on pharmacokinetics, pharmacodynamics, or effectiveness of taliglucerase alfa products.
Neutralizing Antibodies
In Trials 1, 2 and 3 with a total number of 72 patients, 30 of the 31 ELELYSO-treated adult and pediatric patients who developed ADA or tested positive for ADA at baseline were evaluated for neutralizing activity of the ADA in the mannose receptor binding and enzyme activity assays.
Although the effectiveness was numerically lower (less spleen and liver volume reduction) in ELELYSO-treated patients who developed Nab compared to those that did not develop Nab, the data were not sufficient to fully assess whether the observed Nab reduces effectiveness.
Other Antibodies
Nine (29%) of the 31 ELELYSO-treated adult and pediatric patients who developed ADA during treatment or tested positive for ADA at baseline also developed antibodies against plant-specific glycans in ELELYSO.
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