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Agalsidase alfa in pediatric patients with Fabry disease: a 6.5-year open-label follow-up study.

Schiffmann R, Pastores GM, Lien YH, Castaneda V, Chang P, Martin R, Wijatyk A - Orphanet J Rare Dis (2014)

Bottom Line: As early treatment with ERT has the potential to reduce complications arising from disease progression, children in particular could benefit.Cardiac endpoints remained stable within normal range for LVMI and a trend towards improved HRV, although some patients experienced a reduction in heart rate.Plasma and urinary Gb3 reductions were maintained.

View Article: PubMed Central - PubMed

Affiliation: Institute of Metabolic Disease, Baylor Research Institute, 3812 Elm Street, Dallas, TX, 75226, USA. raphael.schiffmann@baylorhealth.edu.

ABSTRACT

Background: Signs and symptoms of the X-linked disorder, Fabry disease (FD), can occur early during childhood with heterogeneous clinical manifestations including potential cardiac and renal dysfunction. Several studies support the efficacy of the enzyme replacement therapy (ERT) agalsidase alfa, in adults with FD, though published data on the long-term safety and efficacy of agalsidase alfa in children are limited. As early treatment with ERT has the potential to reduce complications arising from disease progression, children in particular could benefit. The objective of this study was to evaluate the safety and efficacy of long-term agalsidase alfa ERT in children with FD.

Methods: TKT029 was a 6.5-year open-label, multicenter, extension study of children who completed TKT023 (26-week, open-label, every-other-week, intravenous 0.2 mg/kg agalsidase alfa). TKT029 was divided into two phases (before and after an agalsidase alfa manufacturing process change); only patients who participated in both phases were included in the analysis. Primary endpoints included safety, tolerability, and heart rate variability (HRV). Additional efficacy parameters included left ventricular mass index (LVMI), estimated glomerular filtration rate (eGFR), and plasma/urine globotriaosylceramide (Gb3).

Results: Eleven patients participated (phase 1 baseline median [range] age: 10.8 [8.6-17.3] years; 10 [90.9%] males). During TKT029 (6.5 years), all patients experienced ≥1 treatment-emergent adverse event (AE); eight patients had ≥1 possibly/probably drug-related AE. Six patients experienced infusion-related AEs, but none discontinued due to AEs. Eight serious AEs arose (two patients); none were deemed drug-related. No deaths occurred. Three patients developed anti-agalsidase alfa antibodies, with IgG antibodies in one patient that were agalsidase alfa neutralizing, but without apparent clinical impact. Renal (eGFR) endpoints remained generally in normal range. Cardiac endpoints remained stable within normal range for LVMI and a trend towards improved HRV, although some patients experienced a reduction in heart rate. Plasma and urinary Gb3 reductions were maintained.

Conclusions: TKT029 represents the longest assessment of ERT in children with FD in a clinical trial setting. Overall, agalsidase alfa was well tolerated and demonstrated a stabilizing clinical effect. Agalsidase alfa may be a useful clinical therapeutic option for long-term treatment initiated during childhood in patients with FD.

Trial registration: http://ClinicalTrials.gov identifier NCT00084084 .

No MeSH data available.


Related in: MedlinePlus

Estimated glomerular filtration rate (eGFR; mL/min/1.73 m2) over time in the transition safety population. (a) Individual patients and (b) mean (± SD) change from baseline; the dotted line represents the annualized slope. Baseline mean ± SD eGFR values at the beginning of phase 1 were 123.29 ± 16.00 mL/min/1.73 m2 (measured at study TKT023 week 25/26). Agalα, agalsidase alfa; CI, confidence interval; eGFR, estimated glomerular filtration rate; SD, standard deviation; yr, year.
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Fig4: Estimated glomerular filtration rate (eGFR; mL/min/1.73 m2) over time in the transition safety population. (a) Individual patients and (b) mean (± SD) change from baseline; the dotted line represents the annualized slope. Baseline mean ± SD eGFR values at the beginning of phase 1 were 123.29 ± 16.00 mL/min/1.73 m2 (measured at study TKT023 week 25/26). Agalα, agalsidase alfa; CI, confidence interval; eGFR, estimated glomerular filtration rate; SD, standard deviation; yr, year.

Mentions: Mean (SD) phase 1 baseline eGFR was 123.29 (16.00) mL/min/1.73 m2. Most individuals showed relatively stable eGFR over time, although a reduction in mean values was observed in the last three phase 2 visits (Figure 4). For some patients, eGFR fluctuated over time, although no consistent trends were detected suggesting clinical deterioration, so these fluctuations were attributed to random variability. One male patient (004–0004; Figure 4a) exhibited eGFR values that declined to 73 mL/min/1.73 m2 by end of phase 2. This patient enrolled in study HGT-REP-059 (clinicaltrials.gov identifier NCT01031173) and experienced an eGFR increase during that study for a final level of 110 mL/min/1.73 m2, suggesting the eGFR decline was transient. In addition, protein:creatinine ratio (evaluated from available 8-hour urine samples) remained relatively stable over the course of treatment (annualized slope: +0.02 [95% confidence interval (CI): 0.00, 0.03]). Eight of 11 patients entered into proteinuria range (protein:creatinine ratio ≥0.2) during the course of treatment for one (n =4), two (n =2), or three assessments (n =2); none had proteinuria for more than three assessments, nor during their final visit.Figure 4


Agalsidase alfa in pediatric patients with Fabry disease: a 6.5-year open-label follow-up study.

Schiffmann R, Pastores GM, Lien YH, Castaneda V, Chang P, Martin R, Wijatyk A - Orphanet J Rare Dis (2014)

Estimated glomerular filtration rate (eGFR; mL/min/1.73 m2) over time in the transition safety population. (a) Individual patients and (b) mean (± SD) change from baseline; the dotted line represents the annualized slope. Baseline mean ± SD eGFR values at the beginning of phase 1 were 123.29 ± 16.00 mL/min/1.73 m2 (measured at study TKT023 week 25/26). Agalα, agalsidase alfa; CI, confidence interval; eGFR, estimated glomerular filtration rate; SD, standard deviation; yr, year.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4260255&req=5

Fig4: Estimated glomerular filtration rate (eGFR; mL/min/1.73 m2) over time in the transition safety population. (a) Individual patients and (b) mean (± SD) change from baseline; the dotted line represents the annualized slope. Baseline mean ± SD eGFR values at the beginning of phase 1 were 123.29 ± 16.00 mL/min/1.73 m2 (measured at study TKT023 week 25/26). Agalα, agalsidase alfa; CI, confidence interval; eGFR, estimated glomerular filtration rate; SD, standard deviation; yr, year.
Mentions: Mean (SD) phase 1 baseline eGFR was 123.29 (16.00) mL/min/1.73 m2. Most individuals showed relatively stable eGFR over time, although a reduction in mean values was observed in the last three phase 2 visits (Figure 4). For some patients, eGFR fluctuated over time, although no consistent trends were detected suggesting clinical deterioration, so these fluctuations were attributed to random variability. One male patient (004–0004; Figure 4a) exhibited eGFR values that declined to 73 mL/min/1.73 m2 by end of phase 2. This patient enrolled in study HGT-REP-059 (clinicaltrials.gov identifier NCT01031173) and experienced an eGFR increase during that study for a final level of 110 mL/min/1.73 m2, suggesting the eGFR decline was transient. In addition, protein:creatinine ratio (evaluated from available 8-hour urine samples) remained relatively stable over the course of treatment (annualized slope: +0.02 [95% confidence interval (CI): 0.00, 0.03]). Eight of 11 patients entered into proteinuria range (protein:creatinine ratio ≥0.2) during the course of treatment for one (n =4), two (n =2), or three assessments (n =2); none had proteinuria for more than three assessments, nor during their final visit.Figure 4

Bottom Line: As early treatment with ERT has the potential to reduce complications arising from disease progression, children in particular could benefit.Cardiac endpoints remained stable within normal range for LVMI and a trend towards improved HRV, although some patients experienced a reduction in heart rate.Plasma and urinary Gb3 reductions were maintained.

View Article: PubMed Central - PubMed

Affiliation: Institute of Metabolic Disease, Baylor Research Institute, 3812 Elm Street, Dallas, TX, 75226, USA. raphael.schiffmann@baylorhealth.edu.

ABSTRACT

Background: Signs and symptoms of the X-linked disorder, Fabry disease (FD), can occur early during childhood with heterogeneous clinical manifestations including potential cardiac and renal dysfunction. Several studies support the efficacy of the enzyme replacement therapy (ERT) agalsidase alfa, in adults with FD, though published data on the long-term safety and efficacy of agalsidase alfa in children are limited. As early treatment with ERT has the potential to reduce complications arising from disease progression, children in particular could benefit. The objective of this study was to evaluate the safety and efficacy of long-term agalsidase alfa ERT in children with FD.

Methods: TKT029 was a 6.5-year open-label, multicenter, extension study of children who completed TKT023 (26-week, open-label, every-other-week, intravenous 0.2 mg/kg agalsidase alfa). TKT029 was divided into two phases (before and after an agalsidase alfa manufacturing process change); only patients who participated in both phases were included in the analysis. Primary endpoints included safety, tolerability, and heart rate variability (HRV). Additional efficacy parameters included left ventricular mass index (LVMI), estimated glomerular filtration rate (eGFR), and plasma/urine globotriaosylceramide (Gb3).

Results: Eleven patients participated (phase 1 baseline median [range] age: 10.8 [8.6-17.3] years; 10 [90.9%] males). During TKT029 (6.5 years), all patients experienced ≥1 treatment-emergent adverse event (AE); eight patients had ≥1 possibly/probably drug-related AE. Six patients experienced infusion-related AEs, but none discontinued due to AEs. Eight serious AEs arose (two patients); none were deemed drug-related. No deaths occurred. Three patients developed anti-agalsidase alfa antibodies, with IgG antibodies in one patient that were agalsidase alfa neutralizing, but without apparent clinical impact. Renal (eGFR) endpoints remained generally in normal range. Cardiac endpoints remained stable within normal range for LVMI and a trend towards improved HRV, although some patients experienced a reduction in heart rate. Plasma and urinary Gb3 reductions were maintained.

Conclusions: TKT029 represents the longest assessment of ERT in children with FD in a clinical trial setting. Overall, agalsidase alfa was well tolerated and demonstrated a stabilizing clinical effect. Agalsidase alfa may be a useful clinical therapeutic option for long-term treatment initiated during childhood in patients with FD.

Trial registration: http://ClinicalTrials.gov identifier NCT00084084 .

No MeSH data available.


Related in: MedlinePlus