Limits...
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

Mean ± SD change over time in plasma/urine Gb3in the transition safety population. (a) Plasma Gb3 (nmol/g creatinine) and (b) urine Gb3 (nmol/mL); the dotted lines represent the annualized slope. Baseline mean ± SD plasma Gb3 and urine Gb3 values at the beginning of phase 1 were 3.61 ± 1.60 nmol/mL and 538.09 ± 681.27 nmol/g creatinine, respectively (both measured at study TKT023 week 25/26). Agalα, agalsidase alfa; CI, confidence interval; Gb3, globotriaosylceramide; SD, standard deviation; yr, year.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig5: Mean ± SD change over time in plasma/urine Gb3in the transition safety population. (a) Plasma Gb3 (nmol/g creatinine) and (b) urine Gb3 (nmol/mL); the dotted lines represent the annualized slope. Baseline mean ± SD plasma Gb3 and urine Gb3 values at the beginning of phase 1 were 3.61 ± 1.60 nmol/mL and 538.09 ± 681.27 nmol/g creatinine, respectively (both measured at study TKT023 week 25/26). Agalα, agalsidase alfa; CI, confidence interval; Gb3, globotriaosylceramide; SD, standard deviation; yr, year.

Mentions: Plasma Gb3 levels remained below phase 1 baseline (mean ± SD, 3.61 ± 1.60 nmol/mL; measured at study TKT023 week 25/26) for most patients throughout the study (annualized slope −0.01 nmol/mL [95% CI: −0.14, 0.12]; Figure 5a). Reductions in plasma Gb3 were maintained in patients with moderately and more severely elevated baseline plasma Gb3, except for one patient. In patients with high levels of Gb3 at baseline, reductions were seen throughout phases 1 and 2 and, despite transient fluctuations, were maintained at last visit. The observed fluctuations in plasma Gb3 were expected based on the biologic variability inherent to this parameter. For patients with normal Gb3 levels at baseline, these levels remained normal throughout the study. Similar to the plasma Gb3 profile, levels of urine Gb3 excretion fluctuated over time, but decreased from the phase 1 baseline value (mean ± SD: 538.09 ± 681.27 nmol/g) with an annualized slope of −50.02 nmol/g (95% CI: −152.41, 52.37; Figure 5b). Urine Gb3 excretion remained generally stable, but for some patients, urine Gb3 fluctuated over time. However, no trends were found that suggested clinical deterioration.Figure 5


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)

Mean ± SD change over time in plasma/urine Gb3in the transition safety population. (a) Plasma Gb3 (nmol/g creatinine) and (b) urine Gb3 (nmol/mL); the dotted lines represent the annualized slope. Baseline mean ± SD plasma Gb3 and urine Gb3 values at the beginning of phase 1 were 3.61 ± 1.60 nmol/mL and 538.09 ± 681.27 nmol/g creatinine, respectively (both measured at study TKT023 week 25/26). Agalα, agalsidase alfa; CI, confidence interval; Gb3, globotriaosylceramide; 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

Fig5: Mean ± SD change over time in plasma/urine Gb3in the transition safety population. (a) Plasma Gb3 (nmol/g creatinine) and (b) urine Gb3 (nmol/mL); the dotted lines represent the annualized slope. Baseline mean ± SD plasma Gb3 and urine Gb3 values at the beginning of phase 1 were 3.61 ± 1.60 nmol/mL and 538.09 ± 681.27 nmol/g creatinine, respectively (both measured at study TKT023 week 25/26). Agalα, agalsidase alfa; CI, confidence interval; Gb3, globotriaosylceramide; SD, standard deviation; yr, year.
Mentions: Plasma Gb3 levels remained below phase 1 baseline (mean ± SD, 3.61 ± 1.60 nmol/mL; measured at study TKT023 week 25/26) for most patients throughout the study (annualized slope −0.01 nmol/mL [95% CI: −0.14, 0.12]; Figure 5a). Reductions in plasma Gb3 were maintained in patients with moderately and more severely elevated baseline plasma Gb3, except for one patient. In patients with high levels of Gb3 at baseline, reductions were seen throughout phases 1 and 2 and, despite transient fluctuations, were maintained at last visit. The observed fluctuations in plasma Gb3 were expected based on the biologic variability inherent to this parameter. For patients with normal Gb3 levels at baseline, these levels remained normal throughout the study. Similar to the plasma Gb3 profile, levels of urine Gb3 excretion fluctuated over time, but decreased from the phase 1 baseline value (mean ± SD: 538.09 ± 681.27 nmol/g) with an annualized slope of −50.02 nmol/g (95% CI: −152.41, 52.37; Figure 5b). Urine Gb3 excretion remained generally stable, but for some patients, urine Gb3 fluctuated over time. However, no trends were found that suggested clinical deterioration.Figure 5

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