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

Left ventricular mass indexed to height (LVMI; g/m2.7) 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 LVMI values at the beginning of phase 1 were 30.66 ± 5.96 g/m2.7 (measured at study TKT023 week 25/26). Agalα, agalsidase alfa; CI, confidence interval; LVMI, left ventricular mass index; SD, standard deviation; ULN, upper limit of normal.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig3: Left ventricular mass indexed to height (LVMI; g/m2.7) 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 LVMI values at the beginning of phase 1 were 30.66 ± 5.96 g/m2.7 (measured at study TKT023 week 25/26). Agalα, agalsidase alfa; CI, confidence interval; LVMI, left ventricular mass index; SD, standard deviation; ULN, upper limit of normal.

Mentions: For all patients, baseline LVMI measurements (measured at study TKT023 week 25/26) were within normal range (upper limit of normal range: males =51 g/m2.7, females =48 g/m2.7), with baseline values ranging from 22.7 to 42.3 (mean ± SD phase 1 baseline 30.66 ± 5.96) g/m2.7 (Figure 3). Through phase 1, LVMI decreased from baseline (mean change −3.25 g/m2.7 at week 185 in phase 1, which was used instead of the last phase 1 study visit at week 211 that only included three patients) and LVMI continued to decrease through phase 2 (except week 104). Despite LVMI fluctuations observed in individual patients, levels remained below left ventricular hypertrophy criteria throughout the study.Figure 3


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)

Left ventricular mass indexed to height (LVMI; g/m2.7) 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 LVMI values at the beginning of phase 1 were 30.66 ± 5.96 g/m2.7 (measured at study TKT023 week 25/26). Agalα, agalsidase alfa; CI, confidence interval; LVMI, left ventricular mass index; SD, standard deviation; ULN, upper limit of normal.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig3: Left ventricular mass indexed to height (LVMI; g/m2.7) 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 LVMI values at the beginning of phase 1 were 30.66 ± 5.96 g/m2.7 (measured at study TKT023 week 25/26). Agalα, agalsidase alfa; CI, confidence interval; LVMI, left ventricular mass index; SD, standard deviation; ULN, upper limit of normal.
Mentions: For all patients, baseline LVMI measurements (measured at study TKT023 week 25/26) were within normal range (upper limit of normal range: males =51 g/m2.7, females =48 g/m2.7), with baseline values ranging from 22.7 to 42.3 (mean ± SD phase 1 baseline 30.66 ± 5.96) g/m2.7 (Figure 3). Through phase 1, LVMI decreased from baseline (mean change −3.25 g/m2.7 at week 185 in phase 1, which was used instead of the last phase 1 study visit at week 211 that only included three patients) and LVMI continued to decrease through phase 2 (except week 104). Despite LVMI fluctuations observed in individual patients, levels remained below left ventricular hypertrophy criteria throughout the study.Figure 3

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