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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

Change from baseline in heart rate variability (mean ± SD SDNN) by visit in the transition safety population. HRV assessed by 2-hour Holter monitoring. Baseline mean ± SD SDNN was 91.96 ± 33.21 msec at the beginning of phase 1 (measured at study TKT023 week 25/26). Phase 2 began ~197–223 (mean 210) weeks after phase 1 baseline. Agalα, agalsidase alfa; HRV, heart rate variability; msec, milliseconds; SDNN, standard deviation of all filtered RR intervals for the length of the analysis.
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Fig2: Change from baseline in heart rate variability (mean ± SD SDNN) by visit in the transition safety population. HRV assessed by 2-hour Holter monitoring. Baseline mean ± SD SDNN was 91.96 ± 33.21 msec at the beginning of phase 1 (measured at study TKT023 week 25/26). Phase 2 began ~197–223 (mean 210) weeks after phase 1 baseline. Agalα, agalsidase alfa; HRV, heart rate variability; msec, milliseconds; SDNN, standard deviation of all filtered RR intervals for the length of the analysis.

Mentions: Baseline mean (SD) SDNN was 91.96 (33.21) msec at the beginning of phase 1 (measured at study TKT023 week 25/26). Analysis of SDNN showed that the only negative change from baseline occurred at phase 2 week 13 (mean change of −2.99 msec from phase 2 baseline). All other weeks exhibited consistent mean HRV increases relative to baseline at all time points, with an overall change from phase 1 baseline value of +53.56 msec at the final assessment (Figure 2). Mean SDNN continued an upward trend throughout phase 2 (mean increase of 34.13 msec at the final assessment). Evaluations of r-MSSD and pNN50 showed similar trends for improved HRV over time. At phase 1 baseline, the mean (SD) r-MSSD and pNN50 values were 45.72 (21.57) msec and 16.58% (13.31%), respectively. Mean (SD) r-MSSD increased from 45.72 (21.57) msec (n =11) at phase 1 baseline to 59.88 (39.80) msec (n =9) at week 185. Mean (SD) pNN50 increased from 16.58% (13.31%) (n =11) at phase 1 baseline to 24.11% (22.51%) (n =9) at week 185. Insufficient data were available to assess r-MSSD and pNN50 during study phase 2.Figure 2


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)

Change from baseline in heart rate variability (mean ± SD SDNN) by visit in the transition safety population. HRV assessed by 2-hour Holter monitoring. Baseline mean ± SD SDNN was 91.96 ± 33.21 msec at the beginning of phase 1 (measured at study TKT023 week 25/26). Phase 2 began ~197–223 (mean 210) weeks after phase 1 baseline. Agalα, agalsidase alfa; HRV, heart rate variability; msec, milliseconds; SDNN, standard deviation of all filtered RR intervals for the length of the analysis.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig2: Change from baseline in heart rate variability (mean ± SD SDNN) by visit in the transition safety population. HRV assessed by 2-hour Holter monitoring. Baseline mean ± SD SDNN was 91.96 ± 33.21 msec at the beginning of phase 1 (measured at study TKT023 week 25/26). Phase 2 began ~197–223 (mean 210) weeks after phase 1 baseline. Agalα, agalsidase alfa; HRV, heart rate variability; msec, milliseconds; SDNN, standard deviation of all filtered RR intervals for the length of the analysis.
Mentions: Baseline mean (SD) SDNN was 91.96 (33.21) msec at the beginning of phase 1 (measured at study TKT023 week 25/26). Analysis of SDNN showed that the only negative change from baseline occurred at phase 2 week 13 (mean change of −2.99 msec from phase 2 baseline). All other weeks exhibited consistent mean HRV increases relative to baseline at all time points, with an overall change from phase 1 baseline value of +53.56 msec at the final assessment (Figure 2). Mean SDNN continued an upward trend throughout phase 2 (mean increase of 34.13 msec at the final assessment). Evaluations of r-MSSD and pNN50 showed similar trends for improved HRV over time. At phase 1 baseline, the mean (SD) r-MSSD and pNN50 values were 45.72 (21.57) msec and 16.58% (13.31%), respectively. Mean (SD) r-MSSD increased from 45.72 (21.57) msec (n =11) at phase 1 baseline to 59.88 (39.80) msec (n =9) at week 185. Mean (SD) pNN50 increased from 16.58% (13.31%) (n =11) at phase 1 baseline to 24.11% (22.51%) (n =9) at week 185. Insufficient data were available to assess r-MSSD and pNN50 during study phase 2.Figure 2

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