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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

Timeline and flow of patients in the TKT023 core trial and TKT029 extension study. Seventeen patients who completed TKT023 enrolled in TKT029. Screening values from TKT023 week 25/26 were used as TKT029 baseline values. TKT029 was divided into two phases, before and after a change in the agalsidase alfa manufacturing process. Patients were transitioned to phase 2 treatment ~197 to 223 (mean, 210) weeks after phase 1 baseline agalsidase alfa treatment. Only patients who participated in both phases (the transition safety population) were analyzed for this report. EOW, every other week; agalα, agalsidase alfa; RB, roller bottle; AF, animal free.
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Fig1: Timeline and flow of patients in the TKT023 core trial and TKT029 extension study. Seventeen patients who completed TKT023 enrolled in TKT029. Screening values from TKT023 week 25/26 were used as TKT029 baseline values. TKT029 was divided into two phases, before and after a change in the agalsidase alfa manufacturing process. Patients were transitioned to phase 2 treatment ~197 to 223 (mean, 210) weeks after phase 1 baseline agalsidase alfa treatment. Only patients who participated in both phases (the transition safety population) were analyzed for this report. EOW, every other week; agalα, agalsidase alfa; RB, roller bottle; AF, animal free.

Mentions: Eleven of 17 patients transitioned from study phase 1 to phase 2 (i.e., the TSP); one patient was lost to follow-up in phase 1, four patients were transitioned first to compassionate-use agalsidase alfa and then to commercial therapy, and one patient elected to not continue with additional treatment (Figure 1). Phase 1 baseline TSP patients’ median (range) age was 10.8 (8.6–17.3) years (10 [90.9%] males, one female [9.1%], nine [81.8%] White). Phase 2 began approximately 4 years after phase 1 baseline; thus, some patients aged past 18 years during the study. One patient failed to attend scheduled clinic visits and was withdrawn from the study. Patients in the TSP had mean ± SD duration of agalsidase alfa treatment of 6.5 ± 0.6 years for a total of 71.9 patient-years of agalsidase alfa exposure.Figure 1


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)

Timeline and flow of patients in the TKT023 core trial and TKT029 extension study. Seventeen patients who completed TKT023 enrolled in TKT029. Screening values from TKT023 week 25/26 were used as TKT029 baseline values. TKT029 was divided into two phases, before and after a change in the agalsidase alfa manufacturing process. Patients were transitioned to phase 2 treatment ~197 to 223 (mean, 210) weeks after phase 1 baseline agalsidase alfa treatment. Only patients who participated in both phases (the transition safety population) were analyzed for this report. EOW, every other week; agalα, agalsidase alfa; RB, roller bottle; AF, animal free.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig1: Timeline and flow of patients in the TKT023 core trial and TKT029 extension study. Seventeen patients who completed TKT023 enrolled in TKT029. Screening values from TKT023 week 25/26 were used as TKT029 baseline values. TKT029 was divided into two phases, before and after a change in the agalsidase alfa manufacturing process. Patients were transitioned to phase 2 treatment ~197 to 223 (mean, 210) weeks after phase 1 baseline agalsidase alfa treatment. Only patients who participated in both phases (the transition safety population) were analyzed for this report. EOW, every other week; agalα, agalsidase alfa; RB, roller bottle; AF, animal free.
Mentions: Eleven of 17 patients transitioned from study phase 1 to phase 2 (i.e., the TSP); one patient was lost to follow-up in phase 1, four patients were transitioned first to compassionate-use agalsidase alfa and then to commercial therapy, and one patient elected to not continue with additional treatment (Figure 1). Phase 1 baseline TSP patients’ median (range) age was 10.8 (8.6–17.3) years (10 [90.9%] males, one female [9.1%], nine [81.8%] White). Phase 2 began approximately 4 years after phase 1 baseline; thus, some patients aged past 18 years during the study. One patient failed to attend scheduled clinic visits and was withdrawn from the study. Patients in the TSP had mean ± SD duration of agalsidase alfa treatment of 6.5 ± 0.6 years for a total of 71.9 patient-years of agalsidase alfa exposure.Figure 1

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