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

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 .

Figures

Figure 1

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.

Figure 2

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.

Figure 3

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.

Figure 4

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.

Figure 5

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.