An open-label clinical trial of agalsidase alfa enzyme replacement therapy in children with Fabry disease who are naïve to enzyme replacement therapy

Ozlem Goker-Alpan, Nicola Longo, Marie McDonald, Suma P Shankar, Raphael Schiffmann, Peter Chang, Yinghua Shen, Arian Pano, Ozlem Goker-Alpan, Nicola Longo, Marie McDonald, Suma P Shankar, Raphael Schiffmann, Peter Chang, Yinghua Shen, Arian Pano

Abstract

Background: Following a drug manufacturing process change, safety/efficacy of agalsidase alfa were evaluated in enzyme replacement therapy (ERT)-naïve children with Fabry disease.

Methods: In an open-label, multicenter, Phase II study (HGT-REP-084; Shire), 14 children aged ≥7 years received 0.2 mg/kg agalsidase alfa every other week for 55 weeks. Primary endpoints: safety, changes in autonomic function (2-hour Holter monitoring). Secondary endpoints: estimated glomerular filtration rate, left ventricular mass index (LVMI), midwall fractional shortening, pharmacodynamic parameters, and patient-reported quality-of-life.

Results: Among five boys (median 10.2 [range 6.7, 14.4] years) and nine girls (14.8 [10.1, 15.9] years), eight patients experienced infusion-related adverse events (vomiting, n=4; nausea, n=3; dyspnea, n=3; chest discomfort, n=2; chills, n=2; dizziness, n=2; headache, n=2). One of these had several hypersensitivity episodes. However, no patient discontinued for safety reasons and no serious adverse events occurred. One boy developed immunoglobulin G (IgG) and neutralizing antidrug antibodies. Overall, no deterioration in cardiac function was observed in seven patients with low/abnormal SDNN (standard deviation of all filtered RR intervals; <100 ms) and no left ventricular hypertrophy: mean (SD) baseline SDNN, 81.6 (20.9) ms; mean (95% confidence interval [CI]) change from baseline to week 55, 17.4 (2.9, 31.9) ms. Changes in SDNN correlated with changes in LVMI (r=-0.975). No change occurred in secondary efficacy endpoints: mean (95% CI) change from baseline at week 55 in LVMI, 0.16 (-3.3, 3.7) g/m(2.7); midwall fractional shortening, -0.62% (-2.7%, 1.5%); estimated glomerular filtration rate, 0.15 (-11.4, 11.7) mL/min/1.73 m(2); urine protein, -1.8 (-6.0, 2.4) mg/dL; urine microalbumin, 0.6 (-0.5, 1.7) mg/dL; plasma globotriaosylceramide (Gb3), -5.71 (-10.8, -0.6) nmol/mL; urinary Gb3, -1,403.3 (-3,714.0, 907.4) nmol/g creatinine, or clinical quality-of-life outcomes.

Conclusion: Fifty-five weeks' agalsidase alfa ERT at 0.2 mg/kg every other week was well tolerated. Disease progression may be slowed when ERT is started prior to major organ dysfunction.

Trial registration: https://ClinicalTrials.gov identifier NCT01363492.

Keywords: Fabry disease; agalsidase alfa; efficacy; enzyme replacement therapy; pediatric study; safety.

Figures

Figure 1
Figure 1
Heart rate variability as assessed by SDNN: individual values at baseline and at 55 weeks. Notes: (A) Observed values of SDNN (ms). (B) SDNN Z-scores. SDNN represents the standard deviation of all filtered RR intervals for the length of the analysis. The different colored shapes within the figure show individual patient data at baseline and 55 weeks.
Figure 2
Figure 2
LVMI over time for the patient who had LVH at baseline. Note: SDNN represents the standard deviation of all filtered RR intervals for the length of the analysis. Abbreviations: LVH, left ventricular hypertrophy; LVMI, left ventricular mass index.
Figure 3
Figure 3
Correlation between change from baseline to week 55 in SDNN and LVMI in patients with baseline SDNN Notes: *r = Pearson correlation coefficient. SDNN represents the standard deviation of all filtered RR intervals for the length of the analysis. Abbreviation: LVMI, left ventricular mass index.
Figure 4
Figure 4
Mean (SE) change from baseline in eGFR. Note: The safety population comprises all enrolled patients who received at least one dose of agalsidase alfa. Abbreviations: eGFR, estimated glomerular filtration rate; SE, standard error; SP, safety population.
Figure 5
Figure 5
Mean plasma Gb3 over time for the overall population and by sex. Notes: (A) Observed values (nmol/mL). (B) Change from baseline. Abbreviation: Gb3, globotriaosylceramide.

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