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


CONCLUSIONS
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.


BACKGROUND
https://ClinicalTrials.gov identifier NCT01363492.
Lysosomal Disorders Unit, Fairfax, VA, USA.
Ozlem
O
Goker-Alpan
University of Utah, Salt Lake City, UT, USA.
Nicola
N
Longo
Department of Pediatrics, Duke University, Durham, NC, USA.
Marie
M
McDonald
Department of Ophthalmology, Emory University School of Medicine, Atlanta, GA, USA; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
Suma P
SP
Shankar
Institute of Metabolic Disease, Baylor Research Institute, Dallas, TX, USA.
Raphael
R
Schiffmann
Shire, Lexington, MA, USA.
Peter
P
Chang
Shire, Lexington, MA, USA.
Yinghua
Y
Shen
Shire, Lexington, MA, USA.
Arian
A
Pano
D061605:Administration, Intravenous; D000293:Adolescent; D002648:Child; D056947:Enzyme Replacement Therapy; D000795:Fabry Disease / Q000175:diagnosis / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use; D008297:Male; D011994:Recombinant Proteins; D000519:alpha-Galactosidase / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*
D007527:Isoenzymes; D011994:Recombinant Proteins; C000627036:agalsidase alfa; D000519:alpha-Galactosidase
Fabry disease; agalsidase alfa; efficacy; enzyme replacement therapy; pediatric study; safety