An open-label clinical trial of agalsidase alfa enzyme replacement therapy in children with Fabry disease who are naïve to enzyme replacement therapy
Authors Goker-Alpan O, Longo N, McDonald M, Shankar S, Schiffmann R, Chang P, Shen Y, Pano A
Received 18 December 2015
Accepted for publication 1 March 2016
Published 25 May 2016 Volume 2016:10 Pages 1771—1781
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Qinghua Deng
Peer reviewer comments 4
Editor who approved publication: Prof. Dr. Wei Duan
Ozlem Goker-Alpan,1 Nicola Longo,2 Marie McDonald,3 Suma P Shankar,4,5 Raphael Schiffmann,6 Peter Chang,7 Yinghua Shen,7 Arian Pano7
1Lysosomal Disorders Unit, Fairfax, VA, 2University of Utah, Salt Lake City, UT, 3Department of Pediatrics, Duke University, Durham, NC, 4Department of Ophthalmology, 5Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 6Institute of Metabolic Disease, Baylor Research Institute, Dallas, TX, 7Shire, Lexington, MA, USA
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/m2.7; midwall fractional shortening, -0.62% (-2.7%, 1.5%); estimated glomerular filtration rate, 0.15 (-11.4, 11.7) mL/min/1.73 m2; 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: agalsidase alfa, efficacy, enzyme replacement therapy, Fabry disease, pediatric study, safety
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