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An open-label clinical trial of agalsidase alfa enzyme replacement therapy in children with Fabry disease who are naïve to enzyme replacement therapy.
Drug Des Devel Ther. 2016; 10:1771-81.DD

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.

Authors+Show Affiliations

Lysosomal Disorders Unit, Fairfax, VA, USA.University of Utah, Salt Lake City, UT, USA.Department of Pediatrics, Duke University, Durham, NC, USA.Department of Ophthalmology, Emory University School of Medicine, Atlanta, GA, USA; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.Institute of Metabolic Disease, Baylor Research Institute, Dallas, TX, USA.Shire, Lexington, MA, USA.Shire, Lexington, MA, USA.Shire, Lexington, MA, USA.

Pub Type(s)

Clinical Trial, Phase II
Journal Article
Multicenter Study

Language

eng

PubMed ID

27307708

Citation

Goker-Alpan, Ozlem, et al. "An Open-label Clinical Trial of Agalsidase Alfa Enzyme Replacement Therapy in Children With Fabry Disease Who Are Naïve to Enzyme Replacement Therapy." Drug Design, Development and Therapy, vol. 10, 2016, pp. 1771-81.
Goker-Alpan O, Longo N, McDonald M, et al. An open-label clinical trial of agalsidase alfa enzyme replacement therapy in children with Fabry disease who are naïve to enzyme replacement therapy. Drug Des Devel Ther. 2016;10:1771-81.
Goker-Alpan, O., Longo, N., McDonald, M., Shankar, S. P., Schiffmann, R., Chang, P., Shen, Y., & Pano, A. (2016). An open-label clinical trial of agalsidase alfa enzyme replacement therapy in children with Fabry disease who are naïve to enzyme replacement therapy. Drug Design, Development and Therapy, 10, 1771-81. https://doi.org/10.2147/DDDT.S102761
Goker-Alpan O, et al. An Open-label Clinical Trial of Agalsidase Alfa Enzyme Replacement Therapy in Children With Fabry Disease Who Are Naïve to Enzyme Replacement Therapy. Drug Des Devel Ther. 2016;10:1771-81. PubMed PMID: 27307708.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - An open-label clinical trial of agalsidase alfa enzyme replacement therapy in children with Fabry disease who are naïve to enzyme replacement therapy. AU - Goker-Alpan,Ozlem, AU - Longo,Nicola, AU - McDonald,Marie, AU - Shankar,Suma P, AU - Schiffmann,Raphael, AU - Chang,Peter, AU - Shen,Yinghua, AU - Pano,Arian, Y1 - 2016/05/25/ PY - 2016/6/17/entrez PY - 2016/6/17/pubmed PY - 2017/3/23/medline KW - Fabry disease KW - agalsidase alfa KW - efficacy KW - enzyme replacement therapy KW - pediatric study KW - safety SP - 1771 EP - 81 JF - Drug design, development and therapy JO - Drug Des Devel Ther VL - 10 N2 - 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. SN - 1177-8881 UR - https://www.unboundmedicine.com/medline/citation/27307708/An_open_label_clinical_trial_of_agalsidase_alfa_enzyme_replacement_therapy_in_children_with_Fabry_disease_who_are_naïve_to_enzyme_replacement_therapy_ L2 - https://dx.doi.org/10.2147/DDDT.S102761 DB - PRIME DP - Unbound Medicine ER -