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Evaluation of the efficacy and safety of three dosing regimens of agalsidase alfa enzyme replacement therapy in adults with Fabry disease.
Drug Des Devel Ther. 2015; 9:3435-44.DD

Abstract

PURPOSE

Efficacy and safety of agalsidase alfa at 0.2 mg/kg weekly were compared with 0.2 mg/kg every other week (EOW). Exploratory analyses were performed for 0.4 mg/kg weekly.

PATIENTS AND METHODS

This was a 53-week, Phase III/IV, multicenter, open-label study (NCT01124643) in treatment-naïve adults (≥18 years) with Fabry disease. Inclusion criteria were left ventricular hypertrophy at baseline, defined as left ventricular mass indexed to height >50 g/m(2.7) for males and >47 g/m(2.7) for females. Primary endpoint was reduction of left ventricular mass indexed to height as assessed by echocardiography. Secondary endpoints included cardiac (peak oxygen consumption, 6-minute walk test, Minnesota Living with Heart Failure Questionnaire, New York Heart Association classification), renal (Modification of Diet in Renal Disease, estimated glomerular filtration rate), and biomarker (plasma globotriaosylceramide) assessments. Safety endpoints were adverse events and anti-agalsidase alfa antibodies.

RESULTS

Twenty patients were randomized to 0.2 mg/kg EOW (mean age, 50.3 years; 70% male), 19 to 0.2 mg/kg weekly (51.8 years; 53% male), and 5 to 0.4 mg/kg weekly (49.4 years; 40% male). The mean change in left ventricular mass indexed to height by Week 53 in the 0.2-mg/kg EOW and weekly groups was 3.2 g/m(2.7) and 0.5 g/m(2.7), with no significant difference between groups. No clinically meaningful changes by Week 53 were found within or between the 0.2-mg/kg groups for peak oxygen consumption, 6-minute walk test, or Minnesota Living with Heart Failure Questionnaire. Two patients in each group improved by ≥1 New York Heart Association classification. No significant differences were found between 0.2 mg/kg EOW and weekly for mean change in estimated glomerular filtration rate (-1.21 mL/min/1.73 m(2) vs -3.32 mL/min/1.73 m(2)) or plasma globotriaosylceramide (-1.05 nmol/mL vs -2.13 nmol/mL), respectively. Infusion-related adverse events were experienced by 25% and 21% in the 0.2-mg/kg EOW and weekly groups. Tachycardia, fatigue, and hypotension were experienced by two or more patients overall. Anti-agalsidase alfa antibodies were detected in 11.4% of patients and neutralizing antibodies in 6.8%. Infusion-related reactions did not appear to be correlated with antibody status.

CONCLUSION

No efficacy or safety differences were found when the approved EOW dosage of agalsidase alfa was increased to weekly administration. Exploratory analyses for 0.4 mg/kg weekly showed similar results.

Authors+Show Affiliations

First Faculty of Medicine, Department of Cardiovascular Medicine, Charles University, Prague, Czech Republic.Lysosomal Research and Treatment Unit, Fairfax, VA, USA.Stead Family Department of Pediatrics, Division of Medical Genetics, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.Division of Medicine, Turku University Hospital, Turku, Finland.Institute of Cardiology, Warsaw, Poland.Department of Medicine, Center for Medicine and Clinical Research, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.First Faculty of Medicine, Department of Cardiovascular Medicine, Charles University, Prague, Czech Republic.Department of Internal Medicine, Jagiellonian University Medical College, Krakow, Poland.Department of Nephrology, Royal Melbourne Hospital and the University of Melbourne, VIC, Australia.Instituto Privado de Hematologia E Investigacion Clinica (IPHIC), Asuncion, Paraguay.Salford Royal NHS Foundation Trust, Salford, UK.General Hospital Slovenj Gradec, Slovenj Gradec, Slovenia.Shire, Lexington, MA, USA.Shire, Lexington, MA, USA.

Pub Type(s)

Clinical Trial, Phase III
Clinical Trial, Phase IV
Comparative Study
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26185417

Citation

Goláň, Lubor, et al. "Evaluation of the Efficacy and Safety of Three Dosing Regimens of Agalsidase Alfa Enzyme Replacement Therapy in Adults With Fabry Disease." Drug Design, Development and Therapy, vol. 9, 2015, pp. 3435-44.
Goláň L, Goker-Alpan O, Holida M, et al. Evaluation of the efficacy and safety of three dosing regimens of agalsidase alfa enzyme replacement therapy in adults with Fabry disease. Drug Des Devel Ther. 2015;9:3435-44.
Goláň, L., Goker-Alpan, O., Holida, M., Kantola, I., Klopotowski, M., Kuusisto, J., Linhart, A., Musial, J., Nicholls, K., Gonzalez-Rodriguez, D., Sharma, R., Vujkovac, B., Chang, P., & Wijatyk, A. (2015). Evaluation of the efficacy and safety of three dosing regimens of agalsidase alfa enzyme replacement therapy in adults with Fabry disease. Drug Design, Development and Therapy, 9, 3435-44. https://doi.org/10.2147/DDDT.S80928
Goláň L, et al. Evaluation of the Efficacy and Safety of Three Dosing Regimens of Agalsidase Alfa Enzyme Replacement Therapy in Adults With Fabry Disease. Drug Des Devel Ther. 2015;9:3435-44. PubMed PMID: 26185417.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Evaluation of the efficacy and safety of three dosing regimens of agalsidase alfa enzyme replacement therapy in adults with Fabry disease. AU - Goláň,Lubor, AU - Goker-Alpan,Ozlem, AU - Holida,Myrl, AU - Kantola,Ikka, AU - Klopotowski,Mariusz, AU - Kuusisto,Johanna, AU - Linhart,Aleš, AU - Musial,Jacek, AU - Nicholls,Kathleen, AU - Gonzalez-Rodriguez,Derlis, AU - Sharma,Reena, AU - Vujkovac,Bojan, AU - Chang,Peter, AU - Wijatyk,Anna, Y1 - 2015/07/08/ PY - 2015/7/18/entrez PY - 2015/7/18/pubmed PY - 2016/4/19/medline KW - adverse events KW - exercise tolerance KW - left ventricular hypertrophy KW - lysosomal storage disorder KW - quality of life KW - renal function SP - 3435 EP - 44 JF - Drug design, development and therapy JO - Drug Des Devel Ther VL - 9 N2 - PURPOSE: Efficacy and safety of agalsidase alfa at 0.2 mg/kg weekly were compared with 0.2 mg/kg every other week (EOW). Exploratory analyses were performed for 0.4 mg/kg weekly. PATIENTS AND METHODS: This was a 53-week, Phase III/IV, multicenter, open-label study (NCT01124643) in treatment-naïve adults (≥18 years) with Fabry disease. Inclusion criteria were left ventricular hypertrophy at baseline, defined as left ventricular mass indexed to height >50 g/m(2.7) for males and >47 g/m(2.7) for females. Primary endpoint was reduction of left ventricular mass indexed to height as assessed by echocardiography. Secondary endpoints included cardiac (peak oxygen consumption, 6-minute walk test, Minnesota Living with Heart Failure Questionnaire, New York Heart Association classification), renal (Modification of Diet in Renal Disease, estimated glomerular filtration rate), and biomarker (plasma globotriaosylceramide) assessments. Safety endpoints were adverse events and anti-agalsidase alfa antibodies. RESULTS: Twenty patients were randomized to 0.2 mg/kg EOW (mean age, 50.3 years; 70% male), 19 to 0.2 mg/kg weekly (51.8 years; 53% male), and 5 to 0.4 mg/kg weekly (49.4 years; 40% male). The mean change in left ventricular mass indexed to height by Week 53 in the 0.2-mg/kg EOW and weekly groups was 3.2 g/m(2.7) and 0.5 g/m(2.7), with no significant difference between groups. No clinically meaningful changes by Week 53 were found within or between the 0.2-mg/kg groups for peak oxygen consumption, 6-minute walk test, or Minnesota Living with Heart Failure Questionnaire. Two patients in each group improved by ≥1 New York Heart Association classification. No significant differences were found between 0.2 mg/kg EOW and weekly for mean change in estimated glomerular filtration rate (-1.21 mL/min/1.73 m(2) vs -3.32 mL/min/1.73 m(2)) or plasma globotriaosylceramide (-1.05 nmol/mL vs -2.13 nmol/mL), respectively. Infusion-related adverse events were experienced by 25% and 21% in the 0.2-mg/kg EOW and weekly groups. Tachycardia, fatigue, and hypotension were experienced by two or more patients overall. Anti-agalsidase alfa antibodies were detected in 11.4% of patients and neutralizing antibodies in 6.8%. Infusion-related reactions did not appear to be correlated with antibody status. CONCLUSION: No efficacy or safety differences were found when the approved EOW dosage of agalsidase alfa was increased to weekly administration. Exploratory analyses for 0.4 mg/kg weekly showed similar results. SN - 1177-8881 UR - https://www.unboundmedicine.com/medline/citation/26185417/Evaluation_of_the_efficacy_and_safety_of_three_dosing_regimens_of_agalsidase_alfa_enzyme_replacement_therapy_in_adults_with_Fabry_disease_ L2 - https://dx.doi.org/10.2147/DDDT.S80928 DB - PRIME DP - Unbound Medicine ER -