Abstract
BackgroundFabry disease (FD) is an X-linked lysosomal storage disorder resulting from the α-galactosidase A gene mutations. Enzyme-replacement-therapy (ERT) products for FD currently used include agalsidase alfa and agalsidase beta. There are many reports on efficacy and safety of ERT. However, most of the previous studies are done as a retrospective medical records analysis.MethodsThe Japan Fabry Research - 002 (JFR-002) was a prospective observational clinical study of 36 ERT-naïve FD patients (14 men and 22 women) at baseline (BL) and after initiation of ERT with agalsidase alfa 0.2 mg/kg every two weeks, a median period 62.5 months. The parameters measured included globotriaosylceramide (Gb3), globotriaosylsphingosine (Lyso-Gb3), left ventricular mass index (LVMI), brain natriuretic peptide (BNP), high-sensitivity troponin I (hs-Trop I), estimated glomerular filtration rate (eGFR), and anti-agalsidase alfa IgG antibody formation.ResultsAll parameters remained steady during ERT treatment period. BNP levels in 14 patients whose BL levels were within the normal range (<19.5 pg/mL) remained within the same range, while 22 patients whose BL levels were abnormally high (≥19.5 pg/mL) gradually showed decreased levels after start of ERT. Gb3 and Lyso-Gb3 levels remarkably decreased after the initiation of ERT and remained low.ConclusionThe JFR-002 suggests that agalsidase alfa is effective in maintaining organ function in FD patients, and that the incidence of infusion reactions related to the treatment with agalsidase alfa is low, indicating the good tolerability to this ERT.Trial registrationThe JFR-002 was retrospectively registered at Japan Medical Association Center for Clinical Trials (Registration number: JMA-IIA00291) on May 19th, 2017.
Highlights
Fabry disease (FD) is an X-linked lysosomal storage disorder resulting from the α-galactosidase A gene mutations
Thirty-six ERT treatment-naïve FD patients (14 male patients, mean age: 26.6 years old; 22 female patients, mean age: 45.4 years old) (Table 1) were prospectively enrolled into this clinical observational trial based on the inclusion and exclusion of criteria
The brain natriuretic peptide (BNP) levels remained within the normal range in 14 patients with grade 1 and gradually decreased in 22 patients with grade 2, which indicated a certain level of improvement, but still stayed within the abnormal range (Fig. 1c and d). These results suggest the efficacy of ERT with agalsidase alfa, and that early intervention with ERT when cardiac or myocardial dysfunction is still mild, may prevent the progression to subsequent cardiac failure and improve cardiac involvement of FD (Fig. 1)
Summary
Fabry disease (FD) is an X-linked lysosomal storage disorder resulting from the α-galactosidase A gene mutations. Most of the previous studies are done as a retrospective medical records analysis. Fabry disease (FD, OMIM number #301500) is an inborn error of metabolism caused by the reduced or deficient α-galactosidase A (α-Gal) activity in cells. This leads to the progressive accumulation of glycosphingolipids, including globotriaosylceramide (Gb3), in many tissues and body fluids, such as in the walls of blood vessels and vascular endothelial cells throughout the body, as well as in parts of the nervous system. Most of the previous studies were done as a retrospective, medical records analysis, so it would be difficult to control and Tsuboi and Yamamoto BMC Pharmacology and Toxicology (2017) 18:43 remove inter-institutional bias. It would be an issue to keep accuracy of clinical records
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