Reduction of Plasma Globotriaosylsphingosine Levels After Switching from Agalsidase Alfa to Agalsidase Beta as Enzyme Replacement Therapy for Fabry Disease

Abstract

Introduction: Agalsidase alfa and agalsidase beta, recombinant enzyme preparations for treatment of Fabry disease (FD), have different approved dosing schedules: 0.2 mg/kg and 1.0 mg/kg every other week (EOW), respectively.Methods: This open-label, multicenter, exploratory phase 4 study evaluated plasma globotriaosylsphingosine (lyso-GL-3) and plasma and urine globotriaosylceramide (GL-3) levels at baseline and 2, 4, and 6 months after the switch from agalsidase alfa (0.2 mg/kg EOW for !12 months) to agalsidase beta (1.0 mg/kg EOW) in 15 male patients with FD. Immunoglobulin (Ig)G antidrug antibody titers were assessed, and safety was monitored throughout the study.Results: Plasma lyso-GL-3 concentrations decreased significantly within 2 months after switch and reductions continued through month 6 (mean absolute changes, À12.8, À16.1, and À16.7 ng/mL at 2, 4, and 6 months, respectively; all P < 0.001). The mean percentage reduction from baseline was 39.5% (P < 0.001) at month 6. For plasma GL-3, the mean absolute change from baseline (À0.9 mg/mL) and percentage reduction (17.9%) at month 6 were both significant (P < 0.05). Urine GL-3 measurements showed intra-patient variability and changes from baseline were not significant. No clinical outcomes were assessed in this 6-month study, and, therefore, no conclusions can be drawn regarding the correlation of observed reductions in glycosphingolipid concentrations with clinically relevant outcomes. There were no differences in IgG antidrug antibody titers between the two enzymes. The switch from agalsidase alfa to agalsidase beta was well tolerated.Conclusion: Plasma lyso-GL-3 and GL-3 levels reduced after switching from agalsidase alfa to agalsidase beta, indicating that agalsidase beta has a greater pharmacodynamic effect on these markers at the recommended dose. These data further support the use of agalsidase beta 1.0 mg/kg EOW as enzyme replacement therapy in FD.

Lucerastat, an Iminosugar for Substrate Reduction Therapy: Tolerability, Pharmacodynamics, and Pharmacokinetics in Patients With Fabry Disease on Enzyme Replacement

“…Plasma Gb3 is elevated in patients with Fabry disease and has been demonstrated to be reduced by treatment with ERT . A decrease in plasma GlcCer, LacCer, Gb3, and urine Gb3 was observed, demonstrating that lucerastat 1,000 mg b.i.d.…”

“…Neither ERT nor miglustat conclusively improved renal and cardiac function in randomized Plasma Gb3 is elevated in patients with Fabry disease and has been demonstrated to be reduced by treatment with ERT. 45 A decrease in plasma GlcCer, LacCer, Gb3, and urine Gb3 was observed, demonstrating that lucerastat 1,000 mg b.i.d. inhibits GCS and provides a-GalA substrate reduction with a fast onset.…”

Genotype, phenotype and disease severity reflected by serum LysoGb3 levels in patients with Fabry disease

“…Multivariate linear regression analysis showed that LysoGb3 levels were independently associated with, serum creatinine (β=0.09, 95%CI 0.04-0.13, P<0.001) and the presence of cardiomyopathy (β=25, 95%CI 9.8-41, P=0.002). LysoGb3 levels were higher in males with frame-shift and nonsense mutations than in males with missense mutations (84 [72-109] vs 41 [37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52]ng/ml, P=0.002).…”

European expert consensus statement on therapeutic goals in Fabry disease

“…Failure to reduce plasma lyso-GL-3 levels to (near-)normal levels may be an indication to intensify ERT and evaluate anti-drug IgG antibodies [17]. No timeframe for monitoring the lyso-GL-3 response to ERT has been included at this time and needs further research.…”