Reduction of elevated plasma globotriaosylsphingosine in patients with classic Fabry disease following enzyme replacement therapy

Abstract

Fabry disease is treated by two-weekly infusions with α-galactosidase A, which is deficient in this X-linked globotriaosylceramide (Gb3) storage disorder. Elevated plasma globotriaosylsphingosine (lysoGb3) is a hallmark of classical Fabry disease. We investigated effects of enzyme replacement therapy (ERT) on plasma levels of lysoGb3 and Gb3 in patients with classical Fabry disease treated with agalsidase alfa at 0.2mg/kg, agalsidase beta at 0.2mg/kg or at 1.0mg/kg bodyweight. Each treatment regimen led to prominent reductions of plasma lysoGb3 in Fabry males within 3 months (P=0.0313), followed by relative stability later on. Many males developed antibodies against α-galactosidase A, particularly those treated with agalsidase beta. Patients with antibodies tended towards smaller correction in plasma lysoGb3 concentration, whereas treatment with high dose agalsidase beta allowed a reduction comparable to patients without antibodies. Pre-treatment plasma lysoGb3 concentrations of Fabry females were relatively low. In all females and with each treatment regimen, ERT gave reduction or stabilisation of plasma lysoGb3. Our investigation revealed that ERT of Fabry patients reduces plasma lysoGb3, regardless of the recombinant enzyme used. This finding shows that ERT can correct a characteristic biochemical abnormality in Fabry patients.

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

“…These results underscore the importance of dose in the treatment of FD and corroborate findings by other groups (Smid et al 2011;Tøndel et al 2013;van Breemen et al 2011;Weidemann et al 2014). In previously untreated patients, plasma lyso-GL-3 decreased, reaching almost stable levels within 3 months of initiation of treatment with either agalsidase alfa or agalsidase beta administered at 0.2 mg/kg, and with 1.0 mg/kg of agalsidase beta (van Breemen et al 2011). However, the reduction of plasma lyso-GL-3 was significantly greater for patients treated with agalsidase beta 1.0 mg/kg versus patients who received agalsidase alfa or agalsidase beta at a dose of 0.2 mg/kg.…”

“…The reductions provide further evidence that the in vivo activity of agalsidase alfa at its recommended dose is below that of agalsidase beta at its recommended dose. These results underscore the importance of dose in the treatment of FD and corroborate findings by other groups (Smid et al 2011;Tøndel et al 2013;van Breemen et al 2011;Weidemann et al 2014). In previously untreated patients, plasma lyso-GL-3 decreased, reaching almost stable levels within 3 months of initiation of treatment with either agalsidase alfa or agalsidase beta administered at 0.2 mg/kg, and with 1.0 mg/kg of agalsidase beta (van Breemen et al 2011).…”

“…Plasma lyso-GL-3 concentrations tended to be higher in antibody-positive males when treated with agalsidase alfa or agalsidase beta at 0.2 mg/kg, compared with antibody-negative males. This was not the case after 12 months of agalsidase beta 1.0 mg/ kg; the lyso-GL-3 reduction at this dose was similar for antibody-positive and antibody-negative patients (van Breemen et al 2011), suggesting that a dose increase can compensate for potentially reduced efficacy in patients with anti-agalsidase antibodies. Another study reported a significant increase in lyso-GL-3 concentration in adult male patients who switched from agalsidase beta 1.0 mg/kg to agalsidase alfa 0.2 mg/kg or received a reduced agalsidase beta dose (one group subsequently switched to agalsidase alfa), suggesting recurrence of disease activity (Smid et al 2011).…”

“…Importantly, no relationship was apparent between IgG antibody titers and concentration of plasma lyso-GL-3, plasma GL-3, or urine GL-3 in patients receiving agalsidase beta 1.0 mg/kg EOW. In contrast, as noted above, patients with antibodies receiving 0.2 mg/kg of either agalsidase alfa or agalsidase beta tended toward smaller correction in plasma lyso-GL-3 concentrations compared with patients receiving agalsidase beta 1.0 mg/kg, who experienced a reduction similar to patients without antibodies (van Breemen et al 2011). It is important to note that, to date, a comparison of antibody test results obtained from different laboratories and different studies has been hampered by the Fig.…”

“…Recently, lyso-GL-3 has emerged as a more sensitive biomarker that may correlate with disease severity and/or organ involvement in FD (Rombach et al 2010). Untreated patients with classic FD typically have highly elevated plasma levels of lyso-GL-3 (Aerts et al 2008;Togawa et al 2010;Niemann et al 2014), and plasma lyso-GL-3 decreased within 3 months of initiation of treatment in naive FD patients treated with either agalsidase alfa or agalsidase beta, with significantly larger reductions with agalsidase beta 1.0 mg/kg versus agalsidase alfa and agalsidase beta 0.2 mg/kg (van Breemen et al 2011). Recurrent elevations in plasma lyso-GL-3 have been reported in patients whose agalsidase dose was reduced.…”