Enzyme replacement therapy (ERT) with recombinant α‐galactosidase A (r‐αGAL A) for the treatment of Fabry disease has been available for over 15 years. Long‐term treatment may slow down disease progression, but cardiac, renal, and cerebral complications still develop in most patients. In addition, lifelong intravenous treatment is burdensome. Therefore, several new treatment approaches have been explored over the past decade. Chaperone therapy (Migalastat; 1‐deoxygalactonojirimycin) is the only other currently approved therapy for Fabry disease. This oral small molecule aims to improve enzyme activity of mutated α‐galactosidase A and can only be used in patients with specific mutations. Treatments currently under evaluation in (pre)clinical trials are second generation enzyme replacement therapies (Pegunigalsidase‐alfa, Moss‐aGal), substrate reduction therapies (Venglustat and Lucerastat), mRNA‐ and gene‐based therapy. This review summarises the knowledge on currently available and potential future options for the treatment of Fabry disease.

Fabry Disease (FD) is a rare, X-linked, lysosomal storage disease that mainly causes renal, cardiac and cerebral complications. Enzyme replacement therapy (ERT) with recombinant alpha-galactosidase A is available, but approximately 50% of male patients with classical FD develop inhibiting anti-drug antibodies (iADAs) that lead to reduced biochemical responses and an accelerated loss of renal function. Once immunization has occurred, iADAs tend to persist and tolerization is hard to achieve. Here we developed a pre-treatment prediction model for iADA development in FD using existing data from 120 classical male FD patients from three European centers, treated with ERT. We found that nonsense and frameshift mutations in the α-galactosidase A gene (p = 0.05), higher plasma lysoGb3 at baseline (p < 0.001) and agalsidase beta as first treatment (p = 0.006) were significantly associated with iADA development. Prediction performance of a Random Forest model, using multiple variables (AUC-ROC: 0.77) was compared to a logistic regression (LR) model using the three significantly associated variables (AUC-ROC: 0.77). The LR model can be used to determine iADA risk in individual FD patients prior to treatment initiation. This helps to determine in which patients adjusted treatment and/or immunomodulatory regimes may be considered to minimize iADA development risk.

Background: Fabry disease is a very heterogeneous X-linked lysosomal storage disease. Disease manifestations in the kidneys, heart, and brain vary greatly, even between patients of the same sex and with the same disease classification (classical or nonclassical). A biomarker with a strong association with the development of disease manifestations is needed to determine the need for Fabry-specific treatment and appropriate frequency of follow-up because clinical manifestations of the disorder may take decennia to develop. Methods: We investigated the levels of plasma lysoGb3 levels over time and its association with disease manifestations and disease course in 237 untreated patients with Fabry disease (median age 42 years, 38% male) using linear mixed-effect models. Results: LysoGb3 levels are stable over time in plasma of untreated patients with Fabry disease. Higher levels of lysoGb3 were associated with steeper decline in eGFR (P = 0.05) and a faster increase in albuminuria (measured as the urinary albumin-to-creatinine ratio, P < 0.001), left ventricular mass (measured on echocardiography, P < 0.001), left atrial volume index (P = 0.003), and Fazekas score (P = 0.003). In addition, regardless of age, higher lysoGb3 levels were associated with higher relative wall thickness (P < 0.001) and unfavorable functional markers on echocardiography, including septal mitral annular early diastolic velocity (e′, P < 0.001) and the ratio of early transmitral velocity (E) to e′ (E/e′, P = 0.001). Conclusions: In an individual patient with Fabry disease, the plasma lysoGb3 level reached a specific level in early childhood which, in the absence of Fabry-specific treatment, remained stable throughout life. The level of lysoGb3 in untreated patients was associated with nearly all Fabry-specific disease manifestations, regardless of the sex of the patient.

Male patients with the classical phenotype of Fabry disease (FD) are at risk of developing inhibiting antidrug antibodies (iADAs) against recombinant α‐galactosidase‐A, administered in the form of enzyme replacement therapy (ERT). The presence of ADAs is linked to infusion‐associated reactions (IARs) and reduced ERT effectiveness. This study evaluates the incidence of iADAs and IARs in ERT treated classical male FD patients, their interrelatedness and the effect of an adjusted ERT initiation protocol, aimed at inducing immune tolerance. In this monocenter cohort study, a retrospective analysis was performed to evaluate the occurrence of iADAs and IARs. Prospectively, a stepwise dose escalation ERT initiation protocol was evaluated in classical male FD patients with a calculated high risk of iADA formation and compared to the standard initiation protocol. Retrospectively ( n = 52), the proportion of patients experiencing IARs was higher in patients that developed iADAs (20/27 seropositive patients, 0/19 seronegative, p < 0.001). Higher iADA titers were associated with persisting iADA titers ( p = 0.004). Prospectively ( n = 17), none of the patients in the intervention group (stepwise dose escalation) experienced IARs (0/8), compared to half of the patients in the control group (5/9, p = 0.029). The proportion of patients developing iADAs was not different between the two groups (respectively, 4/8 and 6/9, p = 0.52). To conclude, iADA development is associated with the occurrence of IARs. The stepwise dose escalation at ERT initiation used in the current study in a single cohort seems to prevent IARs in male patients with classical FD, but does not seem to prevent iADA development.