No head-to-head studies of the two forms of α-Gal A used for ERT in pediatric patients with Fabry disease have been conducted, and thus comparisons of the safety and efficacy of agalsidase alfa and agalsidase beta in children based on the published studies are difficult [54
]. Reduction of plasma Gb3 levels in the male patients was similar for the two drugs (i.e., about 50%). The magnitude of the reduction is similar to that reported in clinical trials of the two drugs in adult male patients [64
]. Patients in all three studies reported subjective improvement of symptoms (primarily pain) during ERT, but the only objective evidence of benefit was the statistically significant improvement of abnormal heart rate variability in boys treated with agalsidase alfa [57
], and the disappearance of Gb3 deposits in the dermal capillary endothelial cells [77
]. Different assay methods used to detect antibodies in each study may have influenced the results, but the development of IgG antibodies to each form of the enzyme appeared to be different, with 69% of the boys treated with agalsidase beta seroconverting [77
], compared with 5.3% [57
] and 11.1% [54
] in the studies of agalsidase alfa. This difference is consistent with the results reported in adults. It is not clear what the pharmacologic consequences are concerning the development of IgG antibodies. In a head-to-head study in adults [71
], most of the men with antibodies presented neutralizing activity, and those men with antibodies who were treated with agalsidase alfa (0.2 mg/kg i.v. EOW) exhibited a smaller reduction in urinary Gb3 than patients treated with agalsidase beta (1.0 mg/kg i.v. EOW) or in patients without antibodies. However, with respect to clinical evaluation of renal function, there was no difference between patients who developed antibodies and those who did not, regardless of which form of the enzyme they were receiving [46
]. Schiffmann and colleagues previously had reported that patients treated with agalsidase alfa who developed transient or persistent IgG antibodies against the enzyme also had a smaller reduction in urinary Gb3, but that no effect of antibodies on the progression of kidney dysfunction was apparent [64
]. Importantly, in the pediatric studies, the development of IgE anti-agalsidase antibodies was reported only for agalsidase beta. IgE antibodies to agalsidase beta have been consistently reported in about 6% of adult patients participating in clinical studies [2
]. No IgE antibodies directed against agalsidase alfa have been reported in any clinical studies.
Agalsidase alfa has been reported to significantly improve neuropathic pain in adult men and women with Fabry disease [4
]. In clinical studies, agalsidase alfa tended to reduce the severity of neuropathic pain in children [54
] and significantly reduced the need for neuropathic pain medication [57
]. The latter observation is important because the anticonvulsant drugs used to treat neuropathic pain may have substantial side effects and are reported to negatively influence behavior and cognitive function [28
The issue of when to initiate ERT for Fabry disease remains to be determined. Studies in adults suggest that patients in the early stages of organ involvement may respond better to ERT than patients with advanced disease. For example, Schiffmann and colleagues reported that agalsidase alfa preserved kidney function (as measured by eGFR) in Fabry disease patients with stage 1 or 2 chronic kidney disease (CKD) at baseline, but was less effective in patients with the more serious stage 3 or higher CKD [64
]. Similarly, Banikazemi et al. reported that agalsidase beta had a lesser effect in reducing the incidence of major clinical events in patients with proteinuria in excess of 1.0 g/day, which they considered a marker for more advanced disease [2
The observations in adults suggest that initiation of ERT in childhood might slow or stop the progression of organ damage before irreversible changes occur. As noted above, Gb3 accumulation begins during fetal development [10
], but signs and symptoms of Fabry disease take years to appear. ERT initiated in childhood might delay or prevent major organ damage by reducing Gb3 storage, but final evidence supporting or refuting this concept has not been demonstrated [60
Interpretation of the small studies presented here is complicated by the lack of a placebo control group, the range of ages of the patients studied, their different mutations, the natural variation in the phenotypic expression, and the progression of signs and symptoms seen in Fabry patients. To date, no surrogate markers have been described that might identify Fabry disease patients who are at greatest risk for disease progression and who might benefit most from early ERT. Gb3 is a bad biomarker of disease activity but, recently, some hope has been deposited in its derivative (lyso-Gb3) that may better reflect pathophysiological changes [1
Current guidelines indicate that ERT should be initiated in all males >16 years and in pediatric males at the time of development of significant symptoms [14
]. Asymptomatic boys should be considered for ERT between the ages of 10 and 13 years, but the actual age at which ERT should be started in boys remains to be decided by the physicians, family, and patient. These guidelines also state that ERT in female patients should be started only after the onset of significant symptoms.
After 7 years of ERT in children with Fabry disease and in accord with the three clinical trials presented in this work, safety has been convincingly demonstrated. However, more controlled trials must be done in order to demonstrate the ultimate objective of ERT in children that is the long-term prevention of adult complications. It is important to note that, in addition to ERT, adjunct therapies and preventive measures should be part of the treatment plan for all patients. For example, angiotensin-receptor blockers or angiotensin-converting enzyme inhibitors may be used to prevent or reduce proteinuria, dietary restrictions and H2 blockers may improve GI problems, and anticonvulsants (e.g., phenytoin, carbamazepine) are indicated for the treatment of neuropathic pain.