Table 4.

Summary of the results of clinical trials of the ERT on Fabry-related outcomes

Outcome	AGALA	No. of patients and duration in months	AGALB	No. of patients and duration in months	Clinical comments and limitations of studies for both drugs
Renal	Stabilized renal function in patients with a mild or moderate deterioration in renal function at baseline12,28,35,36,39,44 Long-term stabilization confirmed35,36 Proteinuria category (1 or ≥1 g/day) at baseline significantly predicted the rate of decline of GFR during treatment44	9–545; 12–55	Clearance of microvascular endothelial deposits of GL-35,17,22,38 and stabilized kidney function55 Long-term stabilization up to 54 months38 ERT can be performed during hemodialysis23 Reduced the frequency of and delayed the time to clinical renal events25 In dialysis patients, ERT is safe and effective in improving global quality of life37 Proteinuria category (1 or ≥1g/day) at baseline significantly predicted the rate of decline of GFR during treatment38	8–95; 5–54	Evidence is convincing for both drugs that decline of renal function can be stabilized or slowed Few double-blind RCT Most studies measure surrogate endpoints rather than clinical renal endpoints, such as death, dialysis, and transplantation
Cardiac	Reduced left ventricular size in patients who had an enlarged heart at baseline12,34	15–545; 6–24	Clearance of microvascular endothelial deposits of GL-35 Decreased left ventricular hypertrophy and improved regional myocardial function20,29 Improvement in exercise tolerance24	11–58; 5–45	Data is convincing for both drugs that rate of increase of LV mass can be stabilized or slowed Few data available on clinical cardiac endpoints, such as cardiac death, admission for pacemaker, incidence of significant arrhythmia, etc
Neurological	Does not cross blood–brain barrier Corrected abnormally elevated cerebral blood flow and exaggerated cerebrovascular response.10,11 Decrease in nitrotyrosine staining, which was increased in dermal and cerebral vessels of FD patients10,11 Patients suffer from stroke during treatment36	25–36; 6–54	Does not cross blood–brain barrier Some patients suffered from stroke during treatment22 Variable progression of MRI abnormalities while on treatment6	34–58; 24–36	Studies to date measure surrogate endpoints, such as cerebral blood flow and white matter lesions, but the evidence on white matter lesions is conflicting as there are case reports suggesting that they both improve and deteriorate13 Stroke was part of a composite clinical outcome in one study, but no study has yet been published with the power to detect a significant effect of ERT on stroke as a primary outcome
Pain and peripheral neuropathy	Significant decline in pain score4,12,42 Modest but significant improvement in the clinical manifestations of the small-fiber neuropathy19 Pain severity classification shifted toward lower severity41	26–752; 6–36	Improves function of C-, A-, and A-nerve fibers and intradermal vibration receptors in Fabry neuropathy21	47; 23	Data is convincing that improvements in pain occur but do not always translate into reduction in analgesic requirements In some studies, concomitant use of antipain medications made the inference of improvement solely due to ERT difficult
Quality of life	Significantly improved12,42	120–545; 24	Both ERT and placebo group improved5	58; 5	Data is convincing for both drugs that quality of life improves; studies use tools to measure quality of life which are not disease specific
GI symptoms	Severity and frequency of abdominal pain decreased45	11; 12	Significant improvement in abdominal pain and vomiting compared with baseline33	16; 12	Improvement in GI symptoms is a common clinical finding, but studies carried out to date are of small size and inadequately controlled
Hearing	Improved vestibular function but the difference is not significant14,26 Gradual reversion of the hearing deterioration15	15–21; 6–36	–	–	Effects of ERT on chronically progressive sensorineural hearing loss may differ from those on sudden acute hearing loss, both of which occur in Fabry patients Small sample size Clinical significance of small changes in auditory function not clear
Skin and sweat function	No significant difference on ERT32 Improved19	26–47; 36	Clearance of microvascular endothelial deposits of GL-35	58; 5	Most studies are observational and use surrogate biomarkers No comprehensive studies on the effect of ERT on angiokeratoma

Abbreviations: AGALA, agalsidase α; AGALB, agalsidase β; ERT, enzyme replacement therapy; GFR, glomerular filtration rate; GL-3, globotriaosylceramide; FD, Fabry disease; LV, left ventricular; MRI, magnetic resonance imaging; GI, gastrointestinal.