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West et al. Rare Dis Orphan Drugs J 2024;3:22 https://dx.doi.org/10.20517/rdodj.2023.61 Page 21 of 34

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median annualized rate of eGFR change was -1.4 mL/min/1.73 m /yr for males and -1.1 mL/min/1.73 m /yr
for females.
Real-world evidence of migalastat confirmed its safety and tolerability in 59 adults, along with a significant
reduction in LVM index in both genders . However, eGFR declined in both females
[152]
(-6.9 mL/min/1.73 m²/yr) and males (-5.0 mL/min/1.73 m /yr). The cause of this decrease in renal function
2
[152]
was unclear but was confounded by patients with lower blood pressure . A recent preliminary report of
migalastat use in 55 adults from Canada did not find any untoward eGFR change associated with chaperone
use .
[153]
As patients with advanced Fabry kidney disease were excluded from the migalastat studies, there are limited
data on the effectiveness of chaperone therapy in such patients. An anecdotal case report of eGFR
[154]
stabilization and reduction in proteinuria in stage IIIb CKD needs to be confirmed with further studies .
Early treatment initiation
Some Fabry guidelines recommend initiating ERT in young asymptomatic males with classic GLA variants
by age 15 or 16 years, or even younger; this recommendation stems from the argument that once fibrosis
[155]
occurs, the response to ERT diminishes in both the kidneys and the heart . This position, while initially
based upon expert opinion, is supported by recent observations. Previous studies used age as the benchmark
for starting treatment. In contrast, Hughes et al. considered time elapsed since symptom onset, as this may
provide a more precise indicator for treatment initiation given the variable ages at the onset of disease
progression in Fabry disease patients . In a multivariate Cox regression analysis of data from 1,374 Fabry
[156]
patients, prompt treatment initiation (defined as treatment initiation within < 24 months from symptom
onset) significantly reduced the probability of cardiovascular events (HR = 0.83; P = 0.003) after adjusting
for history of cardiovascular events, sex, and age at treatment initiation. Univariate analysis indicated a
significantly lower likelihood of renal events in the prompt treatment group (P = 0.018); this finding was
attenuated in the multivariate Cox regression analysis [Figure 6].

van der Veen et al. (2023) reported on 30 men with Fabry disease 13 to 27 years old; 7 received ERT via the
FIELD study for about 10 years and the rest were untreated . Baseline characteristics did not differ
[157]
between the two groups. The treated patients had lower median ACR (P = 0.02) and lower LVM index by
both echocardiography and cardiac MRI (P = 0.02) than those untreated. eGFR did not differ between the
two groups. These results support the idea of early ERT initiation in Fabry disease. While a definitive
randomized controlled study is unlikely to be done to answer the question regarding the optimal time to
start ERT, there is an increasing body of evidence supporting early treatment.

ERT dose
There is ongoing debate as to the optimal dose of ERT for Fabry disease, given the five-fold difference in
dose between agalsidase-alfa (0.2 mg/kg) and agalsidase-beta (1.0 mg/kg). The products also differ in the cell
type used in culture to make the enzyme (human fibroblasts vs. Chinese hamster ovary cells) and mix of
surface carbohydrate moieties. It is unknown if these manufacturing details contribute to outcome
differences. The marked phenotypic heterogeneity of Fabry disease makes comparisons difficult. There has
been one randomized controlled study comparing the two versions of ERT at the usual dose, namely the
CFDI study in Canada . This study was disrupted by the failure of randomization to ERT during the three-
[9]
year global shortage of agalsidase-beta. Although 132 patients were enrolled over 10 years, the study ended
due to lack of funding and inadequate enrollment. A number of studies have compared the two treatments,
but most are flawed, retrospective, and short-duration, with differences in the mix of genotypes and
phenotypes. While there are studies showing good renal outcomes after 10 and 20 years of ERT with both