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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 19 of 34

pharmacologic chaperone therapy approved for use in Fabry disease patients ≥ 12 years with an amenable
GLA variant and eGFR > 30 mL/min/1.73 m 2[135] . Amenability is determined in an in vitro HEK assay, with a
positive response defined as an absolute increase in α-Gal activity of at least 3% and a relative increase of at
[136]
least 1.2-fold .

The cost of these long-term treatments is of importance for any health care system since treatment with
ERT at a cost of CAN$280,000/patient/year per Fabry patient results in a significant burden. Chaperone
therapy is priced only slightly less than ERT in Canada.

Enzyme replacement therapy
The introduction of ERT in 2001 was a landmark event, as prior to that, there was no specific therapy for
Fabry nephropathy [137,138] . ERT was shown to reduce both urine and plasma Gb3 [138,139] , as well as Gb3 in
kidney and skin .
[140]

In a randomized controlled study of agalsidase-beta in Fabry adults with chronic kidney disease, ERT was
shown to delay the time to first clinical Fabry event including a 33% increase in serum creatinine and the
development of ESRD with dialysis or transplantation . Patients with baseline eGFR 55 mL/min/1.73 m
[141]
2
2
or less had a poorer response than those with eGFR over 55 mL/min/1.73 m , suggesting that early
treatment was better. Mean proteinuria was unchanged with treatment.
Hyperfiltration confirmed by measured GFR can occur in some men with Fabry nephropathy. With ERT,
GFR quickly fell into the normal range in all 9 men, but it is unknown whether this represented rapid
[26]
disease progression despite ERT or normalization of eGFR, given the limited follow-up .

In a study of 58 adults (97% male) on agalsidase-beta, Germain (2007) noted that 10 patients with higher
2
proteinuria > 1 g/day had a more rapid decline in eGFR, average -7.4 mL/min/1.73 m /yr compared with
[72]
2
eGFR slope of -1.0 mL/min/1.73 m /yr in 42 patients with proteinuria ≤ 1.0 g/day . Similarly, 8 patients
with > 50% baseline glomerular sclerosis had eGFR slope of -8.9 mL/min/1.73 m /yr compared with
2
32 patients who had baseline glomerular sclerosis ≤ 50% and eGFR slope of -1.4 mL/min/1.73 m /yr.
2
Baseline proteinuria and sclerosis were both shown to be important risk factors for the development of
progressive Fabry nephropathy.
In a ten-year follow-up of these 52 patients, 20 had decreased eGFR and proteinuria . It was recognized
[142]
that early treatment and thus younger age, and a low renal involvement (LRI), defined as proteinuria
< 0.5 g/24 h and the absence of fibrosis on renal biopsy, were associated with preservation of renal function
in patients receiving agalsidase-beta. Mean eGFR slopes for LRI and high renal involvement (HRI
proteinuria ≥ 0.5 g/day, and/or fibrosis on renal biopsy) were -1.89 mL/min/1.73 m /yr and
2
-6.82 mL/min/1.73 m /yr, respectively.
2

These results have been confirmed in a larger study with 165 patients treated for up to 21 years with
agalsidase-alfa . The 51 patients with high baseline proteinuria > 0.5 g/24 h, compared with 114 patients
[143]
2
with low baseline proteinuria < 0.5 g/24 h, had a lower baseline mean eGFR (89.1 vs. 106.6 mL/min/1.73 m )
and faster mean eGFR decline (-3.62 vs. -1.61 mL/min/1.73 m /yr; P < 0.0001). The patients with high
2
baseline proteinuria > 0.5 g/24 h. were projected to have a progressive decrease in eGFR, estimated at
-36 mL/min/1.73 m at 10 years and -72 mL/min/1.73 m over 20 years.
2
2