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Page 24 of 34 West et al. Rare Dis Orphan Drugs J 2024;3:22 https://dx.doi.org/10.20517/rdodj.2023.61

Table 4. Fabry nephropathy: response to treatment
Treatment Outcome Reference
Hypertension control Not studied
[104]
RAS inhibitors Reduced proteinuria, improved eGFR slope Warnock et al., 2015
[138]
ERT Decreased plasma Gb3, urine Gb3 Schiffmann et al., 2001
[137]
Eng et al., 2001
[64]
Decreased plasma lyso-Gb3, urine lyso-Gb3 Aerts et al., 2008
Rombach et al., 2012 [163]
[146]
Decreased Gb3 in podocytes, PTC, endothelium, tubular cells Tøndel et al., 2013
Thurberg et al., 2002 [140]
[142] [143]
eGFR slope improved or stable Germain et al., 2015 , Cybulla et al., 2022
Decreased Fabry renal events Banikazemi et al., 2007 [141]
[23]
Reversed nephrogenic diabetes insipidus Wornell et al., 2006
Migalastat Increased α-Gal kidney Germain et al., 2012 [164]
[164]
Decreased plasma Gb3, urine Gb3 Germain et al., 2012
[161]
Decreased plasma lyso-Gb3 Germain et al., 2016
Decreased Gb3 in renal PTC, kidney Germain et al., 2012 [164]
Germain et al., 2016 [161]
eGFR slope improved or stable Bichet et al., 2021 [149]
[165]
Decreased Fabry renal events Hughes et al., 2023
Pegunigalsidase Decreased plasma Gb3 Schiffmann et al., 2019 [166]
[166]
Decreased plasma lyso-Gb3 Schiffmann et al., 2019
Decreased Gb3 in renal peritubular capillaries Schiffmann et al., 2019 [166]
[167] [168]
eGFR slope improved or stable Linhart et al., 2023 , Wallace et al., 2023
RAS: Renin-angiotensin system; ERT: enzyme replacement therapy; Gb3: globotriaosylceramide; lyso-Gb3: globotriaosylsphingosine; PTC:
peritubular capillaries; eGFR: estimated glomerular filtration rate; α-Gal: alpha-galactosidase A.
neutralizing ADA has been successful via immune modulatory therapy (IMT) in infant Pompe disease ,
[176]
no cases of IMT has been published in Fabry disease to date.

Infusion-associated reactions
Infusion-associated reactions (IARs) can occur with any form of ERT. Most IARs are immediate, but some
can be delayed by up to 24 h. Most of these reactions are mild and brief in nature and are easily dealt with
by slowing or interrupting the ERT infusion briefly with the administration of antihistamines and
acetaminophen. Prophylaxis with these agents is often successful in preventing an IAR recurrence.
Occasionally, low-dose prednisone will need to be added prior to ERT to prevent IARs. While most of these
patients will have ADA, IARs can occasionally be T cell-mediated in patients who lack ADA. As ADAs will
usually cross-react, patients with ADAs and IARs will usually experience IARs if switched to another form
of ERT. Most patients with IARs can be reassured that their reactions will be mild, self-limited, and easily
brought under control. It is extremely rare for IARs to be so severe and persistent that ERT must be
withdrawn. In Canada, there are currently only three (< 1%) such patients who have had ERT stopped due
to ongoing IARs out of the 306 that have received ERT since 2007 in the Canadian Fabry Disease registry
(unpublished data M. West). These patients had very high titers of neutralizing ADA and were withdrawn
from ERT also due to lack of effectiveness .
[177]

Investigational therapies
Modified enzyme replacement therapy
Modified ERT (pegunigalsidase, 1.0 mg/kg iv every 2 weeks, Elfabrio®, Chiesi Farmaceutici S.p.A) is now
licensed in several jurisdictions (USA, UK, and EU) based on non-inferiority to agalsidase-beta [166,167,169,178,179] .
This product is an α-Gal A dimer with a number of surface polyethylene glycol (PEG) molecules that result
in a prolonged plasma half-life and increased Cmax. Whether these altered pharmacokinetics provide an