Page 108 - Read Online

West et al. Rare Dis Orphan Drugs J 2024;3:22 https://dx.doi.org/10.20517/rdodj.2023.61 Page 23 of 34
However, changes in plasma lyso-Gb3 correlated with changes in kidney interstitial capillary Gb3 inclusions
[161]
in treatment-naïve patients .
van der Veen et al. (2023) reported on the stability of baseline plasma lyso-Gb3 levels in 237 untreated
[68]
patients with Fabry disease from a single center in the Netherlands . The plasma lyso-Gb3 levels correlated
with Fabry outcomes (cardiac, renal, and brain parameters) during ERT. Both more rapid eGFR slope and a
greater rate of albuminuria rise were associated with a higher plasma lyso-Gb3. The large number of
patients, long study duration, and multiple plasma lyso-Gb3 measurements for each make this the most
important study of plasma lyso-Gb3 and outcomes to date.

Risk factors identified through Cox proportional hazards modeling for the development of renal disease
progression in a study of 117 Chinese Fabry disease patients also included baseline plasma lyso-Gb3, in
addition to the male gender, proteinuria > 1 g/day, and CKD stage III or greater .
[120]

The conflicting data on the plasma lyso-Gb3 and Fabry disease activity are probably due to a number of
study factors, including small patient numbers, short follow-up, use of different outcome measures, and
study populations that vary in terms of gender ratios, GLA variants, and phenotypes. Whether there is a
different lyso-Gb3 response to chaperone therapy compared with ERT is uncertain. It has been speculated
that as studies in mouse models suggest that lyso-Gb3 is either actively formed or preferentially stored in the
liver and spleen, elevated plasma lyso-Gb3 could be a spillover from these organs and, therefore, may not
[160]
reflect the substrate levels in clinically relevant organs such as the heart, kidney, or peripheral nerves . In
addition, as migalastat and lyso-Gb3 occupy distinct compartments (lysosomes versus plasma), not all lyso-
[160]
Gb3 may be subject to catalysis by migalastat-stabilized α-Gal .
It is important to monitor plasma lyso-Gb3 in all Fabry patients on therapy and when switching therapies,
in particular ERT to chaperone therapy, as there have been a few reports of inadequate clinical and
biomarker responses despite in vitro amenability .
[162]
Table 4 summarizes the response of Fabry nephropathy to treatment.

Anti-drug antibodies
Both agalsidase-alfa and agalsidase-beta have been associated with anti-drug antibodies (ADA), with the
[169]
prevalence being slightly greater for the beta version, at least partly due to the 5-fold higher dose . Most
ADA are IgG. IgE antibodies are quite rare and have only been reported in males receiving agalsidase-
[170]
beta . Desensitization protocols have been successful for agalsidase-beta [170,171] . Females have a lower
prevalence of ADA than males, perhaps due to the fact that they have higher residual α-Gal levels than
[172]
males . ADA assays reported by various laboratories differ in terms of sensitivity and specificity, and thus,
the results cannot be compared. Some males with Fabry disease will develop neutralizing ADA, which will
bind the α-Gal enzyme in an in vitro assay . To date, the only female reported to have developed
[173]
neutralizing antibodies in the CFDI registry was a homozygote (unpublished data M. West). Some
neutralizing ADA have been shown to bind the α-Gal enzyme in vivo . Nonsense and frameshift
[173]
mutations, higher baseline plasma lyso-Gb3 and agalsidase-beta as the first treatment were reported as risk
factors for the development of neutralizing ADA . Many of these patients will have undetectable or
[174]
extremely low α-Gal activity. This can result in a blunted response to ERT with higher urine Gb3 and
[173]
plasma lyso-Gb3 levels, as well as a worsening clinical state with lower eGFR and higher proteinuria .
Switching to a higher ERT dose of 1.0 mg/kg to give more antigen to overcome the ADA binding of enzyme
[175]
has been of infrequent or transient benefit so far . While induction of immune tolerance to ERT with