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Schiffmann. Rare Dis Orphan Drugs J 2024;3:4 https://dx.doi.org/10.20517/rdodj.2023.50 Page 5 of 11

[54]
regimen is promising . Unfortunately, the regulatory agencies have not yet approved the every-four-weeks
regimen.

The pharmacological chaperone migalastat does not share some of the drawbacks of ERT that are
mentioned above. It is a small molecule, the size of glucose, that is widely distributed in the body - including
into the heart and kidney - in comparison to the limited penetration of ERT into the heart (cardiomyocytes)
and kidney podocytes [44,55] . The administration of migalastat every other day is calculated to lead to an
overall stable increase of endogenous α-galactosidase A levels in contrast to ERT administration every 14
days. ERT administration (agalsidase beta) is associated with low or no increase in α-galactosidase A activity
in the 5-7 days that precede the following enzyme infusion [56,57] . In addition, migalastat has not been
reported to induce an immune response to itself or to the chaperoned endogenous α-galactosidase A.

On the other hand, migalastat is effective only with certain GLA missense variants termed amenable
mutations, but they represent a large fraction of the total number of missense variants of this gene . Some
[58]
of these amenable variants, e.g., A143T, N215S, and R363C, are particularly common [14,59,60] . Amicus
Therapeutics, Inc. defined amenability in the in vitro HEK-293 cell assay as a ≥ 1.20-fold increase in
α-galactosidase A activity over baseline in the presence of 10 μmol/L of migalastat, with an absolute increase
of ≥ 3.0% of wild-type α-galactosidase A activity . It is important to note that the degree of amenability is
[4]
[61]
highly variable . The most amenable GLA variants are those that increase the enzymatic activity level from
below the disease threshold of 30% of mean normal to above this threshold. Examples include M296I,
L300P, R301Q, A143T and N215S . Such variants can be called super-amenable because the presence of
[4]
migalastat corrects the metabolic abnormality. The second group of amenable variants is associated with a
marked increase in enzyme activity, though still below the disease threshold. These include G104V, R112H,
D136E, and L166G . This group can be termed good amenable variants that show an increased enzyme
[4]
activity that is likely to be clinically meaningful. Patients with variants of these two groups, particularly the
super-amenable, are best treated with migalastat rather than with ERT. The third group consists of the
poorly amenable GLA variants that show a very small increase in enzyme activity in the presence of
migalastat. Examples include M42V, A20P and Y207S . Patients with these variants will probably not
[4]
benefit clinically from migalastat. A fourth group of amenable GLA variants are those not associated with
Fabry disease because their baseline α-galactosidase A activity is above the disease threshold of 30% of mean
[4]
normal . These are sometimes imprecisely called pseudo-deficient variants.
There are three main caveats to the in vitro HEK-293 cell assay. First, enzyme activity in HEK-293 assay
[61]
may be different from the one found in male patients’ white blood cells assay . Second, enzyme levels in
other cell types and organs may be different from the activity in peripheral blood white cells, both at
[62]
baseline and on migalastat . Since we do not assay α-galactosidase A activity in affected organs, it is
important to carefully monitor organ function over time in treated patients. Third, enzyme activity in some
GLA gene variants such as the A143T mutation may vary from patient to patient or from family to family,
and therefore may fall into either super-amenable group in some individuals or into the pseudo-deficient
variant group in others. In any case, it is always important to measure baseline and on-drug α-galactosidase
A activity in the patients’ peripheral blood white cells . This assay will confirm, in males only, the degree of
[57]
amenability of patient cells in vivo and can also serve to assess patient compliance with migalastat therapy.
From the same publication and from others, we see that some patients treated with migalastat have a
paradoxical increase of plasma lyso-Gb3 . Such patients must be followed carefully, and therapy must be
[57]
adjusted or changed as needed. Nevertheless, changes in lyso-Gb3 are not associated with clinical
outcomes .
[63]