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

THERAPY FOR FABRY DISEASE - PRESENT AND FUTURE
Therapy for Fabry disease is best divided into non-Fabry-specific therapy (medical or surgical) and Fabry-
[34]
specific therapy . The organ complications of Fabry disease obey the same physiologic rules as those that
govern similar illnesses in the general population. Therefore, standard medical therapy used to prevent
stroke, kidney failure, and cardiomyopathy caused by common diseases is likely to be useful in Fabry
[35]
disease . Non-Fabry-specific therapy includes antiproteinuric medications and renal transplantation for
[36]
kidney involvement ; various forms of anti-arrhythmic therapies medications, implants, and surgical
approaches (e.g., myectomy and heart transplantation) for cardiac disease ; anti-platelet agents to prevent
[37]
ischemic strokes and various antalgic medications for the symptoms of small-fiber neuropathy [38,39] ; and
even simple interventions such as cholestyramine for gastrointestinal symptoms of Fabry disease (personal
observation). Non-Fabry-specific therapy is often very effective and less costly than Fabry-specific therapy.
Its effect on organ function, however, often confounds the assessment of the net benefits of Fabry-specific
therapy. The effort to optimize and then keep constant antiproteinuric therapy in clinical trials that use
kidney function as a major outcome is an example of attempts to minimize the confounding effect of
standard non-specific therapy.

Currently, Fabry-specific therapy consists of either ERT or pharmacological chaperone. ERT’s main goal is
to prevent organ dysfunction. The current consensus is that ERT in Fabry disease slows the decline of the
glomerular filtration rate in patients with low proteinuria and decreases neuropathic pain and
[34]
gastrointestinal symptoms in some patients . However, it has no proven effect on cardiac outcome or on
the risk of cerebrovascular stroke [40,41] , although some papers suggest a small effect [42,43] . The reasons for the
limited effect of ERT likely include the common initiation of therapy too late in life, the limited access of the
infused enzyme to critical cells in affected organs such as cardiomyocytes, too low a dose or insufficient
frequency of administration, as well as the frequent presence of neutralizing anti-enzyme antibodies,
particularly in males with classic Fabry disease [44-47] . In the US, there are two ERT preparations for Fabry
disease - agalsidase beta and pegunigalsidase alfa-iwxj. Outside of the US, there is also agalsidase alfa. The
FDA and EMA have recently approved pegunigalsidase alfa-iwxj as ERT for Fabry disease [48,49] . This product
has a mean circulation half-life of the active enzyme of 80 hours compared to about one hour of agalsidase
[50]
beta . Its approval was mainly based on the reduction of lysosomal inclusions in kidney capillary
endothelial cells. It was hypothesized that the long circulating half-life would be advantageous and lead to a
greater therapeutic effect, particularly in slowing the decline of renal function by improving the eGFR
slope [47,51] . Therefore, a trial involving this new ERT called the BALANCE study (NCT02795676) was
conducted and showed pegunigalsidase alfa-iwxj to be non-inferior to agalsidase beta in the estimated
glomerular filtration rate (eGFR) slope over two years . Patients in this study were selected to have an
[51]
eGFR slope at the entry that was more negative than -2 mL/min/1.73 m /year, and indeed, at baseline, both
2
pegunigalsidase alfa-iwxj and agalsidase beta groups had a mean eGFR slope of about
-8 mL/min/1.73 m /year . However, throughout the study, both groups had a much better eGFR slope,
2
[51]
with a mean slope of -3.6 and 3.2, respectively, over the two years. While this is a slower eGFR decline than
measured at study entry, it is still faster than normal, or about -1 mL/min/1.73 m /year . The reason for the
2
[52]
apparent ‘slowing’ of the renal decline in the agalsidase beta group is not easily explained. It may be that the
eGFR slope for inclusion was not accurate, and in fact, these patients were slower progressors. Alternatively,
it represents a type of Hawthorne effect . A more careful evaluation, possibly a case-control study,
[53]
comparing not only between patient groups but also tracking the effect of a switch from agalsidase beta to
pegunigalsidase alfa-iwxj on the eGFR slope of the same subject may help shed further light on the possible
differential effect in eGFR slope between intermittent (short circulating half-life) and continuous (long
circulating half-life) supply of α-galactosidase A to the kidney. For increased patient convenience, this
product can also be administered every four weeks at a dose of 2 mg/kg. An open-label study shows that this