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Giliberti et al. J Transl Genet Genom 2024;8:340-54 https://dx.doi.org/10.20517/jtgg.2024.41 Page 344

In a randomized, double-blind, placebo-controlled clinical trial, Hughes et al. demonstrated the efficacy of
[41]
agalsidase α in reversing hypertrophic cardiomyopathy in FD patients . MRI studies revealed a reduction
in left ventricular mass after 6 months of treatment with agalsidase α compared to placebo, accompanied by
[41]
a mean 20% decrease in myocardial Gb3 content, as evidenced by multiple myocardial biopsies .

Pegunigalsidase α
Pegunigalsidase α (PRX-102) is a chemically cross-linked and PEGylated α-Gal A generated within the cells
of the tobacco plant. It is added with a molecule of polyethylene glycol (PEG) to enhance the enzyme’s
stability and extend its half-life. Since this enzyme is plant-derived, it does not present M6P on its surface
glycans, indicating a different mechanism of cellular uptake and potentially leading to a distinct
[42,43]
biodistribution profile compared to agalsidase α and agalsidase β .

In vitro studies using human plasma and in vivo studies using a mouse model have demonstrated its greater
steadiness. The murine model showed superior biodistribution of pegunigalsidase α relative to agalsidase α,
[43]
with significant reductions in Gb3 deposits in heart and kidney tissues .
An open-label phase I/II trial demonstrated that pegunigalsidase α has a significantly longer plasma half-life
of 80 h, compared to less than 1 h for agalsidase β in 16 patients, thanks to its distinct pharmacokinetics and
low immunogenicity. Additionally, a reduction in Gb3 by 84% was observed in kidney biopsies following
treatment .
[12]
The 2-year BALANCE study, a randomized phase III trial, evaluated the non-inferiority of pegunigalsidase α
compared to agalsidase β in adult patients with FD who had received agalsidase β for at least one year and
exhibited an annualized estimated glomerular filtration rate (eGFR) decline of more than
-2 mL/min/1.73 m /year. Moreover, pegunigalsidase α was associated with reduced rates of treatment-
2
[44]
emergent adverse events and infusion-related reactions .
The BRIDGE trial, another important phase III open-label study, assessed the safety and efficacy of
pegunigalsidase α (1 mg/kg every 2 weeks) in adults with FD who had previously been treated with
agalsidase α (0.2 mg/kg every 2 weeks) for at least 2 years. The results demonstrated a reduction in the slope
of eGFR in patients treated with pegunigalsidase α compared to previous treatment with agalsidase α and no
adverse impact of anti-pegunigalsidase α antibodies on eGFR decline .
[45]

The results from the phase III, open-label, BRIGHT study indicated that patients with FD receiving ERT
every other week can successfully switch to pegunigalsidase α (2 mg/kg every 4 weeks), demonstrating that
this regimen could be an effective maintenance therapy with a favorable safety profile .
[46]

PEGylation appears to conceal certain epitopes from recognition by the immune system, which leads to a
reduction in immunogenicity. This process involves attaching polyethylene glycol (PEG) molecules to
therapeutic proteins, effectively shielding them from immune cells that would otherwise trigger an immune
response. Furthermore, research has demonstrated that pegunigalsidase can not only reduce the formation
of anti-drug antibodies but also reverse existing ones. This action can promote immune tolerance, making
the therapy more effective and less likely to cause adverse immune reactions [12,43] .

Although rare cases of hypersensitivity reactions and a case of immune-complex-mediated
glomerulonephritis have been reported, the drug has been approved at a recommended dose of 1 mg/kg
every 2 weeks by the European Medicines Agency and the Food and Drug Administration. It represents a