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Page 347 Giliberti et al. J Transl Genet Genom 2024;8:340-54 https://dx.doi.org/10.20517/jtgg.2024.41

Table 1. Characteristics of emerging therapies
New therapy Administration Advantages Trials
Moss- • Repeated administration ◆ Safety and tolerability • Phase 1 clinical trial (NCT02995993)
galactosidase alfa ◆ Prolonged reduction of Gb3
excretion
◆ Expression of the mannose
receptor on kidney cells
Venglustat • 15 mg once daily ◆ Oral administration • 3-year open-label phase 2 trials (NCT02228460 -
◆ Linear pharmacokinetics NCT02489344)
◆ Rapid absorption • PERIDOT (randomized, double-blind, placebo-
controlled, 12-month Phase 3 study NCT05206773)
◆ Favorable safety and tolerability
profile • CARAT (phase III clinical trial NCT05280548)
◆ Ability to pass the blood-brain
barrier
Lucerastat • 100, 300, 500, 1,000 mg ◆ Oral administration • SAD (single-ascending dose study NCT02944487)
once daily ◆ Favorable safety and tolerability • MAD (multiple-ascending dose study NCT02944474)
• 200, 500, 1,000 mg b.i.d. profile • MODIFY (multicenter, double-blind, randomized,
◆ Ability to pass the blood-brain placebo-controlled phase III study NCT03425539)
barrier
Gene therapy • Single administration ◆ Long-term treatment • Open-label phase I/II trial (NCT04519749)
◆ All damaged cells and tissues
involved
mRNA-based • Repeated administration ◆ No immunogenicity • Preclinical studies
therapy ◆ Long-term treatment
◆ Endogenous α-Gal expression by
the targeted tissues
◆ No risk of insertional
mutagenesis
◆ Prolonged half-lives and duration

Phase 1 studies have demonstrated its linear pharmacokinetics, rapid absorption, and a favorable safety and
tolerability profile in healthy volunteers .
[60]

Data from a 26-week open-label Phase 2a study (NCT02228460) and a 130-week extension trial
(NCT02489344) demonstrated the safety and efficacy of Venglustat in treatment-naïve adult males with FD
(15 mg once daily oral dose) .
[61]

Patients treated with Venglustat exhibited decreased levels of key glycosphingolipid pathway markers.
While proximal markers showed a rapid decline, more distal markers such as plasma Gb3 and
globotriaosylsphingosine demonstrated a gradual reduction. Importantly, no biochemical or histological
evidence of disease progression was observed over three years of follow-up.

However, the efficacy and safety of Venglustat need to be confirmed in larger studies.

A phase III clinical trial, CARAT, is currently underway to evaluate the effect of Venglustat on left
[62]
ventricular mass index compared to traditional therapies .
There is another ongoing trial, the PERIDOT trial, that aims to evaluate the efficacy of Venglustat in
[63]
reducing neuropathic and abdominal pain in treatment-naïve patients with FD .
The drug is also being evaluated for the treatment of other diseases, including Parkinson’s disease associated
with GBA mutations, Gaucher disease type 3, GM2 gangliosidosis, and autosomal dominant polycystic
kidney disease .
[60]