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Politei et al. Rare Dis Orphan Drugs J 2024;3:10 https://dx.doi.org/10.20517/rdodj.2023.46 Page 7 of 12

even develop new GI symptoms while undergoing ERT, underscoring its continued significance as a source
[42]
of morbidity . This underscores the necessity for concurrent, targeted, GI-specific treatment.
In addition to ERT, a pharmacological chaperone (oral migalastat 123 mg every other day) is approved for
patients (> 12 years old) with an amenable mutation and an estimated glomerular filtration rate (eGFR)
≥ 30 mL/min per 1.73 m . In 2019, Germain et al. reported that in male patients with classic phenotype
2
previously ERT-untreated, migalastat treatment resulted in a significant reduction of GI symptoms
measured by the GSRS, after 24 months . Furthermore, in patients who had previously undergone ERT,
[46]
migalastat demonstrated an improvement in diarrhea, as evidenced by the Minimum Clinically Important
Difference (MCID) score, in comparison to those receiving a placebo . See a summary of treatment option
[47]
in the flow diagram [Figure 4].

Substrate reduction therapy (SRT) acts on a previous step in the metabolic pathway, by inhibiting the
enzymatic conversion of ceramide to glucosylceramide-1 (GL-1) . GL-1 is a key metabolic precursor of
[48]
more complex glycosphingolipids, including GL-3. MODIFY was the first clinical study in patients with FD
to measure the effect of lucerastat on neuropathic pain as a primary endpoint and GI manifestations as a
secondary endpoint. Despite the reduction of plasma Gb3, no significant reduction in neuropathic pain was
observed after six months of treatment .
[49]

Venglustat, an investigational orally available compound, serves as a potent, brain-penetrant GL-1 synthase
inhibitor, potentially introducing a novel mechanistic avenue for treating FD with potential advantages over
current treatment modalities. The outcomes of a Phase II study encompassing a 3-year open-label
assessment, examining the safety, pharmacokinetics, pharmacodynamics, and exploratory efficacy of once-
daily venglustat administration, have been reported . This study included adult male patients with classic
[50]
FD who had not previously received disease-specific therapy and displayed no clinically significant organ
involvement. At baseline, six out of 11 patients reported gastrointestinal pain based on the IBS GI
Questionnaire. By Week 26 (n = 5), the severity of pain decreased in four patients and increased in one
patient. At Week 156 (n = 4), all four patients experienced a decrease in pain severity. Additionally, the
frequency of GI pain in every 10 days decreased in all patients with available data (n = 5) at Week 26, and in
[49]
three out of four patients at Week 156 . A phase III study is currently underway to evaluate the effect of
venglustat tablets on neuropathic and abdominal pain in adult male and female participants with FD
(NCT05206773).

Non-specific therapy
Certain adjunctive treatments can offer symptomatic relief for specific gastrointestinal symptoms. For
instance, the pro-motility agent metoclopramide has demonstrated some efficacy in improving symptoms
in patients with gastroparesis . The use of pancreatic enzymes and bile acids supplementation
[25]
demonstrated a prospective value for improving diarrhea in FD patients . Other medications used to
[12]
control manifestations include ondansetron to reduce nausea, proton pump inhibitors (e.g., omeprazole) to
relieve upper gastrointestinal symptoms, and antidiarrheal medications (loperamide). Unfortunately, this
pharmacological approach rarely results in complete control of symptoms in Fabry patients. Furthermore, it
should be highlighted that ondansetron is not suited for continuous and prolonged use [5,12] . The use of
gabapentin and carbamazepine showed a beneficial effect in patients with small fiber neuropathies and
chronic neuropathic pain [51,52] . Therefore, these "pain killers" can be considered beneficial in the treatment of
GI manifestations, justifying their indication as part of the non-specific therapy. Additionally, tetracycline
has been explored as a potential treatment for bacterial overgrowth, yielding resolution of diarrhea within
two days of treatment in a singular case report .
[7]