A multicenter, double-blind, randomized, placebo-controlled, parallel-group study to determine the efficacy and safety of lucerastat oral monotherapy in adult subjects with Fabry disease.

Screening visit criteria
1. Signed and dated ICF prior to any study-mandated procedure;
2. Male or female subjects; 18-years old and above;
3. FD diagnosis confirmed with local genetic test results (i.e., resence of at
least 1 mutation in GLA, the gene coding for α-galactosidase A *α-GalA*);
4. Fabry-associated neuropathic pain, as defined by the subject, in the last 3
months prior to screening;
5. ERT treatment status:
a) Subject never treated with ERT; or
b) Subject has not received ERT for at least 6 months prior to screening; or
c) Subject treated with ERT at the time of the screening visit and meeting all
of the following criteria at the time of screening:
i) ERT administration for the last 12 months;
ii) Stable ERT dose regimen during the last 3 months;
iii) Subject agrees to stop ERT administration at the screening visit for
approximately 8 months (6-7 weeks screening + 6 months of double-blind
treatment).
6. A woman of childbearing potential [see definition in Section 4.5.1 of the
core protocol] is eligible only if the following applies:
- Negative serum pregnancy test at screening and a negative urine pregnancy
test at randomization;
- Agreement to undertake monthly urine pregnancy tests during the study and up
to at least 30 days after study treatment discontinuation;
- Agreement to follow a highly effective contraception scheme as described in
Section 4.5.2 of the core protocol from screening up to at least 30 days after
study treatment discontinuation.
- Agreement not to donate ova from screening visit and up to 30 days after
study treatment discontinuation.
7. A fertile male (physiologically capable of conceiving a child according to
investigator judgment) who is sexually active with a woman of childbearing
potential is eligible only if the following applies:
- Agreement to use a condom during the treatment period (starting at
randomization) and for up to 3 months after study treatment discontinuation; and
- Agreement not to father a child during this period.
In addition, male subjects must agree not to donate sperm (except for study
semen sampling) during the treatment period (starting at randomization) and for
up to 3 months after study treatment discontinuation.
Randomization visit criteria
8. Adequate subject compliance with completion of an electronic diary (eDiary)
during the screening period;
9. Subjects with moderate or severe neuropathic pain as determined from daily
entries of the modified Brief Pain Inventory-Short Form item 3 (BPI-SF3) score
of *neuropathic pain at its worst in the last 24 hours* in the eDiary during
the screening period.

Screening visit criteria:
Disease/condition:
1. Pregnant / planning to become pregnant up to 30 days after study treatment
discontinuation or lactating subject;
2. Severe renal insufficiency defined as an estimated glomerular filtration
rate (eGFR) per the Chronic Kidney Disease Epidemiology Collaboration
creatinine equation < 30 mL/min/1.73 m2 at screening (as reported by the
central laboratory);
3. Subject on regular dialysis for the treatment of chronic kidney disease;
4. Subject has undergone, or is on a waiting list for, or is scheduled to
undergo kidney or other organ transplantation.
5. Known and documented transient ischemic attack, stroke, unstable angina or
myocardial infarction within 6 months prior to screening;
6. Clinically significant unstable cardiac disease in the opinion of the
investigator (e.g., uncontrolled symptomatic arrhythmia, New York Heart
Association class III or IV congestive heart failure);
7. Any other subject at high risk of developing clinical signs of organ
involvement within the time period of the study, as per investigator judgment.
8. Any known factor or disease that might interfere with treatment compliance,
study conduct or interpretation of the results such as:
a) Other disease or condition associated with a pain component that could
confound assessment of neuropathic pain (e.g., diabetic neuropathy,
chemotherapy- or radiation-induced peripheral neuropathy, chronic inflammatory
demyelinating polyneuropathy);
b) Other disease of the GI tract that could interfere with the assessment of GI
symptoms in FD (e.g., inflammatory bowel disease);
c) Documented poorly controlled diabetes mellitus (i.e., HbA1c > 8.0% at
screening as reported by the central laboratory);
d) Significant neurological disorder;
e) Significant psychiatric disease; suicidal ideation at screening or history
of suicide attempt or behavior within 6 months prior to screening as per
investigator judgment;
f) History of drug dependence (including opioids) or alcohol dependence;
g) Inability to complete an eDiary on a daily basis.
9. Known concomitant life-threatening disease with a life expectancy < 18
months;
Treatments:
10. Subject planned for imminent initiation of treatment with ERT;
11. Known hypersensitivity to lucerastat or drug of the same chemical class of
iminosugars (e.g., miglitol, miglustat, migalastat), or any of their excipients;
12. Initiation or treatment at an unstable dose within 4 weeks prior to
screening with any of the following medications:
a) Angiotensin-converting enzyme (ACE) inhibitor and/or angiotensin receptor
blocker (ARB);
b) Anti-epileptic;
c) Tricyclic antidepressant (TCA) and/or other antidepressants belonging to the
serotonin-norepinephrine re-uptake inhibitor (SNRI) and selective serotonin
re-uptake inhibitor (SSRI) classes.
13. Planned or current treatment with another investigational treatment within
3 months prior to screening;
14. Treatment with any inhibitor of the glucosylceramide synthase (GCS) (e.g.,
miglustat, lucerastat, eliglustat, ibiglustat/venglustat) or an α-GalA
chaperone (e.g., migalastat) within 6 months prior to screening;, Randomization
visit criteria:
15. Treatment with ERT (agalsidase alfa, agalsidase beta) during the screening
period.