| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Fabry Disease (X-linked lysosomal storage disease) |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 24.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10016016 |
| E.1.2 | Term | Fabry's disease |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the safety and tolerability of ST-920 |
|
| E.2.2 | Secondary objectives of the trial |
•To assess α-Gal A activity and the presence of its substrates in plasma over time
•To assess impact of ST-920 on ERT administration required for subjects on ERT
•To assess the impact of ST-920 on renal function
•To assess the impact of ST-920 on cardiac function and left ventricular hypertrophy
•To evaluate ST-920 vector DNA shedding over time
Exploratory Objectives: To assess
• clinical impact of ST-920 on Fabry disease
• the α-Gal activity overtime in skin
• the presence of Gb3 inclusion levels substrates in skin in ERT-naïve and ERT-pseudo-naïve subjects (defined as not having received ERT treatment during the 6 months prior to baseline) and selected subjects previously on migalastat
• the presence of α-Gal A substrates in urine for all subjects over time
• immune response to AAV2/6 and to α-Gal A
• the impact of ST-920 on substrate deposition in the kidney (via kidney biopsy) in ERT-naïve and ERT
pseudo-naïve subject sand selected subjects previously on migalastat |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. ≥ 18 years of age
2. Signed, written informed consent
3. Diagnosis of Fabry disease
4. One or more of the following symptoms: i) cornea verticillata, ii) acroparesthesia, iii) anhidrosis, iv) angiokeratoma
5. Subjects who are on ERT or are ERT-naïve or are ERT-pseudo-naïve (defined as not having received ERT treatment during the 6 months prior to baseline). For subjects receiving ERT, ERT must have been administered at a stable dose and regimen for at least 6 months (defined as not having missed more than 3 doses of ERT during the 6 months prior to consent).
6. Subjects on migalastat (Galafold™) must agree to withdraw migalastat prior to Baseline and, if non-responder to migalastat (based on clinical and/or biochemical assessments), undergo an incisional skin biopsy and kidney biopsy.
7. Male subjects must refrain from sperm donation from the time of ST-920 administration until a minimum of 3 consecutive semen samples are negative for AAV2/6 after administration of ST-920 and a minimum of 90 days after ST-920 administration.
8. Subjects must agree to use a highly effective form of contraception from the time of ST-920 administration until a minimum of 90 days after ST-920 administration and a minimum of 3 consecutive semen samples are negative for AAV2/6 after administration of ST-920. Highly effective birth control methods include:
a. a documented vasectomy or permanent sterilization
b. condom
c. sexual abstinence is acceptable only as true abstinence and when in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
9. Subject must be fully vaccinated (as per the Centers for Disease Control and Prevention (CDC) definition in the US and as per local guidelines in other countries) for COVID-19 at least one month prior to dosing
10. Renal function (not applicable for Renal cohort):
a. eGFR ≥60 ml/min/1.73m2
b. <1 g/g urine albumin to creatinine ratio (UACR) determined in a morning urine spot sample (and also determined by 24 hour urine analysis if the UACR is >500 mg/g)
Additional inclusion criteria for:
Cohorts 1-4b:
11. Male subjects with classical Fabry disease as defined by <5% α-Gal A activity in either plasma or leukocytes.
a. For male subjects who do not have documented diagnostic αGal A activity, a blood sample will be taken to measure αGal A activity (in plasma). For subjects who are on ERT, this blood draw must be taken at least 13 days after their last ERT infusion (trough)
b. If the subject’s α-Gal A activity is >5% and the subject is on ERT, this level of enzyme activity may be due to residual α-Gal A activity from the last ERT infusion. In this case, the diagnosis of classical Fabry disease may be confirmed if the following three criteria are fulfilled:
i. two or more documented symptomatic characteristics outlined in inclusion criterion #4. If there is documented clustered periumbilicial angiokeratoma, this symptom alone is sufficient as it is a pathognomonic sign of classical Fabry disease;
ii. a mutation that is indicative of classical Fabry (i.e. listed in a database, such as http://dbfgp.org); and
iii. the α-Gal A activity at trough is below the lower limit of the normal range of the assay
Renal and Cardiac cohorts:
12. Symptomatic Fabry disease defined for male subjects by <30% α-Gal A activity in either plasma or leukocytes
AND
Renal cohort:
13. Screening eGFR value between 40-90 mL/min/1.73 m²
14. Linear negative eGFR slope (estimated from at least 3 historical serum creatinine values [within 18 months, including the value obtained during screening visit]) of ≥ 2mL/min/1.73 m²/year
Cardiac cohort:
15. Left ventricular hypertrophy (LVH) in 2D echocardiography or CMR defined as an end diastolic septum and posterior wall thickness ≥12mm with no other explanation for LVH, OR presentation with cardiac changes indicative of disease progression such as decreased global longitudinal strain on 2D strain echocardiography or low native T1 mapping on CMR |
|
| E.4 | Principal exclusion criteria |
1. Positive neutralizing antibodies to AAV6
2. Intercurrent illness expected to impair evaluation of safety or efficacy during the observation period of the study
3. Patients receiving warfarin or other anticoagulants interfering with the ability to perform renal or skin biopsies, or patients with a clinically significant bleeding disorder
4. Active infection with hepatitis A virus (HAV ribonucleic acid [RNA] positive), active or occult hepatitis B virus infection (positive HBV-DNA or anti-HBc positive), active infection with hepatitis C virus (HCV RNA positive), infection with the human immunodeficiency virus (HIV) as measured by quantitative polymerase chain reaction (qPCR), or active or latent infection with tuberculosis (TB) measured by quantiferon test
5. Partner planning to become pregnant during required period of contraception.
6. History of liver disease such as clinically significant steatosis, fibrosis, non-alcoholic steatohepatitis (NASH) and cirrhosis, biliary disease within 6 months of informed consent; except for Gilbert’s syndrome
7. Elevated circulating serum AFP
8. For subjects receiving ERT, recent or recurrent hypersensitivity reaction manifested by significant infusion reaction to ERT treatment within 6 months prior to consent
9. One or more of the following:
i. Albumin ≤ 3.5 g/dL
ii. Total bilirubin > upper limit of normal (ULN) and direct bilirubin ≥ 0.5 mg/dL
iii. Alkaline phosphatase (ALP) > 2.0 x ULN
iv. Alanine aminotransferase (ALT) > 1.5 x ULN
v. Aspartate aminotransferase (AST) > 1.5 x ULN
vi. Platelet count < 100 x 109/L
10. Current or history of systemic intravenous (IV) or oral immunomodulatory agents, or biologics or steroid use in the past 6 months prior to consent (topical and inhaled treatment are allowed, [e.g., for asthma or eczema]). Occasional use of systemic steroid may be allowed based on discussion and agreement with the Medical Monitor.
11. Contraindication to use of corticosteroids (including but not limited to uncontrolled glaucoma, diabetes mellitus or hypertension)
12. History of malignancy, except for non-melanoma skin cancer and localized prostate cancer treated with curative intent
13. Recent history of alcohol or substance abuse. The use of marijuana may be considered on an individual basis with discussion and agreement from the Medical Monitor.
14. Participation in prior investigational interventional drug or medical device study throughout the duration of this study and within the last 3 months prior to consent (with the exception of implantable loop recorders as in the RaILRoAD trial)
15. Prior treatment with a gene therapy product
16. Known hypersensitivity to components of ST-920 formulation
17. Any other reason that, in the opinion of the Site Investigator or Medical Monitor, would render the subject unsuitable for participation in the study, including but not limited to risk of COVID-19 infection
18. Females
Additional exclusion criteria for:
Cohorts 1-4 and renal cohort:
19. Subjects who meet New York Heart Association (NYHA) Class III and IV
Renal cohort:
20. History of renal dialysis or transplantation
21. History of acute kidney insufficiency in the 6 months prior to screening
22. Angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy initiated within 4 weeks prior to screening or changed ACE inhibitor or ARB dose in the 4 weeks prior to screening
23. Urine protein to creatinine ratio (UPCR) >0.5 g/g who are not being treated with an ACE inhibitor or ARB
Cardiac cohort:
24. Significant cardiac fibrosis defined as having more than 3segments full thickness of late gadolinium enhancement on CMR
25. Any contraindications to CMR as per local hospital/institution guidelines
26. ACE inhibitor or ARB therapy initiated within 4 weeks prior to screening or changed ACE inhibitor or ARB dose in the 4 weeks prior to screening
27. NYHA Class IV |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Incidence of treatment-emergent adverse events (TEAEs)
Additional safety evaluations will include:
o Routine hematology, chemistry, and liver tests, vital signs, ECG and ECHO
o Serial alpha fetoprotein (AFP) testing and magnetic resonance imaging (MRI) of liver (or equivalent imaging modality) to monitor for any liver mass
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
-AE Assessment: Screening, Baseline(BL), Day 1, 2, 8 , Weeks (Wks) 2, 4, 6, 8, 12, 16, 20, 24, 28, 32,36, 40, 44, 48,
52 (EOS) & Early Termination Visit (ETV)
-Clinical laboratory tests: Screening, BL, Day 1, 2, Weeks 2, 4, 6, 8, 12, 16, 20, 24, 36, 52 & ETV
-Liver Panel: Screening, BL, twice weekly during the first 20 weeks after ST-920 infusion while the subject is on prednisone or other equipotent steroid, Weekly for 4 Wks (Wks 21, 22, 23, 24 [±2 days]) following discontinuation of
immunosuppression & then monthly thereafter
-Vital Signs: Screening, BL, Day 1, 2, 8, Wks 2, 4, 6, 8, 12, 16, 20, 24, 36, 52 & ETV
-ECG: Screening,BL, Day 8, Wks 24, 52 & ETV
-ECHO: Screening, EOS & ETV
-AFP testing: Screening, Wks 4, 8, 12, 24, 52 & ETV
-MRI of liver: Screening, Wks 24, 52 & ETV |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints:
• Change from baseline at specific time points over the 1-year study period in:
o α-Gal A activity in plasma
o Gb3 and lyso-Gb3 levels in plasma
• Change from baseline at specific time points over the 1-year study period in:
o Frequency of ERT infusion
• Change from baseline at specific time points over the 1-year study period in:
o Estimated glomerular filtration rate (eGFR) using the CKD-EPI formula
• Change from baseline at specific time points over the 1-year study period in:
o Ejection fraction, global longitudinal strain, l Left ventricular mass index (LVMI), left ventricular systolic function measured by cardiac magnetic resonance imaging (CMR)
• ST-920 vector clearance measured by level of vector genome in blood (plasma), saliva, urine, stool, and semen (if applicable)
Exploratory Endpoints:
• Change from baseline at specific time points over the 1-year study period in:
o Late gadolinium enhancement (LGE), native myocardial T1 values and T2 mapping measured by cardiac MRI (CMR)
o High sensitivity troponin T, N-terminal pro-hormone B- type natriuretic peptide (NT-proBNP) and other cardiac biomarkers
o Minnesota Living With Heart Failure Questionnaire (MLHF-Q) summary score
o Urine protein to creatinine ratio (UPCR) and urine albumin to creatinine ratio (UACR)
o Biomarkers of renal function in urine
o Neuropathic pain measured by the Brief Pain Inventory (BPI)
o Frequency of pain medication use
o Gastrointestinal (GI) symptoms measured by the GI symptoms rating scale
o Mainz Severity Score Index (MSSI)
o Quality of life (QOL) patient-reported outcome measured by the SF-36 questionnaire
o Pulmonary function
o Audiologic function
• Change from baseline at specific time points over the 1-year study period in:
o α-Gal A activity measured in skin
• Change from baseline at specific time points over the 1-year study period in:
o Gb3 inclusion levels measured in skin in ERT-naïve and ERT-pseudo-naïve subjects, and selected subjects previously on migalastat
• Change from baseline at specific time points over the 1-year study period in:
o Gb3 and lyso-Gb3 levels in urine for all subjects over time
• Measurement of antibodies to AAV2/6
• Assessment of cell-mediated immune response to AAV2/6
• Measurement of immune response to α-Gal A
• Percent reduction from baseline at Week 24: Gb3 inclusion in the kidney (assessed by kidney biopsy) in ERT naïve and ERT-pseudo-naïve subjects, and selected subjects previously on migalastat |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary:
-α-Gal A, Gb3 &/or Lyso-Gb3 levels: Screening,BL, every 2 weeks during the first 20 wks after ST-920 infusion,then week 24,28,32,36,40,44,48,52&ETV
-ERT administration log: Before & after ST-920 infusion (All timepoints except day 2)
-eGFR: Screening,BL, Day 8, Wk 4,8,12,16,20,24,28,32,36, 40,44,48,52 & ETV
-AAV2/6 clearance:BL, Day 8,Wk 2,4,8,12,16,20,24,36,52
Exploratory:
Cardiac MRI, GI Symptoms rating scale, MSSI, QOL: BL,Wk 24,52&ETV
Protein & albumin to creatinine ratio in urine, Neuropathic pain: BL, Wk 12,24,36,52 &ETV
Frequency of pain medication use: All intervals except Day 1,2&8
AAV Immunogenicity: BL,Wk4,12,24,36,52 (Additional samples when liver toxicity is suspected)
Immune response to α-Gal A: Screening,BL,Wk4,8,12,16,24,36,52&ETV
Renal Biopsy: BL&Wk24 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Taiwan |
| Australia |
| Canada |
| United Kingdom |
| United States |
| Germany |
| Italy |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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