Fabry Disease (X-linked lysosomal storage disease) MedDRA version: 20.0 Level: PT Classification code 10016016 Term: Fabry's disease System Organ Class: 10010331 - Congenital, familial and genetic disorders
Conditions
Interventions
Product Name: Recombinant Adeno-associated virus 2/6 vector encoding the cDNA for human alpha galactosidase A
Product Code: ST-920
Pharmaceutical Form: Solution for inj
Sponsors
Sangamo Therapeutics, Inc.
Eligibility
Sex/Gender
Male
Inclusion criteria
Inclusion criteria: Subjects must meet all of the following criteria to be included in the study: 1) Subjects with documented diagnosis of classical Fabry disease as defined by 5% and the subject is on ERT, this level of enzyme activity may be due to residual a-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: a. two or more of the following documented symptomatic characteristics of classical Fabry: cornea verticillata, acroparesthesia, anhidrosis, angiokeratoma. If there is documented clustered periumbilicial angiokeratoma, this symptom alone is sufficient as it is a pathognomonic sign of classical Fabry disease; b. a mutation that is indicative of classical Fabry (i.e. listed in a database, such as http://dbfgp.org); and c. the a-Gal A activity at trough is below the lower limit of the normal range of the assay. 2. Subjects who are on ERT (14 days [± 3 days] regimen); or are ERT-naïve; or are ERT-pseudo-naïve (defined as not having received ERT treatment in the 6 months prior to consent). 3. For subjects receiving ERT, ERT must have been administered at a stable dose for at least 6 months (defined as not having missed more than 3 doses of ERT during the 6 months prior to consent) and regimen (14 days ± 3 days for at least 3 months prior to enrollment). 4. Male subjects = 18 years of age 5. Sexually mature subjects must agree to use a condom and refrain from sperm donation from the time of ST-920 administration until a minimum of 3 consecutive semen samples are negative for rAAV2/6 after administration of ST-920 and a minimum of 90 days after ST-920 administration 6. Signed, written informed consent of the subject Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 30 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: Subjects who meet any of the following criteria will be excluded from participating in the study: 1. Known to be unresponsive to ERT in the opinion of the Site Investigator and Medical Monitor (e.g., no documented substrate level decrease on ERT) 2. Current treatment with migalastat (Galafold™) or prior treatment within 3 months of informed consent 3. Positive neutralizing antibody response to AAV6 4. Intercurrent illness expected to impair evaluation of safety or efficacy during the observation period of the study in the opinion of the Site Investigator or Medical Monitor 5. eGFR = 60 ml/min/1.73m^2 6. New York Heart Association Class III or higher 7. Active infection with hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV) or human immunodeficiency virus (HIV) or an infection with tuberculosis (TB) 8. History of liver disease such as secondary steatosis, non-alcoholic steatohepatitis (NASH) and cirrhosis, cholangitis or biliary disease within 6 months of informed consent; except for Gilbert’s syndrome 9. Abnormal circulating AFP 10. For subjects receiving ERT, recent or continued hypersensitivity response to ERT treatment within 6 months prior to consent, as manifested by significant infusion reaction to ERT in the opinion of the Site Investigator and Medical Monitor 11. 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 12. Current or history of systemic (IV or oral) immunomodulatory agent or steroid use in the past 6 months (topical treatment is allowed, e.g. asthma or eczema). Occasional use of systemic steroid may be allowed after discussion with the Medical Monitor. 13. Contraindication to use of corticosteroids for immunosuppression 14. History of malignancy except for non-melanoma skin cancer 15. History of alcohol or substance abuse 16. Participation in prior investigational interventional drug or medical device study within the last 3 months prior to consent (with the exception of implantable loop recorders as in the RaILRoAD trial) 17. Prior treatment with a gene therapy product 18. Known hypersensitivity to components of ST-920 formulation 19. Any other reason that, in the opinion of the Site Investigator or Medical Monitor, would render the subject unsuitable for participation in the study
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess the safety and tolerability of ST-920; Secondary Objective: Secondary Objectives: •To assess the pharmacodynamics of a-Gal A 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 evaluate ST-920 vector DNA shedding over time Exploratory Objectives: • To assess clinical impact of ST-920 on classical Fabry disease • To assess the pharmacodynamics of a-Gal A and the presence of its substrates in urine and tissue over time • To assess the pharmacokinetics of a-Gal A over time • To assess immune response to rAAV2/6 and a-Gal A • To evaluate the impact of pre-existing antibodies to a-Gal A on the enzymatic activity levels of a-Gal A produced by ST-920 • To assess the impact of ST-920 on substrate deposition in the kidney (via renal biopsy) in ERT-naïve and ERT-pseudo-naïve (defined as not having received ERT treatment during the 6 months prior to consent) subjects ; 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 MRI of liver (or equivalent imaging modality) to monitor for any liver mass ; 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, | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary Endpoints: •Change from baseline at specific time points over the 1-year study period in: o a-Gal A activity in plasma o Gb3 levels in plasma o Lyso-Gb3 levels in plasma o Frequency of Fabrazyme® (or equivalent ERT) infusion o Estimated glomerular filtration rate (eGFR) using the CKD-EPI formula • ST-920 vector clearance measured by level of vector genome in blood, saliva, urine, stool, and semen Exploratory Endpoints: •Change from baseline at specific time points over the 1-year study period in: o Left ventricular mass measured by cardiac magnetic resonance imaging (MRI) o Total protein and albumin to creatinine ratios in urine o a-Gal A levels measured in tissues o Substrate levels measured in tissues and urine 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 • Antibody response to rAAV2/6 and a-Gal A and cell-mediated immune response to rAAV2/6 Substrate deposition in the kidney (via renal biopsy) in ERT-naïve and ERT-pseudo-naïve subjects ; Timepoint(s) of evaluation of this end point: -a-Gal A, Gb3 & Lyso-Gb3 levels: Twice weekly 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 & | — |
Countries
United Kingdom, United States
Contacts
Public ContactST-920-201 Information Desk
Sangamo Therapeutics, Inc.
Outcome results
None listed