Fabry Disease (X-linked lysosomal storage disease) MedDRA version: 24.1 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 injection/infusion
INN or Proposed
Sponsors
Sangamo Therapeutics, Inc.
Eligibility
Sex/Gender
Male
Inclusion criteria
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. 500 mg/g) Additional inclusion criteria for: Cohorts 1-4b: 11. Male subjects with 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: 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 a-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% a-Gal A activity in either plasma or leukocytes AND Renal cohort: 13. Screening eGFR va
Exclusion criteria
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 0.5 g/g who are not being treated with an AC
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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;Main Objective: To assess the safety and tolerability of ST-920;Secondary Objective: •To assess a-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 a-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 a-Gal A substrates in urine for all subjects over time • immune response to AAV2/6 and to a-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 ;Primary end point(s): • Incidence of treatment-emergent adverse events (TEAEs) Additional safet | — |
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 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 a-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 | — |
Countries
Australia, Canada, Germany, Italy, Taiwan, United Kingdom, United States
Contacts
Public ContactST-920-201 Information Desk
Sangamo Therapeutics, Inc.
Outcome results
None listed