A Phase I/II Study to Assess the Safety and Tolerability of ST-920, an AAV2/6 Human Alpha Galactosidase A Gene Therapy, in Subjects with Fabry Disease.

Prior treatment

• Current treatment with migalastat (Galafold®).
• Positive neutralizing antibodies to AAV6.
• Additional exclusion criteria for Renal cohort: History of acute kidney insufficiency in the 6 months prior to screening.
• Additional exclusion criteria for Renal cohort: 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.
• Additional exclusion criteria for Cardiac cohort: 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.
• For subjects receiving ERT, recent or recurrent hypersensitivity reaction manifested by significant infusion reaction to ERT treatment within 6 months prior to consent.
• Current or history of systemic 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.
• Contraindication to use of corticosteroids.
• Participation in 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).
• Prior treatment with a gene therapy product.

Other illness

• 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.
• Additional exclusion criteria for Cohorts 1- 4, anti α-Gal A Ab positive and negative, female and renal cohort: Subjects who meet New York Heart Association (NYHA) Class III and IV.
• Additional exclusion criteria for Renal cohort: History of renal dialysis or transplantation.
• Additional exclusion criteria for Cardiac cohort: Significant cardiac fibrosis.
• Additional exclusion criteria for Cardiac cohort: Any contraindications to Cardiovascular magnetic resonance (CMR) as per local hospital/institution guidelines.
• Intercurrent illness expected to impair evaluation of safety or efficacy during the observation period of the study.
• 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.
• 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.
• Additional exclusion criteria for Cardiac cohort: New York Heart Association Class IV.
• History of malignancy, except for non-melanoma skin cancer and localized prostate cancer treated with curative intent.
• 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.
• Known hypersensitivity to components of ST-920 formulation.

Lab values

• Additional exclusion criteria for Renal cohort: Urine protein to creatinine ratio (UPCR) > 0.5 g/g who are not being treated with an ACE inhibitor or ARB.
• One or more of the following: a. Albumin ≤ 3.5 g/dL b. Total bilirubin > upper limit of normal (ULN) and direct bilirubin ≥ 0.5 mg/dL c. Alkaline phosphatase (ALP) > 2.0 x ULN d. Alanine aminotransferase (ALT) > 1.5 x ULN
• Elevated circulating serum Alpha fetoprotein (AFP).

Other

• Estimated glomerular filtration rate <40 mL/min/1.73m2.
• Breastfeeding at screening or breastfeeding during required period of contraception.

• ≥ 18 years of age.
• Subjects who are on ERT or are ERT-naïve or are ERT-pseudo-naïve. 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).
• Male subjects must agree to use an effective form of contraception and 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. Sexual abstinence is acceptable only as true abstinence and when in line with the preferred and usual lifestyle of the subject. Periodic abstinence and withdrawal are not acceptable methods of contraception.
• Female subjects must refrain from egg donation from the time of ST-920 administration until all the samples are negative for AAV2/6 after administration of ST-920
• Female subjects from menarche until becoming post-menopausal or permanently sterile must have a negative serum pregnancy test at screening and must agree to use a highly effective contraception method from screening through the end of the study.
• 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.
• Additional inclusion criteria for Cohorts 1-4b, anti α-Gal A Ab positive and negative: Male subjects with classical Fabry disease as defined by <5% α-Gal A activity in either plasma or leukocytes.
• Additional inclusion criteria for Female cohort: Female subjects with a documented mutation that is indicative of classical Fabry (i.e., listed in a database, such as http://dbfgp.org) and treatment (ERT) is clinically indicated.
• Additional inclusion criteria for Renal and Cardiac cohorts: Symptomatic Fabry disease defined for male subjects by <30% α-Gal A activity in either plasma or leukocytes and for female subjects based on genetic test results consistent with Fabry pathogenic mutation, or in the case of novel mutations a firstdegree male family member with Fabry disease with the same mutation.
• Additional inclusion criteria for Renal cohort: Screening eGFR value between 40-90 mL/min/1.73 m².
• Additional inclusion criteria for Renal cohort: Linear negative eGFR slope.
• Signed, written informed consent.
• Diagnosis of Fabry disease.
• One or more of the following symptoms: i) cornea verticillata, ii) acroparesthesia, iii) anhidrosis, iv) angiokeratoma.