Safety and Tolerability Assessment of Isaralgagene Civaparvovec Gene Therapy in Fabry Disease: A Phase I/II, Multicenter, Open-Label, Dose-Ranging Study

Trial ID: 2024-512695-34-00
Protocol: ST-920-201
Sponsor: Sangamo Therapeutics Inc.

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Diseases & Conditions

Fabry's disease

Objectives

The primary objective of this study is to assess the **safety** and **tolerability** of ST-920, an AAV2/6 human alpha-galactosidase A gene therapy, in subjects with **Fabry Disease**. This is clinically relevant as it aims to determine the potential risks and adverse effects associated with the administration of this novel gene therapy, which is crucial for ensuring patient safety and guiding future therapeutic applications.

Secondary objectives include:

To assess α-Gal A activity and the presence of its substrates in plasma over time.
To assess the impact of ST-920 on enzyme replacement therapy (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.

Participants

The clinical trial involves a total of **38 participants** diagnosed with **Fabry Disease**, an X-linked lysosomal storage disorder. The study population consists exclusively of male subjects, aged 18 years and older, who are not considered part of a vulnerable population. Participants were selected based on specific inclusion criteria, including a confirmed diagnosis of Fabry Disease and the presence of one or more symptoms such as cornea verticillata, acroparesthesia, anhidrosis, or angiokeratoma. Subjects may be enzyme replacement therapy (ERT) naïve, pseudo-naïve, or currently receiving ERT, provided it has been administered at a stable dose and regimen for at least six months prior to consent. All participants are required to be fully vaccinated against COVID-19 according to CDC guidelines or local regulations. Lifestyle considerations include the requirement for male subjects to use effective contraception and refrain from sperm donation until specific post-treatment conditions are met. The trial does not include female subjects, and no data on diet or physical activity is provided by the sponsor.

Plans and Procedures

The clinical trial is a **Phase I/II**, multicenter, open-label, single-dose, dose-ranging study designed to assess the safety and tolerability of **ST-920**, an **AAV2/6 human alpha-galactosidase A gene therapy**, in subjects with **Fabry disease**. The trial is not categorized as low intervention and is expected to conclude by March 2025, with recruitment having commenced in June 2023. The study involves the administration of **isaralgagene civaparvovec** via **intravenous use**. Participants will be involved in the study for approximately one year, during which they will undergo a series of study visits.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility is confirmed based on criteria such as age, diagnosis of Fabry disease, and stable enzyme replacement therapy (ERT) regimen, among others. Following the screening, eligible participants will receive a single dose of the investigational product. Subsequent follow-up visits will be scheduled at specific intervals to monitor safety and efficacy outcomes. These visits will include assessments such as routine hematology, chemistry, liver tests, vital signs, electrocardiogram (ECG), echocardiogram (ECHO), and magnetic resonance imaging (MRI) of the liver. The primary endpoint focuses on the incidence of treatment-emergent adverse events (TEAEs), while secondary endpoints include changes in **α-Gal A activity**, **Gb3** and **lyso-Gb3** levels, frequency of ERT infusion, estimated glomerular filtration rate (eGFR), and cardiac function parameters over the study period.

The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments will be conducted to evaluate the long-term safety and tolerability of the gene therapy. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with study procedures, or withdraw consent. The study is conducted in accordance with ethical guidelines, and all participants are required to provide signed, written informed consent prior to participation.

Treatment

The clinical trial involves the administration of **ST-920**, a gene therapy product developed by Sangamo Therapeutics, Inc. The active substance in ST-920 is **isaralgagene civaparvovec**, which is a recombinant adeno-associated virus serotype 2/6 vector encoding the cDNA for human alpha-galactosidase A. This investigational product is formulated as a **solution for injection/infusion** and is administered via the **intravenous route**. The study is designed as a Phase I/II, multicenter, open-label, single-dose, dose-ranging study to evaluate the safety and tolerability of ST-920 in subjects diagnosed with **Fabry disease**. The gene therapy aims to deliver the **hGLA transgene** to the patients, facilitating the production of the deficient enzyme in Fabry disease.

ST-920 is classified as an orphan drug, with the designation number EU/3/19/2241, indicating its intended use for a rare condition. The product is not a pediatric formulation and is specifically tailored for adult patients. The study does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The administration of ST-920 is a single-dose regimen, and the trial does not specify a maximum daily or total dose amount, nor a maximum treatment period. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.

Efficacy

Efficacy in this clinical trial will be assessed through a series of secondary endpoints designed to evaluate the therapeutic impact of **ST-920** in subjects with Fabry disease. The primary focus will be on changes from baseline at specific time points over a one-year study period. Key parameters include the activity of **α-Gal A** in plasma, levels of Gb3 and lyso-Gb3 in plasma, and the frequency of enzyme replacement therapy (ERT) infusion. Additionally, renal function will be monitored through changes in estimated glomerular filtration rate (eGFR) using the CKD-EPI formula. Cardiac function will be evaluated by measuring ejection fraction, global longitudinal strain, left ventricular mass index (LVMI), and left ventricular systolic function using cardiac magnetic resonance imaging (CMR).

Furthermore, the clearance of the **ST-920** vector will be assessed by measuring the level of vector genome in various biological samples, including blood (plasma), saliva, urine, stool, and semen, if applicable. These assessments will be conducted at predetermined intervals throughout the study to provide a comprehensive evaluation of the gene therapy's efficacy. The data collected will be analyzed to determine the therapeutic benefits and potential improvements in clinical outcomes for subjects receiving the treatment.

Inclusion and Exclusion Criteria

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Inclusion Criteria

≥ 18 years of age.
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.
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.

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Exclusion Criteria

Current treatment with migalastat (Galafold®).
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
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.
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.
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.
Known hypersensitivity to components of ST-920 formulation.
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.
Positive neutralizing antibodies to AAV6.
Additional exclusion criteria for Renal cohort: History of renal dialysis or transplantation.
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 Renal cohort: Urine protein to creatinine ratio (UPCR) > 0.5 g/g who are not being treated with an ACE inhibitor or ARB.
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.
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.
Intercurrent illness expected to impair evaluation of safety or efficacy during the observation period of the study.
Estimated glomerular filtration rate <40 mL/min/1.73m2.
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.
Breastfeeding at screening or breastfeeding during required period of contraception.
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.
Elevated circulating serum Alpha fetoprotein (AFP).
For subjects receiving ERT, recent or recurrent hypersensitivity reaction manifested by significant infusion reaction to ERT treatment within 6 months prior to consent.
Additional exclusion criteria for Cardiac cohort: New York Heart Association Class IV.