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.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Sangamo Therapeutics Inc.

Participant type

Patients

Age range

18-64 years

Gender

Male

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Trial duration

28 Jun 2022 → 10 Apr 2025

Decision date (initial)

2024-07-26

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Sangamo Therapeutics Inc.

External identifiers

EU CT number

2024-512695-34-00

EudraCT number

2019-000667-24

WHO UTN

U1111-1305-1998

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacodynamic, Efficacy, Dose response, Pharmacokinetic, Therapy

To assess the safety and tolerability of ST-920.

Secondary objectives 5

1. 1. To assess α-Gal A activity and the presence of its substrates in plasma over time.
2. 2. To assess impact of ST-920 on ERT administration required for subjects on ERT.
3. 3. To assess the impact of ST-920 on renal function.
4. 4. To assess the impact of ST-920 on cardiac function and left ventricular hypertrophy.
5. 5. To evaluate ST-920 vector DNA shedding over time.

Conditions and MedDRA coding

Fabry Disease (X-linked lysosomal storage disease).

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. 1. ≥ 18 years of age.
2. 10. 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.
3. 11. 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.
4. 12. 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.
5. 13. Additional inclusion criteria for Renal cohort: Screening eGFR value between 40-90 mL/min/1.73 m².
6. 14. Additional inclusion criteria for Renal cohort: Linear negative eGFR slope.
7. 2. Signed, written informed consent.
8. 3. Diagnosis of Fabry disease.
9. 4. One or more of the following symptoms: i) cornea verticillata, ii) acroparesthesia, iii) anhidrosis, iv) angiokeratoma.
10. 5. 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).
11. 6. 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.
12. 7. 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
13. 8. 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.
14. 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.

Exclusion criteria 27

1. 1. Current treatment with migalastat (Galafold®).
2. 10. 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
3. 11. 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.
4. 12. Contraindication to use of corticosteroids.
5. 13. History of malignancy, except for non-melanoma skin cancer and localized prostate cancer treated with curative intent.
6. 14. 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.
7. 15. 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).
8. 16. Prior treatment with a gene therapy product.
9. 17. Known hypersensitivity to components of ST-920 formulation.
10. 18. 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.
11. 19. 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.
12. 2. Positive neutralizing antibodies to AAV6.
13. 20. Additional exclusion criteria for Renal cohort: History of renal dialysis or transplantation.
14. 21. Additional exclusion criteria for Renal cohort: History of acute kidney insufficiency in the 6 months prior to screening.
15. 22. 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.
16. 23. 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.
17. 24. Additional exclusion criteria for Cardiac cohort: Significant cardiac fibrosis.
18. 25. Additional exclusion criteria for Cardiac cohort: Any contraindications to Cardiovascular magnetic resonance (CMR) as per local hospital/institution guidelines.
19. 26. 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.
20. 3. Intercurrent illness expected to impair evaluation of safety or efficacy during the observation period of the study.
21. 4. Estimated glomerular filtration rate <40 mL/min/1.73m2.
22. 5. 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.
23. 6. Breastfeeding at screening or breastfeeding during required period of contraception.
24. 7. 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.
25. 8. Elevated circulating serum Alpha fetoprotein (AFP).
26. 9. For subjects receiving ERT, recent or recurrent hypersensitivity reaction manifested by significant infusion reaction to ERT treatment within 6 months prior to consent.
27. 27. Additional exclusion criteria for Cardiac cohort: New York Heart Association Class IV.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 1. Incidence of treatment-emergent adverse events (TEAEs). Additional safety evaluations will include: o Routine hematology, chemistry, and liver tests, vital signs, electrocardiogram (ECG) and echocardiogram (ECHO). o Serial alpha fetoprotein (AFP) testing and magnetic resonance imaging (MRI) of liver (or equivalent imaging modality) to monitor for liver mass.

Secondary endpoints 5

1. 1. 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
2. 2. Change from baseline at specific time points over the 1-year study period in: o Frequency of ERT infusion
3. 3. 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
4. 4. Change from baseline at specific time points over the 1-year study period in: o Ejection fraction, global longitudinal strain, left ventricular mass index (LVMI), left ventricular systolic function measured by cardiac magnetic resonance imaging (CMR)
5. 5. ST-920 vector clearance measured by level of vector genome in blood (plasma), saliva, urine, stool, and semen (if applicable)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Sangamo Therapeutics Inc.

Sponsor organisation

Sangamo Therapeutics Inc.

Address

501 Canal Boulevard Suite A100

City

Richmond

Postcode

94804-3522

Country

United States

Scientific contact point

Organisation

Sangamo Therapeutics Inc.

Contact name

Information Desk

Public contact point

Organisation

Sangamo Therapeutics Inc.

Contact name

Information Desk

Third parties 7

Locations

2 EU/EEA countries · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 4 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications