Clinical Trials Register

Summary
EudraCT Number:	2019-000667-24
Sponsor's Protocol Code Number:	ST-920-201
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2019-03-19
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2019-000667-24

A.3

Full title of the trial

A Phase I/II, Multicenter, Open-Label, SingleDose, Dose-Ranging Study to Assess the Safety and Tolerability of ST-920, a rAAV2/6 Human Alpha Galactosidase A Gene Therapy in Subjects with Fabry Disease

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A Phase I/II Study to Assess the Safety and Tolerability of ST-920, a rAAV2/6 Human Alpha Galactosidase A Gene Therapy, in Subjects with Fabry Disease

A.4.1

Sponsor's protocol code number

ST-920-201

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Sangamo Therapeutics, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Sangamo Therapeutics, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Sangamo Therapeutics, Inc.
B.5.2	Functional name of contact point	ST-920-201 Information Desk
B.5.3	Address:
B.5.3.1	Street Address	7000 Marina Blvd.
B.5.3.2	Town/ city	Brisbane, CA
B.5.3.3	Post code	94005
B.5.3.4	Country	United States
B.5.4	Telephone number	+16282527545
B.5.5	Fax number	+15103237388
B.5.6	E-mail	ST920201-Notifcation@sangamo.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Recombinant Adeno-associated virus 2/6 vector encoding the cDNA for human alpha galactosidase A
D.3.2	Product code	ST-920
D.3.4	Pharmaceutical form	Solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Not yet assigned
D.3.9.2	Current sponsor code	ST-920
D.3.9.3	Other descriptive name	Adeno-associated virus serotype 2/6 encoding human alpha-galactosidase A cDNA
D.3.10	Strength
D.3.10.1	Concentration unit	vector genomes (vg)/mL
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	5000000000000 to 25000000000000
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	Yes
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	Yes
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Fabry Disease (X-linked lysosomal storage disease)

E.1.1.1

Medical condition in easily understood language

Fabry disease

E.1.1.2

Therapeutic area

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

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10016016
E.1.2	Term	Fabry's disease
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the safety and tolerability of ST-920

E.2.2

Secondary objectives of the trial

Secondary Objectives:
•To assess the pharmacodynamics of α-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 α-Gal A and the presence of its substrates in urine and tissue over time
• To assess the pharmacokinetics of α-Gal A over time
• To assess immune response to rAAV2/6 and α-Gal A
• To evaluate the impact of pre-existing antibodies to α-Gal A on the enzymatic activity levels of α-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

E.2.3

Trial contains a sub-study

E.3

Principal 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% α-Gal A activity in either plasma or leukocytes and one or more of the following symptomatic characteristics of classical Fabry disease: i) cornea verticillata, ii) acroparesthesia, iii) anhidrosis, iv) angiokeratoma.
For subjects who do not have a documented diagnostic α-Gal A activity level, a blood sample should be taken to measure α-Gal A activity levels (in plasma and/or leukocytes).
For those subjects who are on ERT, this blood draw must be taken at least 13 days after their last ERT infusion (trough).
i. If the subject’s level of α-Gal A activity is > 5% and the subject is on ERT, this level of enzyme activity may be due to residual α-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 α-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

E.4

Principal 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

E.5 End points

E.5.1

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

E.5.1.1

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

E.5.2

Secondary end point(s)

Secondary Endpoints:
•Change from baseline at specific time points over the 1-year study period in:
o α-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 α-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 α-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

E.5.2.1

Timepoint(s) of evaluation of this end point

-α-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 & ETV
-AAV2/6 clearance: BL, Day 8, Wk 2,4,8,12,16,20,24,36,52
Exploratory Endpoints:
Cardiac MRI, GI Symptoms rating scale, MSSI, QOL: BL,Wk 24,52 &ETV
Protein & albumin to creatinine ratio in urine, Neuropathic pain: BL,Wk 12,24,36,52 &ETV
Frequency of pain medication use: All intervals except Day 1,2& 8
AAV Immunogenicity: BL,Wk 4,12,24,36,52(Additional samples when liver toxicity is suspected)
Immune response to α-Gal A: Screening,BL,Wk 4,8,12,16,24,36,52 &ETV
Renal Biopsy: BL &Wk 24

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

Yes

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Upon completion of this study, subjects will be strongly encouraged to participate in a separate long-term follow-up study for upto 4 years to monitor the long term safety of the study treatment.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2019-10-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-11-12

P. End of Trial
P.	End of Trial Status	GB - no longer in EU/EEA

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