Clinical Trials Register

Summary
EudraCT Number:	2018-000192-33
Sponsor's Protocol Code Number:	SB-913-1602
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:	2018-04-09
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

2018-000192-33

A.3

Full title of the trial

A Phase 1/2, Multicenter, Open-label, Single-dose, Dose-ranging Study to Assess the Safety and Tolerability of SB-913, a rAAV2/6-based Gene Transfer in Subjects with Mucopolysaccharidosis II (MPS II)

A.3.1

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

A phase 1/2 study to evaluate the safety and tolerability of SB-913, a rAAV2/6-based gene therapy in patients with Mucopolysaccharidosis II (MPS II)

A.4.1

Sponsor's protocol code number

SB-913-1602

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03041324

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	SB-913-1602 Information Desk
B.5.3	Address:
B.5.3.1	Street Address	501 Canal Blvd., Suite A100
B.5.3.2	Town/ city	Richmond CA
B.5.3.3	Post code	94804
B.5.3.4	Country	United States
B.5.4	Telephone number	+15109706000
B.5.5	Fax number	+15103237388
B.5.6	E-mail	SB9131602-Notification@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	Yes
D.2.5.1	Orphan drug designation number	EU/3/17/1956
D.3 Description of the IMP
D.3.1	Product name	rAAV2/6 Left ZFN Vector
D.3.2	Product code	SB-47171
D.3.4	Pharmaceutical form	Solution for 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.3.9.1	CAS number	2143578-31-6
D.3.9.2	Current sponsor code	SB-47171
D.3.9.3	Other descriptive name	Adeno-associated virus serotype 2/6 encoding Left side-zinc finger nuclease (ZFN1), SB-A6P-ZLEFT Vector
D.3.10	Strength
D.3.10.1	Concentration unit	vector genomes (vg)/mL
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10000000000000
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.IMP: 2
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	Yes
D.2.5.1	Orphan drug designation number	EU/3/17/1956
D.3 Description of the IMP
D.3.1	Product name	rAAV2/6 Right ZFN Vector
D.3.2	Product code	SB-47898
D.3.4	Pharmaceutical form	Solution for 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.3.9.1	CAS number	2143578-32-7
D.3.9.2	Current sponsor code	SB-47898
D.3.9.3	Other descriptive name	Adeno-associated virus serotype 2/6 encoding Right side-zinc finger nuclease (ZFN2), SB-A6P-ZRIGHT Vector
D.3.10	Strength
D.3.10.1	Concentration unit	vector genomes (vg)/mL
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10000000000000
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.IMP: 3
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	Yes
D.2.5.1	Orphan drug designation number	EU/3/17/1956
D.3 Description of the IMP
D.3.1	Product name	rAAV 2/6 hIDS DONOR
D.3.2	Product code	hIDS DONOR
D.3.4	Pharmaceutical form	Solution for 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.3.9.1	CAS number	2143580-10-1
D.3.9.2	Current sponsor code	SB-IDS
D.3.9.3	Other descriptive name	Adeno-associated virus serotype 2/6 encoding Human Iduronate 2-sulfatase (hIDS) gene donor vector, SB-A6P-HNT Donor Vector
D.3.10	Strength
D.3.10.1	Concentration unit	vector genomes (vg)/mL
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10000000000000
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

Mucopolysaccharidosis type II (MPS II)

E.1.1.1

Medical condition in easily understood language

Hunter Syndrome, is a rare, inherited disease caused by a deficiency in an enzyme called iduronate-2-sulfatase. This causes glycosaminoglycans (GAGs) to build up in the body and cause damage.

E.1.1.2

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	PT
E.1.2	Classification code	10056889
E.1.2	Term	Mucopolysaccharidosis II
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 evaluate the safety and tolerability of SB-913

E.2.2

Secondary objectives of the trial

Secondary Objectives:
• To evaluate change from Baseline over time in the following assessments:
o IDS activity in blood.
o GAG testing in urine.
o Frequency of ERT administration.
• AAV2/6 clearance.
Exploratory Objectives:
• To evaluate change from Baseline over time in the following assessments:
o GAG testing in tissues (including blood, liver tissue, and cerebrospinal fluid [CSF]).
o Gene modification at the albumin locus in the liver.
o Imaging, functional, and neurocognitive testing related to MPS II.
o Immune response to AAV 2/6, ZFNs and IDS.
From consenting subjects, residual samples may be used for future research objectives.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion Criteria
Subjects must meet all of the following criteria to be included in the study:
1. Signed informed consent.
2. ≥5 years of age:
a. Adult cohorts 1 through 4: ≥ 18 years of age;
b. Pediatric cohorts 5 and 6: 12 to 17 years of age; and
c. Pediatric cohorts 7 and 8: 5 to 11 years of age.
3. Clinical diagnosis of MPS II (based on evidence of hepatosplenomegaly, dysostosis multiplex by X-ray, valvular heart disease, or obstructive airway disease); IDS deficiency confirmed by gene sequencing.
4. Sexually mature subjects must agree to use a barrier contraceptive method for prevention of AAV transfer as follows: for female subjects this means that the subjects’ partners must use a condom from dosing with SB-913 and until at least 3 consecutive plasma samples after administration of SB-913 are negative for AAV2/6; for male subjects this means that the subjects must use a condom and must refrain from sperm donation from the time of SB-913 administration until at least 3 consecutive semen samples after administration of SB-913 are negative for AAV2/6. In addition, female participants of child-bearing potential must consent to use a highly effective method of contraception.
5. MRI negative for liver mass as read by a radiologist

E.4

Principal exclusion criteria

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.
2. Neutralizing antibodies in serum (immune response) to AAV2/6.
3. Serious intercurrent illness or clinically significant organic disease (unless secondary to MPS II) such as cardiovascular, hepatic, pulmonary, neurologic, or renal disease.
4. Receiving antiviral therapy for hepatitis B or C, or with active hepatitis B (HBV DNA positive or HBV surface antigen positive) or hepatitis C (HCV RNA viral load) or human immunodeficiency virus (HIV)-1/2 (HIV RNA viral load or HIV antibody positive); to be considered negative for hepatitis C after treatment of an active HCV infection, viral assays in 2 samples collected at least 6 months apart must be negative.
5. Lack of tolerance to idursulfase treatment with significant infusion-associated reactions (IARs) or occurrence of anaphylaxis.
6. Polymorphisms in the ZFN-targeted region of the albumin locus.
7. Liver fibrosis score of 3 or 4 on a 0 to 4 point scale (Desmet et al. 1994) if subject has had a liver biopsy within 2 years of Screening.
8. Markers of hepatic dysfunction as evidenced by one or more of the following:
a) Platelet count <100,000/μL
b) Albumin ≤3.2 g/dL
c) Total bilirubin >1.5 x upper limit of normal (ULN) and direct bilirubin ≥0.5 mg/dL
d) Alkaline phosphatase >2.0 x ULN
e) ALT or AST >2.0 x ULN
9. Creatinine ≥ 1.5 mg/dL
10. Weight < 20 kg at Screening visit.
11. Pregnant or breastfeeding female.
12. Contraindication to the use of corticosteroids.
13. Current treatment with systemic (IV or oral) immunomodulatory agent or steroid use (topical treatment allowed, e.g., for asthma or eczema).
14. History of active malignancy in past 5 years (non-melanoma skin cancer or cervical cancer in situ permitted).
15. Participation in prior investigational drug or medical device study within the previous 3 months.
16. Prior treatment with a gene therapy product.
17. History of alcohol or substance abuse that in the opinion of the Principal Investigator may interfere with study compliance.
18. History of therapeutic non-adherence.
19. Elevated or abnormal circulating AFP.
20. Any other reason that, in the opinion of the Principal 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)

Primary Endpoint:
• Incidence of treatment-emergent AEs (including SAEs).
• Additional safety evaluations include:
o Routine hematology, chemistry and liver function laboratory tests, vital signs, physical exam, electrocardiogram (ECG), echocardiogram (ECHO), and concomitant medications.
o Cranial nerve exam and muscle strength testing.
o Serial α-fetoprotein (AFP) testing and magnetic resonance imaging (MRI) of liver to evaluate for liver mass.

E.5.1.1

Timepoint(s) of evaluation of this end point

-Liver Panel: Baseline (BL), twice a week (wk) for at least the first 20 wks post infusion, then tested at wk 24, 28, 32, 36, 40, 44, 48, 52, Month 15, 18, 21, 24, 27, 30, 33, 36 & ETV
-AE assessments and concomitant medications: All time points
-Clinical Laboratory tests: All time points except day 0, Day 7, wk 28, 32, 40, 44 & 52
-Vital signs & physical exam: BL, Day 0, Day 1, Day 7, wk 2, 4, 6, 8, 12, 16, 20, 24, 36, 48, Month 15, 18, 21, 24, 27, 30, 33, 36 & ETV
-ECG, Cranial nerve exam and muscle strength testing: BL, Day 7 (ECG only), wk 24, 48, Month 18, 24, 30, 36 & ETV
-ECHO: Wk 48, Month 24, 36 & ETV
-AFP: Wk 4, 8, 12, 24, 48 Month 18, 24, 30, 36 & ETV
-MRI Liver: Wk 24, 48, Month 18, 24, 30 & 36 & ETV

E.5.2

Secondary end point(s)

Secondary Endpoints:
• Change from Baseline in:
o IDS activity measured in blood.
o Total GAG, DS GAG, and HS GAG levels (expressed as ratio to creatinine) measured in urine.
o Monthly and annualized frequency and dose of idursulfase (or equivalent ERT).
• AAV2/6 clearance measured by vector genomes in plasma, saliva, urine, stool, and semen by PCR.

Exploratory Endpoints:
•Change from Baseline in:
o Total GAG, DS GAG, and HS GAG levels measured in tissues (including blood, liver tissue, and CSF).
o Percentage and durability of gene modification at the albumin locus in liver tissue obtained at biopsy.
o Forced vital capacity measured by pulmonary function tests (PFTs)
o Distance walked measured by six-minute walk test (6MWT).
o Joint range of motion (JROM).
o MRI of liver to evaluate liver and spleen volume.
o MRI of brain and cervical spine to evaluate clinical soft tissue and/or bone
o Neurocognitive abilities by WASI-II (Wechsler Abbreviated Scale of Intelligence, Second Edition; Shapiro et al. 2015), WPPSI-IV (Wechsler Preschool and Primary Scale of Intelligence), or BSID-III (Bayley Scales of Infant Development), and by VABS-II (Vineland Adaptive Behavior Scales).
o Histopathological exam of liver tissue.
o Immune response to AAV 2/6, ZFNs, and IDS measured in serum.

E.5.2.1

Timepoint(s) of evaluation of this end point

-IDS/GAG testing in blood: Baseline (BL), Wk 2, 4, 6, 8, 12, 16, 20, 24, 36, 48, Month 15, 18, 21, 24, 27, 30, 33, 36 & ETV
- GAG testing in Urine: BL, Wk 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, Month 15, 18, 21, 24, 27, 30, 33, 36 & ETV
-AAV2/6 clearance: BL, Day 7, Wk 2, 4, 8, 12, 16, 20, 24, 36, and 48
-Liver biopsy and Lumbar Puncture: BL, Wk 24, 48
-PFT and 6MWT: BL, Wk 24, 48, Month 18, 24, 30, 36 & ETV
-JROM: BL, Wk 24, 48, Month 18, 24, 30, 36 & ETV
-MRI Liver:Wk 24, 48, Month 18, 24, 30 & 36 & ETV
-MRI brain and cervical spine: BL, Wk 48, Month 24, 36 & ETV
-Neurocognitive abilities and VABS-II: BL, Wk 24, 48, Month 18, 24, 30, 36 & ETV
-AAV and ZFN Immunogenicity: BL, Wk 4, 12, 24, 36, 48, Months 18, 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

E.6.7

Pharmacodynamic

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

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

The sponsor has treated 6 (Six) adult patients so far under the ongoing US study (BB-IND 17006)

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

Yes

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

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)

Yes

F.1.1.6.1

Number of subjects for this age range:

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 asked to participate in a separate long-term follow-up study 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

2018-05-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-08-17

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

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