E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Mucopolysaccharidosis type II (MPS II) |
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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. |
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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 |
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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 |
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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. |
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E.2.3 | Trial contains a sub-study | No |
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 |
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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. |
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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. |
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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 |
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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. |
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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 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
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) |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
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 | 4 |
E.8.5 | The trial involves multiple Member States | No |
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 | No |
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 |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
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 | 4 |