A Phase 1/2 open label study in MPS IIIB subjects to investigate the long-term safety and effect of SBC-103 given by IV infusion.

• Register: EUCTR
• Last refreshed on: 30 June 2019
• Main ID: EUCTR2013-003400-39-GB
• Date of registration: 07/05/2014
• Prospective Registration: Yes
• Primary sponsor: Alexion Pharmaceuticals, Inc.
• Public title: A Phase 1/2 open label study in MPS IIIB subjects to investigate the long-term safety and effect of SBC-103 given by IV infusion.
• Scientific title: A Phase I/II Open Label Study in MPS IIIB Subjects to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics/Efficacy of SBC-103 Administered Intravenously
• Date of first enrolment: 15/07/2014
• Target sample size: 9
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2013-003400-39
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: no; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: no
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Spain, United Kingdom, United States

Contacts

• Name: European Clinical Trial Information
• Affiliation: Alexion Europe SAS

• Name: European Clinical Trial Information
• Affiliation: Alexion Europe SAS

Key inclusion & exclusion criteria

Inclusion criteria:
A subject who meets all of the following inclusion criteria will be eligible to participate in this study:
1. Has a definitive diagnosis of MPS IIIB, as determined by either of the following:
a. Documented deficiency in NAGLU enzyme activity =10% of the mean value in normal individuals (Heron, 2011, Am J Med Genet A) based on test results from a central laboratory at Screening.
OR
b. Documented functionally-relevant mutations in both alleles of the NAGLU gene based on historical test results from a local laboratory (if available) or results from the central laboratory at Screening.
2. Greater than or equal to 2 years old and less than 12 years old at the time of written informed consent, and has an age equivalent of =1 year on the Vineland II.
3. Has documented developmental delay with onset before 6 years of age, as defined by:
a. Cognitive delay evaluated by BSID-III or KABC-II.
OR
b. Language delay, plateauing or regression of language skills as determined by the Investigator and confirmed by the Vineland-II (communication domain) administered at Screening (eg, subject uses isolated words, associated words such as two-word combination, sentences, poor or reduced language and/or language difficult to understand).
4. Subject or subject’s parent or legal guardian (if applicable) consents to participate in the study and provides informed consent prior to any study procedures being performed. If the subject is of minor age; he/she is willing to provide assent where required per local regulations, and if deemed able to do so.
5. Female subjects who are of childbearing potential at the time of consent or who become of childbearing potential during participation on study (a) must have a negative urinepregnancy test at Screening, (b) cannot be breast feeding, and (c) must consent to use a highly reliable method of birth control (expected failure rate less than 5% per year) for the duration of the study and for 30 days after last dose of SBC-103. Women may be considered of non-childbearing potential if they have not started their menses or are surgically sterile (ie, total hysterectomy or bilateral salpingo-oophorectomy).
6. Male subjects must consent to use a highly reliable method of birth control (expected failure rate less than 5% per year) during any sexual contact with females of childbearing potential while participating in the study and for 30 days following discontinuation from this study even if he has undergone a successful vasectomy.
7. Willingness and ability to comply with protocol requirements to the extent that may be expected of a subject with cognitive impairment.

Part B
Qualifications for Participation in Part B (Therapy at 1 and/or 3 mg/kg)
Subjects are eligible for continued SBC 103 dosing in Part B if they do not meet any Exclusion criteria and if they meet the following:
1. Completion of Part A with no unmanageable study drug toxicity;
2. Continue to meet Inclusion Criteria items 4-7; and
3. SRC and Sponsor have reviewed the subject’s safety data from Part A and have deemed it acceptable for the subject to re-initiate dosing in Part B.

Exclusion criteria:
A subject who meets any of the following exclusion criteria will be ineligible to participate in this study:
1. Received treatment with gene therapy at any time, or any investigational drug (including high dose genistein > 150 mg/kg/day), or device intended as a treatment for MPS IIIB within 30 days prior to Screening, or is currently being treated in another study that involves an investigational drug or device.
2. Has any internal or non-removable external metal items that may present a safety risk for study assessments that utilize magnetic fields, or any other medical condition or circumstance in which an MRI is contraindicated according to local institutional policy.
3. Previous hematopoietic stem cell or bone marrow transplant.
4. Known or suspected hypersensitivity to anesthesia or the use of a sedative is contraindicated for any other reason.
5. History of poorly controlled seizure disorder.
6. A bleeding disorder, or any other medical condition or circumstance in which a lumbar puncture (for collection of CSF) is contraindicated according to local institutional policy.
7. Known hypersensitivity to eggs. Subjects at high risk for food allergy that may include eggs should be tested according to local guidelines.
8. Other medical conditions or co-morbidities (eg, ALT or AST > 3x ULN, confirmed by repeat testing, analyzed centrally or locally and based on the standardized reference range provided in the central laboratory manual), or other markers of clinically significant liver dysfunction (eg. elevated bilirubin, [with the exception of patients with confirmed Gilberts Disease] confirmed by repeat testing, or elevated prothrombin time [PT]P/ International normalized ratio [INR] confirmed by repeat testing analyzed centrally or locally and based on the standardized reference range provided in the central laboratory manual) which in the opinion of the Investigator, in consultation with the Sponsor, would interfere with study compliance, or confound data interpretation.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Mucopolysaccharidosis III, type B (MPS IIIB), Sanfilippo B
MedDRA version: 19.0 Level: LLT Classification code 10056918 Term: Sanfilippo's syndrome System Organ Class: 10010331 - Congenital, familial and genetic disorders
MedDRA version: 19.0 Level: PT Classification code 10056890 Term: Mucopolysaccharidosis III System Organ Class: 10010331 - Congenital, familial and genetic disorders

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Intervention(s)

Product Name: Recombinant Human Alpha-N-Acetylglucosaminidase (rhNAGLU)
Product Code: SBC-103
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: not available
CAS Number: 1522433-40-4
Current Sponsor code: SBC-103
Other descriptive name: rhNAGLU
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 2-

Primary Outcome(s)

Main Objective: To evaluate the safety and tolerability of the IV administration of SBC-103 in subjects with mucopolysaccharidosis III, type B (MPS IIIB, Sanfilippo B) with evaluable signs or symptoms of developmental delay.

Secondary Objective: • To characterize the PK profile of SBC-103 administered IV.
• To determine the effects of SBC-103 administered IV on the levels, onset and magnitude of changes in total HS in CSF, serum, and urine.
• To evaluate the PD/efficacy of doses of SBC-103 administered IV as measured by neurocognitive and developmental function and change in brain structures.
• To evaluate the impact of temporary interruption of SBC-103 therapy (between Parts A and B) on safety, tolerability, and select PD/efficacy markers, including the reversibility of changes in levels of total HS in CSF, serum, and urine.

Primary end point(s): The primary endpoint of this study is safety and tolerability of SBC-103 in
subjects with MPS IIIB. The safety assessments will include the following:
• Incidence of AEs, serious adverse events (SAEs), and infusion-
associated reactions (IAR)s;
• Changes from baseline in clinical laboratory tests (hematology, serum chemistry, and urinalysis) and CSF findings (cell counts, glucose, and protein);
• Changes from baseline in 12-lead electrocardiograms (ECGs) ;
• Changes in vital signs during and post-infusion, relative to pre-infusion values;
• Physical examination findings;
• Use of concomitant medications/therapies;
• Assessment of ADAs, including seroconversion rate, time to seroconversion, and ADA titer by time point, peak ADA titer, and ADA titer status (positive/negative), and the effect of ADAs on the safety of SBC-103, including the relationship between ADA-
positive subjects and the incidence of IARs.

Timepoint(s) of evaluation of this end point: Every two weeks

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Every two weeks

Secondary end point(s): The secondary endpoints of this study are baseline and post-treatment measures
of the following assessments:
• PK profile of SBC-103 after single and multiple doses:
- Maximum observed serum concentration (Cmax)
- Time to reach Cmax (Tmax)
- Area- under- the- concentration-time -curve from time 0 to the last measurable time
point (AUClast)
- Area-under-the-concentration-time curve extrapolated to infinity (AUC8)
- Half-life (T1/2)
- Clearance (CL)
- Volume of distribution at terminal phase (Vz)
- Accumulation ratio (Rac)
• Effects of SBC-103 treatment on the onset, magnitude, and reversibility of changes in levels of total HS in CSF, serum, and urine.
• Neurocognitive and developmental function as determined by the scores on Vineland Adaptive Behavior Scales, Second Edition (Vineland-II) and, as appropriate to the subject’s age, the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) or Kaufman Assessment Battery for Children, Second Edition (KABC-II), Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, Brief Form (BOT-2 Brief Form), and Children’s Communication Checklist, Second Edition (CCC-2).
• Brain structure as determined by the relative proportion of grey and white matter volume and indices of microstructural integrity as assessed by MRI of the brain.
• Effect of temporary interruption of SBC-103 therapy (between Parts A and B) on safety, tolerability and select PD/efficacy markers

Exploratory endpoints in this study include measures to examine the onset, magnitude, and reversibility of changes in exploratory biomarkers, SBC-103 concentration in CSF, MPS IIIB disease characteristics, symptoms, and QOL after IV administration of SBC-103:
* Biomarkers:
• Change in non-reducing end (NRE) HS derivatives in CSF, serum, and urine
• Changes in serum ferritin and chitotriosidase
• Changes in CSF-disease related biomarkers including but not limited to, hepatocyte growth factor (HGF), calbindin D, Tau, pTau, amyloid ß, albumin, IgG, glutamic acid, and glycine
• Changes in glutamic acid and glycine in relation to plasma (carrier-mediated excitatory amino acids that are markers of transport function)
• Changes in CSF/serum albumin index (CSF-AI).
• Changes in IgG index ( [CSF/serum IgG ratio] / [ CSF-AI] )
• Changes in inflammatory markers in serum
* Disease characteristics, symptoms, and QOL
• Assessment of sleep disorders or dysfunction as determined by the Children's Sleep Habits Questionnaire (CSHQ)
• Assessment of behavior as determined by the Sanfilippo Behavior Rating Scale (SBRS)
• Assessment of subjective QOL as determined by the Short Form Health Survey for Children (SF-10)
• Assessment of caregiver QOL as determined by the Zarit Burden Interview (ZBI) 12 item short form
• Coarsening of features by Facial Dysmorphology Novel Analysis (FDNA)
• Additional blood or urine biomarkers of interest that are identified during the course of this study based on emerging data from the scientific literature or the Sponsor’s MPS IIIB development program (if there is sufficient sample volume and if local regulations permit).
• Assessment of genes that may contribute to and/or modify the disease phenotype via a DNA sample (where local regulations permit and subject to discretionary approval from each center’s Institutional Review Board [IRB)]/Independent Ethics Committee [IEC] and the consent/assent of the subject [and/or consent of the subject’s parent or legal guardian]).

Secondary ID(s)

NGLU-CL02

Source(s) of Monetary Support

Alexion Pharmaceuticals, Inc.

Ethics review

Status: Approved
Approval date:
Contact:

Results

• Results available: Yes
• Date Posted: 02/05/2018
• Date Completed: 16/10/2017
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-003400-39/results