A PROSPECTIVE, LONGITUDINAL STUDY OF POTENTIAL TREATMENT-RESPONSIVE BIOMARKERS AND CLINICAL OUTCOMES IN HUNTER SYNDROME

Completed

• Conditions: Hunter syndrome; mucopolysaccharidosis type II (MPS II); 10027424

• Registration Number: NL-OMON55328
• Lead Sponsor: Denali Therapeutics Inc.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Last Update Posted: 15 April 2024

Recruitment & Eligibility

• Status: Completed
• Sex: Not specified
• Target Recruitment: 3

Inclusion Criteria

Part 1 and 2
Participants in Parts 1 and 2 must have a confirmed diagnosis of MPS II based
on the following:
1) A documented mutation in the IDS gene, AND
2) Reduced IDS activity in plasma, WBCs, and/or skin fibroblasts consistent
with MPS II (e.g., *10% of the lower limit of the normal range, based on the
testing laboratory*s range)
For nMPS II subgroups in Parts 1 and 2participants will have a neuronopathic
phenotype at the time of enrollment based on the following criteria:
* In addition to a diagnosis of MPS II, have a development quotient (DQ) <85
and/or a decline of at least 7.5 points in DQ, assessed at least 6 months
apart, or have the same genetic mutation as a blood relative with confirmed
nMPS II

Part 1
Participants in Part 1 must also meet the following criteria for study entry:
* Informed consent signed by the parent(s) or LAR and participant assent if
required based on local regulations, IRB/IEC requirements, and patient age
* Aged 2 through 10 years at time of consent
* Participant and parent(s) or LAR are willing and able to comply with study
visits and study procedures
* Have the ability to comply with protocol requirements according to the
investigator*s judgment

Part 2
Participants in Part 2 must also meet the following criteria for study entry:
* Consent:
o For minors: informed consent signed by the parent(s) or LAR and participant
assent if required based on local regulations and patient age
o For nonminors: informed consent signed by the participant
* Aged 2 through 30 years at time of consent
* Participant and parent(s) or LAR are willing and able to comply with study
visits and study procedures
* Have the ability to comply with protocol requirements according to the
investigator*s judgment
* Scheduled to undergo CSF sampling for non-study-related medical reasons and
participant or parent(s)/LAR consent to donate CSF for research purposes during
that procedure.

Part 3
Participants in Part 3 must meet the following criteria for study entry:
* Have informed consent signed by the parent(s) or LAR and participant assent
if required based on local regulations, IRB/IEC requirements, and participant
age
* Be < 8 years of age at time of consent
* At least 6 (or one-half) of the participants enrolled must be < 3 years of
age at screening
* Have a confirmed diagnosis of MPS II based on all of the following criteria:
* 1. Documented reduced IDS activity in plasma, WBCs, and/or skin fibroblasts
consistent with MPS II (10% or less of the lower limit of the normal range,
based on the testing laboratory*s range)
* 2. Elevated urine GAG levels consistent with MPS II diagnosis:
* a. At screening in standard-of-care ERT treatment-naïve participants
* b. Pretreatment in participants receiving standard-of-care ERT, if available
by historical report
* 3. A documented likely pathogenic variant in the IDS gene, as determined by
an independent external review panel
* *Have nMPS II based on at least one of the criteria (1, 2, or 3) below:
1. Have a large deletion(s) or rearrangement(s) in the IDS gene or
other definitive mutation indicative of nMPS II, as determined by an
independent external review panel
2. Have a DQ > 55 and < 85 at the baseline neurocognitive assessment
and/or a documented decl

Exclusion Criteria

Patients who meet any of the following criteria will be excluded from study
entry (Part 1 and Part 2):
* Have an unstable medical condition that would make participation in the study
unsafe or would interfere with necessary medical care, in the opinion of the
investigator
* Have received any CNS-targeted MPS II investigational therapy (e.g.,
intrathecal IDS, transferrin or insulin receptor*mediated IDS delivery to CNS,
or stem cell transplantation) within the previous 6 months. Patients may
rescreen for this study after the 6-month washout completes.
* Have received an MPS II gene therapy at any time
* Have a mutation of other genes, including loci adjacent to the IDS gene
(e.g., fragile X mental retardation 1 [FMR1] or AF4/FMR2 family member 2 [i.e.,
AFF2 or FMR2]), that are known to be associated with developmental delay,
seizures, or other significant CNS disorders
* Have documented loss of activity of sulfatases other than IDS, indicating
multiple sulfatase deficiency

Patients in Part 2 who meet any of the following criteria will be excluded from
study entry:
* Have a history of complications from previous LPs or are anticipated to pose
significant technical challenges or unacceptable safety risk in receiving an
LP, in the judgment of the investigator

* Have any bleeding disorders, or any other medical condition or circumstance
in which an LP (for collection of CSF) is contraindicated according to local
institutional policy

Participants who meet any of the following criteria will be excluded from Parts
3 and 4 study entry:
* Have an unstable medical condition that would make participation in the study
unsafe or would interfere with necessary medical care, in the opinion of the
investigator
* Have received any CNS-targeted MPS II investigational therapy (e.g.,
intrathecal IDS, transferrin or insulin receptor*mediated IDS delivery to CNS,
or stem cell transplantation) within the previous 6 months
* Have received an MPS II gene therapy or hematopoietic stem cell transplant at
any time unless prior Sponsor approval has been received
* Have a mutation of other genes, including loci adjacent to the IDS gene
(e.g., fragile X mental retardation 1 [FMR1] or AF4/FMR2 family member 2 [i.e.,
AFF2 or FMR2]), that is known to be associated with developmental delay,
seizures, or other significant CNS disorders
* Have documented loss of activity of sulfatases other than IDS, indicating
multiple sulfatase deficiency

Study & Design

• Study Type: Observational invasive
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>* To characterize the progression of adaptive behavior as measured by the<br /><br>Vineland Adaptive Behavior Scales (VABS)<br /><br>* To characterize the progression of neurocognition as measured by the Bayley<br /><br>Scales of Infant and Toddler Development, Third Edition (BSID-III); Kaufman<br /><br>Assessment Battery for Children*, Second Edition (KABC-II); or Wechsler<br /><br>Intelligence Scale for Children*, Fifth Edition (WISC-V)<br /><br>* To assess levels of potential disease-related or treatment-responsive<br /><br>biomarkers in blood, urine, and/or cerebrospinal fluid (CSF) samples from MPS<br /><br>II participants</p><br>

Secondary Outcome Measures

Name	Time	Method
<p>The exploratory objectives of the study are as follows:<br /><br>*To explore correlations between disease-related biomarkers and clinical<br /><br>measures of disease severity (e.g., function, cognition, and behavior)<br /><br>*To characterize glycosaminoglycan (GAG) levels in serum and urine of MPS II<br /><br>participants<br /><br>*To characterize GAG levels in the CSF of MPS II participants</p><br>