This study has been transitioned to CTIS with ID 2023-508619-22-00 check the CTIS register for the current data. The primary objective of the study is the following:• To characterize the safety and tolerability of DNL310 in pediatric subjects with…
ID
Source
Brief title
Condition
- Other condition
- Metabolic and nutritional disorders congenital
Synonym
Health condition
Lysosomal Storage Diseases, Neurologic Manifestations, Nervous System Diseases
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- Incidence and severity of treatment-emergent adverse events (TEAEs) at 24
weeks, 104 weeks, 261 weeks, and across study
- Change from baseline in safety laboratory values, vital sign measurements,
electrocardiogram (ECG) findings, urine total glycosaminoglycan (GAG) levels,
and physical and neurological assessments at 24 weeks, 104 weeks, 261 weeks,
and across study
- Incidence and severity of infusion-related reactions (IRRs) at 24 weeks, 104
weeks, 261 weeks, and across study
- Change from baseline in concomitant medication at 24 weeks, 104 weeks, 261
weeks, and across study
Secondary outcome
- Percent change from baseline in cerebrospinal fluid (CSF) of heparan sulfate
[Time Frame:24 weeks]
- Participants with improvement in individual disease progression in the
Vineland Adaptive Behavior Scale Adaptive Behavior Composite (ABC)
score [Time Frame: 49 weeks]
- Participants with improvement in individual disease progression in
theVineland Adaptive Behavior Scale subdomain scores at week 49 [Time
Frame: 49 weeks]
- To characterize the CNS effects of DNL310 on adaptive behaviors as assessed
by the Vineland Adaptive Behavior Scale [Time Frame: 49
weeks]
- PK parameter: Maximum observed concentration (Cmax) of DNL310 in serum [Time
Frame: 24 weeks]
- PK parameter: Trough concentration (Cmin) of DNL310 in serum [Time Frame: 24
weeks]
- PK parameter: Time to maximum observed concentration (tmax) of DNL310 in
serum [Time Frame: 24 weeks]
- PK parameter: Area under the concentration-time curve from time zero to the
time of last quantifiable concentration (AUClast) of DNL310 in
serum [Time Frame: 24 weeks]
- PK parameter: Area under the concentration-time curve from time zero to
infinity (AUC*) of DNL310 in serum [Time Frame: 24 weeks]
- PK parameter: Area under the concentration-time curve over a dosing interval
(AUC*) of DNL310 in serum [Time Frame: 24 weeks]
- PK parameter: Apparent terminal elimination half-life (t*) of DNL310 in serum
[Time Frame: 24 weeks]
- Characterization of immunogenicity of DNL310 in serum, as measured by the
incidence of anti-drug antibodies (ADAs) relative to baseline
[Time Frame: 24 weeks]
- Percent change from baseline in urine concentration of heparan sulfate (HS)
[Time Frame: 24 weeks]
- Participants with liver volume in the normal range [Time Frame: 24 weeks and
49 weeks]
- Percentage change form baseline in liver volume [Time Frame: 24 weeks and 49
weeks]
Background summary
"Mucopolysaccharidosis type II (MPS II or Hunter Syndorme), is a rare genetic
condition that occurs almost exclusively in boys. MPS II is caused by lack of
an enzyme resulting in accumulation of certain sugars in the body, causing
abnormalities in many organs, including the skeleton, heart, and respiratory
systems. In severe cases, this leads to early death.
There is no cure for MPS II. Approved enzyme replacement therapies (ERT) may
improve some symptoms of MPS II, especially if started early in the disease.
However, as standard-of-care ERT cannot cross the blood-brain barrier, it does
not treat the cognitive impairment in patients with central nervous system
(CNS) symptoms. There is still a high, unmet medical need for improved
treatment of MPS II."
This Phase 1/2 study in pediatric subjects with Hunter syndrome is the first
clinical investigation of DNL310. DNL310 is an intravenous (IV) ERT designed to
deliver IDS enzyme to both the CNS and peripheral tissues. This study will
evaluate the safety, PK, and pharmacodynamics (PD) of DNL310, as well as
explore its potential clinical efficacy.
The aim of the study is to identify generally safe and well-tolerated doses of
DNL310 that demonstrate pharmacological activity in the CNS and the periphery.
These results will be used to identify a dose to be studied in a separate
efficacy and safety study.
Study objective
This study has been transitioned to CTIS with ID 2023-508619-22-00 check the CTIS register for the current data.
The primary objective of the study is the following:
• To characterize the safety and tolerability of DNL310 in pediatric subjects
with MPS II (all cohorts)
The secondary objectives of the study are as follows:
• To characterize the CNS effects of DNL310 on heparan sulfate (HS)
concentrations in CSF (all cohorts)
• To characterize the CNS effects of DNL310 on adaptive behaviors as assessed
by the Vineland Adaptive Behavior Scale (all cohorts)
• To characterize the PK of once-weekly IV infusions of DNL310 in serum (all
cohorts)
• To characterize immunogenicity of DNL310 in serum (all cohorts)
• To characterize the peripheral effects of DNL310 on HS concentrations in
urine (all cohorts)
• To characterize the peripheral effects of DNL310 on liver volume as measured
by MRI (Cohorts C, D, and E only)
Study design
"This is a multicenter, multiregional, open-label study to assess the safety,
pharmacokinetics (PK), and pharmacodynamics (PD) of DNL310, an investigational
central nervous system (CNS)-penetrant enzyme replacement therapy (ERT),
designed to treat both the peripheral and CNS manifestations of
Mucopolysaccharidosis type II (MPS II; Hunter syndrome).
Participants, whose physicians feel they are deriving benefit, will have the
opportunity to be reconsented into a safety extension and then an open-label
extension for continued evaluation."
Intervention
DNL310 (ETV:IDS) administered intravenously weekly
Study burden and risks
DNL310 is being given to humans for the first time in this study. So far,
participants receiving DNL310 weekly have tolerated the study intervention
well. The most frequently observed treatment-related events were
infusion-related reactions (IRRs), which is consistent with other approved ERTs.
Potential risks (based on known class effects and nonclinical data) are:
• Anti-drug antibody (ADA) formation
• Anemia (decrease in red blood cells)
Please refer to ICF Appendix D for all study related risks and discomforts.
Denali Therapeutics Inc. Oyster Point Blvdr 161
South San Francisco CA 94080
US
Denali Therapeutics Inc. Oyster Point Blvdr 161
South San Francisco CA 94080
US
Listed location countries
Age
Inclusion criteria
- Confirmed diagnosis of MPS II
- Cohort A: Participants aged >= 5 to <=10 years with neuronopathic MPS II (nMPS
II)
- Cohort B: Participants aged >= 1 to <=18 years with non-neuronopathic MPS
II (nnMP II), neuronopathic MPS II, or unknown phenotype
- Cohort C: Participants aged <4 years with neuronopathic MPS II (this cohort
can include participants >=4 years of age if participant is a blood relative
with the same genetic mutation as participant >= 4 to <=18 years of age who will
be enrolled in the study)
- Cohort D: Participants aged <=18 years with nMPS II and nnMPS II and
preexisting hepatomegaly who have never taken standard - of - care ERT
- Cohort E: Neuronopathic MPS II Participants aged >= 6 years at screening,
nnMPS II participants < 6 or >=17 years at screening, and nMPS II participants
>= 1 to <=18 years at screening who have completed at least 48 weeks in Study
DNLI-E-0001
- For participants receiving intravenous iduronate 2-sulfatase (IDS) ERT,
tolerated a minimum of 4 months of therapy during the period immediately prior
to screening.
Exclusion criteria
- Unstable or poorly controlled medical condition(s) or significant medical or
psychological comorbidity or comorbidities that, in the opinion of the
investigator, would interfere with safe participation in the trial or
interpretation of study assessments
- Use of any CNS-targeted MPS II ERT within 3 months before study start for
participants aged >=5 years, and within 6 months before study start for
participants aged <5 years.
- Use of IDS gene therapy or stem cell therapy at any time
- Clinically significant thrombocytopenia, other clinically significant
coagulation abnormality, or significant active bleeding, or required treatment
with an anticoagulant or more than two antiplatelet agents
- Contraindication for lumbar punctures
- Have a clinically significant history of stroke, status epilepticus, head
trauma with loss of consciousness, or any CNS disease that is not MPS
II-related within 1 year of screening
- Have had a ventriculoperitoneal (VP) shunt placed, or any other brain
surgery, or have a clinically significant VP shunt malfunction within 30 days
of screening
- Have any clinically significant CNS trauma or disorder that, in the opinion
of the investigator, may interfere with assessment of study endpoints or make
participation in the study unsafe
- Have clinically significant anemia
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2023-508619-22-00 |
| EudraCT | EUCTR2019-004909-27-NL |
| ClinicalTrials.gov | NCT04251026 |
| CCMO | NL74319.000.20 |