Mucopolysaccharidosis II
Conditions
Keywords
MPS II, Hunter Syndrome, nMPS II
Brief summary
This is a multicenter, multiregional, open-label study to assess the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of tividenofusp alfa (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.
Interventions
Intravenous repeating dose
Sponsors
Denali Therapeutics Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
No minimum to 18 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Confirmed diagnosis of MPS II * Cohort A: Participants aged ≥5 to ≤10 years with neuronopathic MPS II * Cohort B: Participants aged ≥1 to ≤18 years with non-neuronopathic MPS II, neuronopathic MPS II, or unknown phenotype * Cohort C: Participants aged \<4 years with neuronopathic MPS II (this cohort can include participants ≥4 to ≤18 years of age if participant is a blood relative of a participant \<4 years of age) * Cohort D: Participants aged ≤18 years with non-neuronopathic MPS II or neuronopathic MPS II with preexisting hepatomegaly who have never taken standard-of-care ERT * Cohort E: neuronopathic MPS II participants aged ≥6 years at screening, non-neuronopathic MPS II participants \<6 or ≥17 years at screening, and neuronopathic MPS II participants ≥1 to ≤18 years at screening with a history of prior haematopoietic stem cell transplantation or gene therapy 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. Key
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 (except for participants in Cohort E) * 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Incidence and severity of treatment-emergent adverse events (TEAEs) | 24 weeks, 104 weeks, and 357 weeks |
| Change from baseline in urine total glycosaminoglycan (GAG) concentrations | 24 weeks, 104 weeks, and 357 weeks |
| Incidence and severity of infusion-related reactions (IRRs) | 24 weeks, 104 weeks, and 357 weeks |
| Change from baseline in concomitant medications | 24 weeks, 104 weeks, and 357 weeks |
Secondary
| Measure | Time frame |
|---|---|
| PK parameter: Trough concentration (Cmin) of DNL310 in serum | 24 weeks |
| PK parameter: Time to maximum observed concentration (tmax) of DNL310 in serum | 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 | 24 weeks |
| PK parameter: Area under the concentration-time curve from time zero to infinity (AUC∞) of DNL310 in serum | 24 weeks |
| PK parameter: Area under the concentration-time curve over a dosing interval (AUCτ) of DNL310 in serum | 24 weeks |
| Percentage change from baseline in cerebrospinal fluid (CSF) of heparan sulfate | 24 weeks |
| Characterization of immunogenicity of DNL310 in serum, as measured by the incidence of anti-drug antibodies (ADAs) relative to baseline | 24 weeks |
| Percent change from baseline in urine concentration of heparan sulfate (HS) | 24 weeks |
| Participants with liver volume in the normal range | 24 weeks and 49 weeks |
| Percentage change from baseline in liver volume | 24 weeks and 49 weeks |
| PK parameter: Apparent terminal elimination half-life (t½) of DNL310 in serum | 24 weeks |
| Participants with improvement in individual disease progression in the Vineland Adaptive Behavior Scale Adaptive Behavior Composite (ABC) score | 49 weeks |
| Participants with improvement in individual disease progression in the Vineland Adaptive Behavior Scale subdomain scores | 49 weeks |
| PK parameter: Maximum observed concentration (Cmax) of DNL310 in serum | 24 weeks |
Countries
Canada, Netherlands, United Kingdom, United States
Outcome results
None listed