Clinical trial NCT04251026: A Study of Tividenofusp Alfa (DNL310) in Pediatric Participants With Hunter Syndrome
Official title: A Phase 1/2, Multicenter, Open-Label Study to Determine the Safety, Pharmacokinetics, and Pharmacodynamics of DNL310 in Pediatric Participants With Hunter Syndrome
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Mucopolysaccharidosis II
Keywords: MPS II
Hunter Syndrome
nMPS II
Lead sponsor: Denali Therapeutics Inc.
Sponsor class: INDUSTRY
First posted: 2020-01-31
Enrollment: 47
Sex: MALE
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: Incidence and severity of treatment-emergent adverse events (TEAEs)
timeFrame: 24 weeks, 104 weeks, and 261 weeks
measure: Change from baseline in urine total glycosaminoglycan (GAG) concentrations
timeFrame: 24 weeks, 104 weeks, and 261 weeks
measure: Incidence and severity of infusion-related reactions (IRRs)
timeFrame: 24 weeks, 104 weeks, and 261 weeks
measure: Change from baseline in concomitant medications
timeFrame: 24 weeks, 104 weeks, and 261 weeks
Secondary outcomes:
measure: Percentage change from baseline in cerebrospinal fluid (CSF) of heparan sulfate
timeFrame: 24 weeks
measure: Participants with improvement in individual disease progression in the Vineland Adaptive Behavior Scale Adaptive Behavior Composite (ABC) score
timeFrame: 49 weeks
measure: Participants with improvement in individual disease progression in the Vineland Adaptive Behavior Scale subdomain scores
timeFrame: 49 weeks
measure: PK parameter: Maximum observed concentration (Cmax) of DNL310 in serum
timeFrame: 24 weeks
measure: PK parameter: Trough concentration (Cmin) of DNL310 in serum
timeFrame: 24 weeks
measure: PK parameter: Time to maximum observed concentration (tmax) of DNL310 in serum
timeFrame: 24 weeks
measure: PK parameter: Area under the concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) of DNL310 in serum
timeFrame: 24 weeks
measure: PK parameter: Area under the concentration-time curve from time zero to infinity (AUC∞) of DNL310 in serum
timeFrame: 24 weeks
measure: PK parameter: Area under the concentration-time curve over a dosing interval (AUCτ) of DNL310 in serum
timeFrame: 24 weeks
measure: PK parameter: Apparent terminal elimination half-life (t½) of DNL310 in serum
timeFrame: 24 weeks
measure: Characterization of immunogenicity of DNL310 in serum, as measured by the incidence of anti-drug antibodies (ADAs) relative to baseline
timeFrame: 24 weeks
measure: Percent change from baseline in urine concentration of heparan sulfate (HS)
timeFrame: 24 weeks
measure: Participants with liver volume in the normal range
timeFrame: 24 weeks and 49 weeks
measure: Percentage change from baseline in liver volume
timeFrame: 24 weeks and 49 weeks
Other outcomes:
Locations:
city: Oakland
country: United States
facility: UCSF Benioff Children's Hospital
state: California
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Chapel Hill
country: United States
facility: UNC Children's Research Institute
state: North Carolina
city: Pittsburgh
country: United States
facility: UPMC | Children's Hospital of Pittsburgh
state: Pennsylvania
city: Montréal
country: Canada
facility: McGill University Health Centre - Royal Victoria Hospital
state: Quebec
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center
state: South Holland
city: Manchester
country: United Kingdom
facility: St Mary's Hospital, Manchester Academic Health Science Centre
Study officials:
affiliation: Denali Therapeutics
name: Katia Meirelles, MD
role: STUDY_DIRECTOR
References: