A Study of DNL310 in Pediatric Participants With Hunter Syndrome

study id #: NCT04251026

condition: Mucopolysaccharidosis II

status: Recruiting

purpose:

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).

The study has three cohorts:Cohort A will enroll participants with neuronopathic MPS II aged 5 to 10 years; Cohort B will enroll participants with MPS II, either neuronopathic or non-neuronopathic, aged 2 to 18 years; and Cohort C will enroll participants with neuronopathic MPS II aged ≥2 and <4 (Cohort C can include nMPS II participants ≥4 if the participant is a sibling of a participant aged ≥2 and <4).

Participants, whose physicians feel they are deriving benefit, will have the opportunity to be reconsented into a safety extension for continued evaluation.

intervention: DNL310

results: https://clinicaltrials.gov/ct2/show/results/NCT04251026

last updated: February 26, 2022

start date: July 16, 2020

estimated completion: March 2024

last updated: January 11, 2022

phase of development: Phase 1/Phase 2

size / enrollment: 30

primary outcomes:

• Incidence and severity of treatment-emergent adverse events (TEAEs)
  
• 24 weeks
  Incidence and severity of infusion-related reactions (IRRs)
  
• 24 weeks
  Change from baseline in urine total glycosaminoglycan (GAG) concentrations
  
• 24 weeks
  Change from baseline in concomitant medications
  
• 24 weeks
  

secondary outcomes:

• Change from baseline in cerebrospinal fluid (CSF) of heparan sulfate
  24 weeks
• PK parameter: Maximum observed concentration (Cmax) of DNL310 in serum
  24 weeks
• 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
• PK parameter: Apparent terminal elimination half-life (t½) of DNL310 in serum
  24 weeks
• Characterization of immunogenicity of DNL310 in serum, as measured by the incidence of anti-drug antibodies (ADAs) relative to baseline
  24 weeks
• Change from baseline in urine concentration of heparan sulfate (HS)
  24 weeks

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 2 to 18 years with non-neuronopathic MPS II, neuronopathic MPS II, or unknown phenotype
Cohort C: Participants aged ≥2 to <4 years with neuronopathic MPS II (this cohort can include participants ≥4 years of age if participant is a sibling of a participant ≥2 to <4 years of age)
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: 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

sponsor: Denali Therapeutics Inc.

contacts: Clinical Trials At Denali Therapeutics, Email:, clinical-trials@dnli.com

investigators: Anna Bakardjiev, MD,Denali Therapeutics

trial center locations: United States,Netherlands

• United States, California
  UCSF Benioff Children’s Hospital
  Esther Melton, 510-428-3885, esther.melton@ucsf.edu
  
  
• United States, Illinois
  Ann & Robert H. Lurie Children’s Hospital of Chicago
  Marian Krasowski, 312-227-8953, mkrasowski@luriechildrens.org
  
  
• United States, North Carolina
  UNC Children’s Research Institue
  Chen Zhu, 919-966-1447, czhu@email.unc.edu
  
  
• United States, Pennsylvania
  UPMC | Children’s Hospital of Pittsburgh
  Dawn Kolar, 412-692-8343, kolardr@upmc.edu
  
  
• Netherlands, South Holland
  Erasmus Medical Center
  Jacqueline Hardon