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A Study of DNL310 in Pediatric Participants With Hunter Syndrome

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04251026
Recruitment Status : Recruiting
First Posted : January 31, 2020
Last Update Posted : March 29, 2022
Sponsor:
Information provided by (Responsible Party):
Denali Therapeutics Inc.

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Mucopolysaccharidosis II Drug: DNL310 Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 45 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : July 16, 2020
Estimated Primary Completion Date : July 2027
Estimated Study Completion Date : July 2027


Arm Intervention/treatment
Experimental: Cohort A
Dose escalation followed by a consistent dose level in participants with neuronopathic MPS II
Drug: DNL310
Intravenous weekly administration

Experimental: Cohort B
A consistent dose level in participants with non-neuronopathic MPS II, neuronopathic MPS II, or unknown phenotype followed by dose escalation in some participants.
Drug: DNL310
Intravenous weekly administration

Experimental: Cohort C
A consistent dose level in participants with neuronopathic MPS II
Drug: DNL310
Intravenous weekly administration

Experimental: Cohort D
A consistent dose level in participants with non-neuronopathic MPS II or neuronopathic MPS II
Drug: DNL310
Intravenous weekly administration

Experimental: Cohort E
A consistent dose level in participants with non-neuronopathic MPS II or neuronopathic MPS II
Drug: DNL310
Intravenous weekly administration




Primary Outcome Measures :
  1. Incidence and severity of treatment-emergent adverse events (TEAEs) [ Time Frame: 24 weeks ]
  2. Change from baseline in urine total glycosaminoglycan (GAG) concentrations [ Time Frame: 24 weeks ]
  3. Incidence and severity of infusion-related reactions (IRRs) [ Time Frame: 24 weeks ]
  4. Change from baseline in concomitant medications [ Time Frame: 24 weeks ]

Secondary Outcome Measures :
  1. Percentage change from baseline in cerebrospinal fluid (CSF) of heparan sulfate [ Time Frame: 24 weeks ]
  2. Participants with improvement in individual disease progression in the Vineland Adaptive Behavior Scale Adaptive Behavior Composite (ABC) score [ Time Frame: 49 weeks ]
  3. Participants with improvement in individual disease progression in the Vineland Adaptive Behavior Scale subdomain scores [ Time Frame: 49 weeks ]
  4. PK parameter: Maximum observed concentration (Cmax) of DNL310 in serum [ Time Frame: 24 weeks ]
  5. PK parameter: Trough concentration (Cmin) of DNL310 in serum [ Time Frame: 24 weeks ]
  6. PK parameter: Time to maximum observed concentration (tmax) of DNL310 in serum [ Time Frame: 24 weeks ]
  7. 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 ]
  8. PK parameter: Area under the concentration-time curve from time zero to infinity (AUC∞) of DNL310 in serum [ Time Frame: 24 weeks ]
  9. PK parameter: Area under the concentration-time curve over a dosing interval (AUCτ) of DNL310 in serum [ Time Frame: 24 weeks ]
  10. PK parameter: Apparent terminal elimination half-life (t½) of DNL310 in serum [ Time Frame: 24 weeks ]
  11. Characterization of immunogenicity of DNL310 in serum, as measured by the incidence of anti-drug antibodies (ADAs) relative to baseline [ Time Frame: 24 weeks ]
  12. Percent change from baseline in urine concentration of heparan sulfate (HS) [ Time Frame: 24 weeks ]
  13. Participants with liver volume in the normal range [ Time Frame: 24 weeks ]
  14. Percentage change from baseline in liver volume [ Time Frame: 24 weeks ]


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Ages Eligible for Study:   up to 18 Years   (Child, Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
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 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: Participants aged ≥1 to ≤18 years 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04251026


Contacts
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Contact: Clinical Trials at Denali Therapeutics Email: clinical-trials@dnli.com

Locations
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United States, California
UCSF Benioff Children's Hospital Recruiting
Oakland, California, United States, 94609
Contact: Danielle Roth    510-428-3885 ext 4785    Danielle.Roth@ucsf.edu   
Contact       paul.harmatz@ucsf.edu   
Principal Investigator: Paul Harmatz, MD         
United States, Illinois
Ann & Robert H. Lurie Children's Hospital of Chicago Recruiting
Chicago, Illinois, United States, 60611
Contact: Madelaine Pine    312-227-8952    mpine@luriechildrens.org   
Principal Investigator: Barbara Burton, MD         
United States, North Carolina
UNC Children's Research Institute Recruiting
Chapel Hill, North Carolina, United States, 27514
Contact: Chen Zhu    919-966-1447    czhu@email.unc.edu   
Contact       muenzer@med.unc.edu   
Principal Investigator: Joseph Muenzer, MD         
United States, Pennsylvania
UPMC | Children's Hospital of Pittsburgh Recruiting
Pittsburgh, Pennsylvania, United States, 15224
Contact: Dawn Kolar    412-692-8343    kolardr@upmc.edu   
Contact       rajands@upmc.edu   
Principal Investigator: Deepa Soundara Rajan, MD         
Netherlands
Erasmus Medical Center Recruiting
Rotterdam, South Holland, Netherlands, 3015 GD
Contact: Jacqueline Hardon    Email:    j.hardon@erasmusmc.nl   
Contact: Dorine Heemskerk    Email:    t.heemskerk@erasmusmc.nl   
Principal Investigator: Hannerieke van den Hout, MD         
Sponsors and Collaborators
Denali Therapeutics Inc.
Investigators
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Study Director: Anna Bakardjiev, MD Denali Therapeutics
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Responsible Party: Denali Therapeutics Inc.
ClinicalTrials.gov Identifier: NCT04251026    
Other Study ID Numbers: DNLI-E-0002
2019-004909-27 ( EudraCT Number )
First Posted: January 31, 2020    Key Record Dates
Last Update Posted: March 29, 2022
Last Verified: March 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Denali Therapeutics Inc.:
MPS II
Hunter Syndrome
nMPS II
Additional relevant MeSH terms:
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Mucopolysaccharidosis II
Mucopolysaccharidoses
Carbohydrate Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lysosomal Storage Diseases
Mucinoses
Connective Tissue Diseases
Metabolic Diseases
Mental Retardation, X-Linked
Intellectual Disability
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Genetic Diseases, X-Linked
Heredodegenerative Disorders, Nervous System