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A Study of DNL310 in Pediatric Participants With Hunter Syndrome

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ClinicalTrials.gov Identifier: NCT04251026
Recruitment Status : Recruiting
First Posted : January 31, 2020
Last Update Posted : May 14, 2021
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).

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.


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 : 30 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 : March 2024
Estimated Study Completion Date : March 2024


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




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

Secondary Outcome Measures :
  1. Change from baseline in cerebrospinal fluid (CSF) of heparan sulfate [ Time Frame: 24 weeks ]
  2. PK parameter: Maximum observed concentration (Cmax) of DNL310 in serum [ Time Frame: 24 weeks ]
  3. PK parameter: Trough concentration (Cmin) of DNL310 in serum [ Time Frame: 24 weeks ]
  4. PK parameter: Time to maximum observed concentration (tmax) of DNL310 in serum [ Time Frame: 24 weeks ]
  5. 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 ]
  6. PK parameter: Area under the concentration-time curve from time zero to infinity (AUC∞) of DNL310 in serum [ Time Frame: 24 weeks ]
  7. PK parameter: Area under the concentration-time curve over a dosing interval (AUCτ) of DNL310 in serum [ Time Frame: 24 weeks ]
  8. PK parameter: Apparent terminal elimination half-life (t½) of DNL310 in serum [ Time Frame: 24 weeks ]
  9. Characterization of immunogenicity of DNL310 in serum, as measured by the incidence of anti-drug antibodies (ADAs) relative to baseline [ Time Frame: 24 weeks ]
  10. Change from baseline in urine concentration of heparan sulfate (HS) [ Time Frame: 24 weeks ]


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Ages Eligible for Study:   2 Years 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 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:

  • 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

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: Huong Phan    510-428-3885 ext 5917    huong.phan@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: Marian Krasowski    312-227-8953    mkrasowski@luriechildrens.org   
Principal Investigator: Barbara Burton, MD         
United States, North Carolina
UNC Children's Research Institue 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: Alyssa Aburachis    412-692-6340    alyssa.aburachis@chp.edu   
Contact       maria.escolar@chp.edu   
Principal Investigator: Maria Escolar, 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: May 14, 2021
Last Verified: May 2021
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