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A Study of DNL310 in Pediatric Participants With Hunter Syndrome

Primary Purpose

Mucopolysaccharidosis II

Status
Recruiting
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
DNL310
Sponsored by
Denali Therapeutics Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Mucopolysaccharidosis II focused on measuring MPS II, Hunter Syndrome, nMPS II

Eligibility Criteria

undefined - 18 Years (Child, Adult)MaleDoes not accept healthy volunteers

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

Sites / Locations

  • UCSF Benioff Children's HospitalRecruiting
  • Ann & Robert H. Lurie Children's Hospital of ChicagoRecruiting
  • UNC Children's Research InstituteRecruiting
  • UPMC | Children's Hospital of PittsburghRecruiting
  • McGill University Health Centre - Royal Victoria HospitalRecruiting
  • Erasmus Medical CenterRecruiting
  • St Mary's Hospital, Manchester Academic Health Science CentreRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Cohort A

Cohort B

Cohort C

Cohort D

Cohort E

Arm Description

Dose escalation followed by a consistent dose level in participants with neuronopathic MPS II

A consistent dose level in participants with non-neuronopathic MPS II, neuronopathic MPS II, or unknown phenotype followed by dose escalation in some participants.

A consistent dose level in participants with neuronopathic MPS II

A consistent dose level in participants with non-neuronopathic MPS II or neuronopathic MPS II

A consistent dose level in participants with non-neuronopathic MPS II or neuronopathic MPS II

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Percentage change from baseline in cerebrospinal fluid (CSF) of heparan sulfate
Participants with improvement in individual disease progression in the Vineland Adaptive Behavior Scale Adaptive Behavior Composite (ABC) score
Participants with improvement in individual disease progression in the Vineland Adaptive Behavior Scale subdomain scores
PK parameter: Maximum observed concentration (Cmax) of DNL310 in serum
PK parameter: Trough concentration (Cmin) of DNL310 in serum
PK parameter: Time to maximum observed concentration (tmax) of DNL310 in serum
PK parameter: Area under the concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) of DNL310 in serum
PK parameter: Area under the concentration-time curve from time zero to infinity (AUC∞) of DNL310 in serum
PK parameter: Area under the concentration-time curve over a dosing interval (AUCτ) of DNL310 in serum
PK parameter: Apparent terminal elimination half-life (t½) of DNL310 in serum
Characterization of immunogenicity of DNL310 in serum, as measured by the incidence of anti-drug antibodies (ADAs) relative to baseline
Percent change from baseline in urine concentration of heparan sulfate (HS)
Participants with liver volume in the normal range
Percentage change from baseline in liver volume

Full Information

First Posted
January 28, 2020
Last Updated
August 31, 2023
Sponsor
Denali Therapeutics Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT04251026
Brief Title
A Study of 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

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
July 16, 2020 (Actual)
Primary Completion Date
July 2027 (Anticipated)
Study Completion Date
July 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Denali Therapeutics Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Mucopolysaccharidosis II
Keywords
MPS II, Hunter Syndrome, nMPS II

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
45 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Cohort A
Arm Type
Experimental
Arm Description
Dose escalation followed by a consistent dose level in participants with neuronopathic MPS II
Arm Title
Cohort B
Arm Type
Experimental
Arm Description
A consistent dose level in participants with non-neuronopathic MPS II, neuronopathic MPS II, or unknown phenotype followed by dose escalation in some participants.
Arm Title
Cohort C
Arm Type
Experimental
Arm Description
A consistent dose level in participants with neuronopathic MPS II
Arm Title
Cohort D
Arm Type
Experimental
Arm Description
A consistent dose level in participants with non-neuronopathic MPS II or neuronopathic MPS II
Arm Title
Cohort E
Arm Type
Experimental
Arm Description
A consistent dose level in participants with non-neuronopathic MPS II or neuronopathic MPS II
Intervention Type
Drug
Intervention Name(s)
DNL310
Intervention Description
Intravenous repeating dose
Primary Outcome Measure Information:
Title
Incidence and severity of treatment-emergent adverse events (TEAEs)
Time Frame
24 weeks, 104 weeks, and 261 weeks
Title
Change from baseline in urine total glycosaminoglycan (GAG) concentrations
Time Frame
24 weeks, 104 weeks, and 261 weeks
Title
Incidence and severity of infusion-related reactions (IRRs)
Time Frame
24 weeks, 104 weeks, and 261 weeks
Title
Change from baseline in concomitant medications
Time Frame
24 weeks, 104 weeks, and 261 weeks
Secondary Outcome Measure Information:
Title
Percentage change from baseline in cerebrospinal fluid (CSF) of heparan sulfate
Time Frame
24 weeks
Title
Participants with improvement in individual disease progression in the Vineland Adaptive Behavior Scale Adaptive Behavior Composite (ABC) score
Time Frame
49 weeks
Title
Participants with improvement in individual disease progression in the Vineland Adaptive Behavior Scale subdomain scores
Time Frame
49 weeks
Title
PK parameter: Maximum observed concentration (Cmax) of DNL310 in serum
Time Frame
24 weeks
Title
PK parameter: Trough concentration (Cmin) of DNL310 in serum
Time Frame
24 weeks
Title
PK parameter: Time to maximum observed concentration (tmax) of DNL310 in serum
Time Frame
24 weeks
Title
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
Title
PK parameter: Area under the concentration-time curve from time zero to infinity (AUC∞) of DNL310 in serum
Time Frame
24 weeks
Title
PK parameter: Area under the concentration-time curve over a dosing interval (AUCτ) of DNL310 in serum
Time Frame
24 weeks
Title
PK parameter: Apparent terminal elimination half-life (t½) of DNL310 in serum
Time Frame
24 weeks
Title
Characterization of immunogenicity of DNL310 in serum, as measured by the incidence of anti-drug antibodies (ADAs) relative to baseline
Time Frame
24 weeks
Title
Percent change from baseline in urine concentration of heparan sulfate (HS)
Time Frame
24 weeks
Title
Participants with liver volume in the normal range
Time Frame
24 weeks and 49 weeks
Title
Percentage change from baseline in liver volume
Time Frame
24 weeks and 49 weeks

10. Eligibility

Sex
Male
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Clinical Trials at Denali Therapeutics
Phone
Email:
Email
clinical-trials@dnli.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Katia Meirelles, MD
Organizational Affiliation
Denali Therapeutics
Official's Role
Study Director
Facility Information:
Facility Name
UCSF Benioff Children's Hospital
City
Oakland
State/Province
California
ZIP/Postal Code
94609
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Annie Sako
Phone
510-428-3885
Ext
4785
Email
annie.sako@ucsf.edu
Email
paul.harmatz@ucsf.edu
First Name & Middle Initial & Last Name & Degree
Paul Harmatz, MD
Facility Name
Ann & Robert H. Lurie Children's Hospital of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Rachel Katz
Phone
312-227-6764
Email
rkatz@luriechildrens.org
First Name & Middle Initial & Last Name & Degree
Barbara Burton, MD
Facility Name
UNC Children's Research Institute
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27514
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lindsay Torrice
Phone
919-966-1135
Email
lindsay_torrice@med.unc.edu
First Name & Middle Initial & Last Name & Degree
Joseph Muenzer, MD
Facility Name
UPMC | Children's Hospital of Pittsburgh
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15224
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Dawn Kolar
Phone
412-692-8343
Email
kolardr@upmc.edu
Email
rajands@upmc.edu
First Name & Middle Initial & Last Name & Degree
Deepa Soundara Rajan, MD
Facility Name
McGill University Health Centre - Royal Victoria Hospital
City
Montréal
State/Province
Quebec
ZIP/Postal Code
H4A 3J1
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Christine Gannon
Email
christine.gannon@muhc.mcgill.ca
First Name & Middle Initial & Last Name & Degree
Sandra Pepin
Email
sandra.pepin@muhc.mcgill.ca
First Name & Middle Initial & Last Name & Degree
John Mitchell, MD
Facility Name
Erasmus Medical Center
City
Rotterdam
State/Province
South Holland
ZIP/Postal Code
3015 GD
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jacqueline Hardon
Phone
Email:
Email
j.hardon@erasmusmc.nl
First Name & Middle Initial & Last Name & Degree
Dorine Heemskerk
Phone
Email:
Email
t.heemskerk@erasmusmc.nl
First Name & Middle Initial & Last Name & Degree
Hannerieke van den Hout, MD
Facility Name
St Mary's Hospital, Manchester Academic Health Science Centre
City
Manchester
ZIP/Postal Code
M13 9WL
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Study Coordinator
Email
genetics.research@mft.nhs.uk
First Name & Middle Initial & Last Name & Degree
Simon Jones, MD

12. IPD Sharing Statement

Plan to Share IPD
No
Links:
URL
https://www.engagehunter.com/clinical-trials
Description
Engage Hunter Website

Learn more about this trial

A Study of DNL310 in Pediatric Participants With Hunter Syndrome

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