A Study of Tividenofusp Alfa (DNL310) in Pediatric Participants With Hunter Syndrome

A Phase 1/2, Multicenter, Open-Label Study to Determine the Safety, Pharmacokinetics, and Pharmacodynamics of DNL310 in Pediatric Participants With Hunter Syndrome

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Mucopolysaccharidosis II
• Intervention / Treatment: Drug: tividenofusp alfa

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montréal, Quebec, Canada, H4A 3J1
      • McGill University Health Centre - Royal Victoria Hospital
• Netherlands
  • South Holland
    • Rotterdam, South Holland, Netherlands, 3015 GD
      • Erasmus Medical Center
• United Kingdom
  • Manchester, United Kingdom, M13 9WL
    • St Mary's Hospital, Manchester Academic Health Science Centre
• United States
  • California
    • Oakland, California, United States, 94609
      • UCSF Benioff Children's Hospital
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann & Robert H. Lurie Children's Hospital of Chicago
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • UNC Children's Research Institute
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • UPMC | Children's Hospital of Pittsburgh

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 18 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort A; Dose escalation followed by a consistent dose level in participants with neuronopathic MPS II	Drug: tividenofusp alfa; Intravenous repeating dose
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: tividenofusp alfa; Intravenous repeating dose
Experimental: Cohort C; A consistent dose level in participants with neuronopathic MPS II	Drug: tividenofusp alfa; Intravenous repeating dose
Experimental: Cohort D; A consistent dose level in participants with non-neuronopathic MPS II or neuronopathic MPS II	Drug: tividenofusp alfa; Intravenous repeating dose
Experimental: Cohort E; A consistent dose level in participants with non-neuronopathic MPS II or neuronopathic MPS II	Drug: tividenofusp alfa; Intravenous repeating dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Incidence and severity of treatment-emergent adverse events (TEAEs)	24 weeks, 104 weeks, and 357 weeks
Change from baseline in urine total glycosaminoglycan (GAG) concentrations	24 weeks, 104 weeks, and 357 weeks
Incidence and severity of infusion-related reactions (IRRs)	24 weeks, 104 weeks, and 357 weeks
Change from baseline in concomitant medications	24 weeks, 104 weeks, and 357 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Percentage change from baseline in cerebrospinal fluid (CSF) of heparan sulfate	24 weeks
Participants with improvement in individual disease progression in the Vineland Adaptive Behavior Scale Adaptive Behavior Composite (ABC) score	49 weeks
Participants with improvement in individual disease progression in the Vineland Adaptive Behavior Scale subdomain scores	49 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
Percent change from baseline in urine concentration of heparan sulfate (HS)	24 weeks
Participants with liver volume in the normal range	24 weeks and 49 weeks
Percentage change from baseline in liver volume	24 weeks and 49 weeks

Collaborators and Investigators

• Sponsor: Denali Therapeutics Inc.
• Investigators: Study Director: Sam Lu, MD, Denali Therapeutics

Publications and helpful links

Helpful Links

• Engage Hunter Website

Study record dates

Study Major Dates

• Study Start (Actual): July 16, 2020
• Primary Completion (Estimated): February 1, 2031
• Study Completion (Estimated): February 1, 2031

Study Registration Dates

• First Submitted: January 28, 2020
• First Submitted That Met QC Criteria: January 29, 2020
• First Posted (Actual): January 31, 2020

Study Record Updates

• Last Update Posted (Actual): August 7, 2025
• Last Update Submitted That Met QC Criteria: August 4, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: Hunter Syndrome; MPS II; nMPS II
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Connective Tissue Diseases; Neurobehavioral Manifestations; Heredodegenerative Disorders, Nervous System; Mental Retardation, X-Linked; Intellectual Disability; Genetic Diseases, X-Linked; Carbohydrate Metabolism, Inborn Errors; Lysosomal Storage Diseases; Mucinoses; Mucopolysaccharidoses; Mucopolysaccharidosis II
• Other Study ID Numbers: DNLI-E-0002; 2019-004909-27 (EudraCT Number); 2023-508619-22-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No