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

NCT04251026 | Active Not Recruiting Phase 1 DMC FDA Drug

• 3 other identifiers: DNLI-E-00022023-508619-22-002019-004909-27
• Study Type: interventional
• Target: 47
• Locations: 4 countries
• Sites: 7

Brief Summary

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.

Conditions

Mucopolysaccharidosis II

Keywords

MPS II; Hunter Syndrome; nMPS II

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (14)

• 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

Study Arms (5)

Cohort A

EXPERIMENTAL

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

Drug: tividenofusp alfa

Cohort B

EXPERIMENTAL

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

Cohort C

EXPERIMENTAL

A consistent dose level in participants with neuronopathic MPS II

Drug: tividenofusp alfa

Cohort D

EXPERIMENTAL

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

Drug: tividenofusp alfa

Cohort E

EXPERIMENTAL

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

Drug: tividenofusp alfa

Interventions

tividenofusp alfa DRUG

Intravenous repeating dose

Cohort A; Cohort B; Cohort C; Cohort D; Cohort E

Eligibility Criteria

• Age: Up to 18 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Denali Therapeutics Inc.: lead

Study Sites (7)

UCSF Benioff Children's Hospital

Oakland, California, 94609, United States

Location

Ann & Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, 60611, United States

Location

UNC Children's Research Institute

Chapel Hill, North Carolina, 27514, United States

Location

UPMC | Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, 15224, United States

Location

McGill University Health Centre - Royal Victoria Hospital

Montreal, Quebec, H4A 3J1, Canada

Location

Erasmus Medical Center

Rotterdam, South Holland, 3015 GD, Netherlands

Location

St Mary's Hospital, Manchester Academic Health Science Centre

Manchester, M13 9WL, United Kingdom

Location

Related Publications (1)

• Muenzer J, Burton BK, Harmatz P, Rajan DS, Jones SA, van den Hout JMP, Mitchell JJ, Bhalla A, Engmann NJ, Zubizarreta I, Dong W, Model F, Watts RJ, Troyer MD, Chin PS, Ho C. An Intravenous Brain-Penetrant Enzyme Therapy for Mucopolysaccharidosis II. N Engl J Med. 2026 Jan 1;394(1):39-50. doi: 10.1056/NEJMoa2508681.

  PMID: 41467650 DERIVED

MeSH Terms

Conditions

Mucopolysaccharidosis II; Sudden Infant Death

Condition Hierarchy (Ancestors)

X-Linked Intellectual Disability; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Heredodegenerative Disorders, Nervous System; Mucopolysaccharidoses; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Mucinoses; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Death, Sudden; Death; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Infant Death

Study Officials

• Sam Lu, MD

  Denali Therapeutics

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 28, 2020
• First Posted: January 31, 2020
• Study Start: July 16, 2020
• Primary Completion (Estimated): February 1, 2031
• Study Completion (Estimated): February 1, 2031
• Last Updated: August 7, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (4); NL (1); GB (1); CA (1)