An Extension Study of the Long-Term Safety, Tolerability, and Efficacy of Tividenofusp Alfa (DNL310) in Participants With Mucopolysaccharidosis Type II (MPS II) From Study DNLI-E-0002 or Study DNLI-E-0007

An Open-Label Extension to Investigate the Long-Term Safety, Tolerability, and Efficacy of DNL310 in Patients With Mucopolysaccharidosis Type II (MPS II) From Study DNLI-E-0002 or Study DNLI-E-0007

This is a multiregional open-label extension (OLE) to assess the safety, tolerability, and efficacy of long-term treatment with tividenofusp alfa (DNL310), an investigational central nervous system (CNS)-penetrant intravenous (IV) enzyme replacement therapy (ERT) for Hunter syndrome (MPS II). Participants who complete at least through the Week 49 visit in Study DNLI-E-0002 and do not discontinue study intervention early and participants who complete Study DNLI-E-0007 will be enrolled in this OLE. All participants will receive DNL310 for up to 5 years from the time of entry in this OLE. Participants, site staff, and the Sponsor will remain blinded to the original treatment assignment for participants entering this OLE from Study DNLI-E-0007.

Study Overview

• Status: Enrolling by invitation
• Conditions: Mucopolysaccharidosis II
• Intervention / Treatment: Drug: tividenofusp alfa

• Study Type: Interventional
• Enrollment (Estimated): 99
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • Sanatorio Mater Dei
• Belgium
  • Jette, Belgium
    • UZ Brussel
  • Antwerpen
    • Edegem, Antwerpen, Belgium, 2650
      • Universitair Ziekenhuis Antwerpen
• Canada
  • Alberta
    • Edmonton, Alberta, Canada
      • University of Alberta - Faculty of Medicine & Dentistry
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children
  • Quebec
    • Montreal, Quebec, Canada, H4A3J1
      • McGill University Health Center
• Czechia
  • Prague, Czechia, 120 00
    • Vseobecna fakultni nemocnice v Praze
• France
  • Lille, France
    • Hopital Jeanne De Flandre - Metabolic Diseases Unit
• Germany
  • Hamburg, Germany
    • Universitätsklinikum Hamburg-Eppendorf
  • Höchheim, Germany
    • SpinCS GmbH
• Italy
  • Cremona, Italy
    • Asst Di Cremona
  • Udine, Italy
    • Azienda Sanitaria Universitaria Friuli Centrale - PO Universitario Santa Maria della Misericordia
• Netherlands
  • Rotterdam, Netherlands, 3015 GD
    • Erasmus Medical Center - Sophia Children's Hospital
• Spain
  • Barcelona, Spain
    • Hospit U. Vall d'Hebron - PPDS
• Sweden
  • Gothenburg, Sweden
    • Drottning Silvias Barn Och Ungdomssjukhus
• Turkey (Türkiye)
  • Adana, Turkey (Türkiye)
    • University Medical Faculty Balcali Hospital
  • Ankara, Turkey (Türkiye)
    • Gazi Universitesi Tip Fakultes
• United Kingdom
  • Birmingham, United Kingdom
    • Birmingham Women's and Children's NHS Foundation Trust
  • London, United Kingdom, NW3 2QG
    • Royal Free Hospital
  • London, United Kingdom, WC1N 3JH
    • Great Ormond Street Hospital
  • Manchester, United Kingdom
    • Royal Manchester Children's Hospital
• United States
  • California
    • Oakland, California, United States, 94609
      • UCSF Benioff Children's Hospital Oakland
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann and Robert H Lurie Children's Hospital of Chicago
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • UNC Children's Research Institute
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas Medical School at Houston
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• For participants from Study DNLI-E-0002 only: Completed at least through the Week 49 visit in Study DNLI-E-0002 and did not discontinue study intervention early
• For participants from Study DNLI-E-0007 only: Completed the treatment period of 96 weeks in Cohort A for nMPS II participants and 48 weeks in Cohort B for nnMPS II participants

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort A2; Participants with nMPS II, aged ≥5 to ≤10 years	Drug: tividenofusp alfa; Intravenous repeating dose
Experimental: Cohort B2; Participants with nMPS II or nnMPS II, aged ≥1 to ≤18 years	Drug: tividenofusp alfa; Intravenous repeating dose
Experimental: Cohort C2; Participants with nMPS II, aged <4 years	Drug: tividenofusp alfa; Intravenous repeating dose
Experimental: Cohort D2; Participants with nMPS II or nnMPS II, aged ≤18 years with preexisting hepatomegaly who have never taken standard-of-care ERT	Drug: tividenofusp alfa; Intravenous repeating dose
Experimental: Cohort E2; Participants with nMPS II, aged ≥6 years; participants with nnMPS II, aged <6 or ≥17 years; or participants with nMPS II, aged ≥1 to ≤18 years, with a history of prior HSCT or gene therapy and have completed at least 48 weeks in Study DNLI-E-0001	Drug: tividenofusp alfa; Intravenous repeating dose
Experimental: Cohort A7; Participants with nMPS II, aged ≥2 to <6 years	Drug: tividenofusp alfa; Intravenous repeating dose
Experimental: Cohort B7; Participants with nnMPS II, aged ≥6 to <17 years	Drug: tividenofusp alfa; Intravenous repeating dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence and intensity of treatment-emergent adverse events (TEAEs)		5 years
Clinically significant changes in urine total glycosaminoglycan (GAG) concentrations throughout the treatment period		5 years
Incidence and intensity of infusion-related reactions (IRRs)	The intensity of IRRs will be assessed following each infusion of DNL310 using the categories of Mild, Moderate and Severe. IRRs will be summarized overall as well as stratified by intensity.	5 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Percentage change from baseline in cerebrospinal fluid (CSF) heparan sulfate (HS) concentration	5 years
Change from baseline in the Vineland-3 Adaptive Behavior Scale	5 years
Change from baseline in the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) cognitive raw score	5 years
Change from baseline in distance walked (meters) in the Six-Minute Walk Test (6MWT)	5 years
Percent change from baseline in the sum of urine HS and dermatan sulfate (DS) concentrations	5 years
Liver volume within the normal range (normal vs abnormal) as measured by MRI	5 years
Spleen volume within the normal range (normal vs abnormal) as measured by MRI	5 years
Improvement in the Parent/Caregiver Global Impression of Change (CaGI-C) Overall MPS II	5 years

Collaborators and Investigators

• Sponsor: Denali Therapeutics Inc.
• Investigators: Study Director: Medical Monitor, Denali Therapeutics

Publications and helpful links

Helpful Links

• Denali Therapeutics

Study record dates

Study Major Dates

• Study Start (Actual): September 20, 2023
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): June 1, 2027

Study Registration Dates

• First Submitted: September 18, 2023
• First Submitted That Met QC Criteria: October 3, 2023
• First Posted (Actual): October 10, 2023

Study Record Updates

• Last Update Posted (Actual): June 11, 2026
• Last Update Submitted That Met QC Criteria: June 9, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Hunter Syndrome; MPS II; nMPS II; nnMPS II
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Pathologic Processes; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Connective Tissue Diseases; Neurobehavioral Manifestations; Death; Heredodegenerative Disorders, Nervous System; Intellectual Disability; Genetic Diseases, X-Linked; Carbohydrate Metabolism, Inborn Errors; Lysosomal Storage Diseases; Mucinoses; Death, Sudden; Mucopolysaccharidoses; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Skin and Connective Tissue Diseases; X-Linked Intellectual Disability; Infant Death; Mucopolysaccharidosis II; Sudden Infant Death
• Other Study ID Numbers: DNLI-E-0008; 2023-503837-23 (Other Identifier: EU Trial Number)

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