A Study to Determine the Efficacy and Safety of Tividenofusp Alfa (DNL310) vs Idursulfase in Pediatric and Young Adult Participants With Neuronopathic (nMPS II) or Non-Neuronopathic Mucopolysaccharidosis Type II (nnMPS II)

• tividenofusp alfa (Drug): Intravenous repeating dose
• idursulfase (Drug): Intravenous repeating dose

Primary outcomes

• Ratio to baseline in cerebrospinal fluid (CSF) heparan sulfate (HS) concentration (Cohort A) [24 weeks]
• Change from baseline in the Vineland Adaptive Behavior Scale, Third Edition (Vineland-3)(Cohort A) [96 weeks]

Secondary outcomes

• Change from baseline in the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III)(Cohort A only) [96 weeks]
• Change from baseline in the Vineland-3 Adaptive Behavior Composite (ABC) score (Cohort A only) [96 weeks]
• Ratio to baseline in serum neurofilament light chain (NfL) (Cohort A only) [96 weeks]
• Change from baseline in distance walked in the Six-Minute Walk Test (6MWT; Cohort B only) [48 weeks]
• Ratio to baseline in the sum of urine HS and dermatan sulfate (DS) concentrations (normalized to creatinine) (Cohorts A and B) [up to 48 weeks]
• Liver volume within the normal range (normal vs abnormal) as measured by magnetic resonance imaging (MRI) (Cohorts A and B) [48 weeks]
• Spleen volume within the normal range (normal vs abnormal) as measured by MRI (Cohorts A and B) [48 weeks]
• Improvement in Parent/Caregiver Global Impression of Change (CaGI-C) Overall MPS II (Cohorts A and B) [48 weeks]

Sex: All, ages: 2 Years to 25 Years

Key Inclusion Criteria:

* Participants aged ≥2 to <6 years (Cohort A) or ≥6 to <26 years (Cohort B)
* Confirmed diagnosis of MPS II (for Cohort A, nMPS II; for Cohort B, nnMPS II)
* Have no history of treatment with enzyme replacement therapy (ERT) OR not have received continuous ERT for 4 months prior to screening OR be on maintenance ERT and have tolerated idursulfase for a minimum of 4 months prior to screening

Key Exclusion Criteria:

* Have a documented mutation of other genes or genetic diagnosis accounting for developmental delay
* Previously received an iduronate 2-sulfatase (IDS) gene therapy or stem cell therapy
* Received any CNS-targeted MPS ERT within 6 months prior to screening
* Have a contraindication for lumbar punctures and/or magnetic resonance imaging (MRI)
* Participated in any other investigational drug study or used an investigational drug within 60 days prior to screening or intend to receive another investigational drug during the study

• Jose Alcantara Rodriguez, PharmD, Study director, Denali Therapeutics Inc.