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

Sponsor

Denali Therapeutics Inc. (Industry)

Overall Status

Enrolling by invitation

CT.gov ID

NCT06075537

Collaborator

(none)

Enrollment

Location

Arms

44.4

Anticipated Duration (Months)

2.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a multiregional open-label extension (OLE) to assess the safety, tolerability, and efficacy of long-term treatment with 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.

Condition or Disease	Intervention/Treatment	Phase
Mucopolysaccharidosis II	Drug: DNL310	Phase 2/Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

99 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Sep 20, 2023

Anticipated Primary Completion Date :

Jun 1, 2027

Anticipated Study Completion Date :

Jun 1, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort A2 Participants with nMPS II, aged ≥5 to ≤10 years	Drug: DNL310 Intravenous repeating dose
Experimental: Cohort B2 Participants with nMPS II or nnMPS II, aged ≥1 to ≤18 years	Drug: DNL310 Intravenous repeating dose
Experimental: Cohort C2 Participants with nMPS II, aged <4 years	Drug: DNL310 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: DNL310 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: DNL310 Intravenous repeating dose
Experimental: Cohort A7 Participants with nMPS II, aged ≥2 to <6 years	Drug: DNL310 Intravenous repeating dose
Experimental: Cohort B7 Participants with nnMPS II, aged ≥6 to <17 years	Drug: DNL310 Intravenous repeating dose

Outcome Measures

Primary Outcome Measures

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) [5 years]
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.

Secondary Outcome Measures

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 18 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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