Iduronate-2-sulfatase fused to a Fc polypeptide that binds to the human transferrin receptor for Mucopolysaccharidosis type II (Hunter syndrome)

Inclusion criteria

• {"criterion_text":"- Confirmed diagnosis of MPS II"}
• {"criterion_text":"- Cohort A: Participants aged ≥5 to ≤10 years with neuronopathic MPS II"}
• {"criterion_text":"- Cohort B: Participants aged ≥ 1 to ≤ 18 years with non-neuronopathic, neuronopathic MPSII or unknown phenotype"}
• {"criterion_text":"- Cohort C:Participants aged < 4 years with neuronopathic MPS II (this cohort can include participants ≥4 to ≤18 years of age if the participant is a blood relative with the same genetic mutation as a participant aged < 4 years who will be enrolled in the study)"}
• {"criterion_text":"- Cohort D: Participants aged ≤ 18 years, with nMPS II and nnMPS II and preexisting hepatomegaly, who have never taken standard-of-care ERT"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- For participants receiving intravenous iduronate 2-sulfatase (IDS) ERT, tolerated a minimum of 4 months of therapy during the period immediately prior to screening."}

Exclusion criteria

• {"criterion_text":"- 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"}
• {"criterion_text":"- 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."}
• {"criterion_text":"- Use of IDS gene therapy or stem cell therapy at any time (except for participants in Cohort E)"}
• {"criterion_text":"- Clinically significant thrombocytopenia, other clinically significant coagulation abnormality, or significant active bleeding, or required treatment with an anticoagulant or more than two antiplatelet agents"}
• {"criterion_text":"- Contraindication for lumbar punctures"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- Have clinically significant anemia"}

Primary endpoints

• {"endpoint_text":"- Incidence and severity of treatment-emergent adverse events (TEAEs) throughout the 24-week study period, the safety extension (Week 104), the open-label extension (Week 261), and across the study","definition_or_measurement_approach":"Safety assessed by recording incidence and severity of TEAEs throughout specified timeframes (24-week period, Week 104 safety extension, Week 261 open-label extension, and across the study)."}
• {"endpoint_text":"- Incidence and severity of infusion-related reactions (IRRs) throughout the 24-week study period, the safety extension (Week 104), the open-label extension (Week 261), and across the study","definition_or_measurement_approach":"IRRs recorded and graded across specified timeframes (24 weeks, Week 104, Week 261, and across study)."}
• {"endpoint_text":"- Change from baseline in urine total glycosaminoglycan (GAG) concentration throughout the 24-week study period, the safety extension (Week 104), the open-label extension (Week 261), and across the study","definition_or_measurement_approach":"Laboratory measurement of urine total GAG concentration with change-from-baseline analyses across the stated timeframes."}
• {"endpoint_text":"- Change from baseline in concomitant medication throughout the 24-week study period, the safety extension (Week 104), the open-label extension (Week 261), and across the study","definition_or_measurement_approach":"Assessment of changes in concomitant medications compared to baseline over the stated timeframes."}

Secondary endpoints

• {"endpoint_text":"- Percent change from baseline in cerebrospinal fluid (CSF) of heparan sulfate [Time Frame:24 weeks]","definition_or_measurement_approach":"Percent change from baseline in CSF heparan sulfate measured at specified time points up to 24 weeks."}
• {"endpoint_text":"- Participants with improvement in individual disease progression in the Vineland Adaptive Behavior Scale Adaptive Behavior Composite (ABC) score [Time Frame: 49 weeks]","definition_or_measurement_approach":"Assessment of individual participant improvement in Vineland ABC score up to 49 weeks."}
• {"endpoint_text":"- Participants with improvement in individual disease progression in the Vineland Adaptive Behavior Scale subdomain scores [Time Frame: 49 weeks]","definition_or_measurement_approach":"Assessment of subdomain scores of Vineland Adaptive Behavior Scale for improvement up to 49 weeks."}
• {"endpoint_text":"- PK parameter: Maximum observed concentration (Cmax) of DNL310 in serum [Time Frame: 24 weeks]","definition_or_measurement_approach":"Pharmacokinetic measurement of Cmax in serum over 24 weeks."}
• {"endpoint_text":"- PK parameter: Trough concentration (Cmin) of DNL310 in serum [Time Frame: 24 weeks]","definition_or_measurement_approach":"Pharmacokinetic measurement of trough concentration (Cmin) in serum over 24 weeks."}
• {"endpoint_text":"- PK parameter: Time to maximum observed concentration (tmax) of DNL310 in serum [Time Frame: 24 weeks]","definition_or_measurement_approach":"Pharmacokinetic measurement of tmax in serum over 24 weeks."}
• {"endpoint_text":"- PK parameter: Area under the concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) of DNL310 in serum [Time Frame: 24 weeks]","definition_or_measurement_approach":"Measurement of AUClast in serum PK assessments over 24 weeks."}
• {"endpoint_text":"- PK parameter: Area under the concentration-time curve from time zero to infinity (AUC∞) of DNL310 in serum [Time Frame: 24 weeks]","definition_or_measurement_approach":"Measurement of AUC∞ in serum PK assessments over 24 weeks."}
• {"endpoint_text":"- PK parameter: Area under the concentration-time curve over a dosing interval (AUCτ) of DNL310 in serum [Time Frame: 24 weeks]","definition_or_measurement_approach":"Measurement of AUCτ in serum PK assessments over 24 weeks."}
• {"endpoint_text":"- PK parameter: Apparent terminal elimination half-life (t½) of DNL310 in serum [Time Frame: 24 weeks]","definition_or_measurement_approach":"Measurement of apparent terminal elimination half-life (t½) in serum over 24 weeks."}
• {"endpoint_text":"- Characterization of immunogenicity of DNL310 in serum, as measured by the incidence of anti-drug antibodies (ADAs) relative to baseline [Time Frame: 24 weeks]","definition_or_measurement_approach":"Incidence of anti-drug antibodies measured in serum compared to baseline up to 24 weeks."}
• {"endpoint_text":"- Percent change from baseline in urine concentration of heparan sulfate (HS) [Time Frame: 24 weeks]","definition_or_measurement_approach":"Percent change in urine HS concentration compared to baseline measured up to 24 weeks."}
• {"endpoint_text":"- Participants with liver volume in the normal range [Time Frame: 24 weeks and 49 weeks]","definition_or_measurement_approach":"Assessment of liver volume (e.g., MRI) with classification as within normal range at 24 and 49 weeks."}
• {"endpoint_text":"- Percentage change form baseline in liver volume [Time Frame: 24 weeks and 49 weeks]","definition_or_measurement_approach":"Percent change from baseline in liver volume measured by MRI at 24 and 49 weeks."}

Netherlands

Earliest CTIS Part Ii Submission Date

23-05-2024

Latest Decision Or Authorization Date

16-09-2025

Processing Time Days

481

Number Of Sites

1

Number Of Participants

2

Primary sponsor

Full Name

Denali Therapeutics Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

Premier Research Group S.L.

Responsibilities

1,12,2

Name

Fortrea Inc.

Responsibilities

6,7

Name

Fisher Clinical Services GmbH

Responsibilities

15 (Drug Depot/Distribution)

Name

Iqvia Holdings Inc.

Responsibilities

3

Name

WCG Clinical Inc.

Responsibilities

15 (Neurocognitive Rater Training and centralized Neurocognitive Assessment review)

Name

Clario

Responsibilities

15 (Central Imaging - Ultrasound, MRI, and echocardiogram)

Name

Primevigilance Limited

Responsibilities

8

Name

Bioagilytix Labs LLC

Responsibilities

4

Name

Medicover Integrated Clinical Services

Responsibilities

4

Name

Blueprint Genetics Oy

Responsibilities

15 (Genotyping)

Third parties

• {"country":"Spain","full_name":"Premier Research Group S.L.","duties_or_roles":"1,12,2","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Fortrea Inc.","duties_or_roles":"6,7","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Bioagilytix Labs LLC","duties_or_roles":"4","organisation_type":"Pharmaceutical company"}
• {"country":"Poland","full_name":"Medicover Integrated Clinical Services","duties_or_roles":"4","organisation_type":"Industry"}
• {"country":"United Kingdom","full_name":"Primevigilance Limited","duties_or_roles":"8","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Fisher Clinical Services GmbH","duties_or_roles":"15 (Drug Depot/Distribution)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Bioagilytix Labs LLC","duties_or_roles":"4","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Clario","duties_or_roles":"15 (Central Imaging - Ultrasound, MRI, and echocardiogram)","organisation_type":"Health care"}
• {"country":"Finland","full_name":"Blueprint Genetics Oy","duties_or_roles":"15 (Genotyping)","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"United States","full_name":"WCG Clinical Inc.","duties_or_roles":"15 (Neurocognitive Rater Training and centralized Neurocognitive Assessment review)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Iqvia Holdings Inc.","duties_or_roles":"3","organisation_type":"Pharmaceutical company"}