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

• ClinicalTrials.gov Identifier: NCT04251026
• Recruitment Status: Active, not recruiting
• First Posted: January 31, 2020
• Last Update Posted: April 26, 2024
• Sponsor: Denali Therapeutics Inc.
• Information provided by (Responsible Party): Denali Therapeutics Inc.

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Mucopolysaccharidosis II	Drug: tividenofusp alfa	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 47 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1/2, Multicenter, Open-Label Study to Determine the Safety, Pharmacokinetics, and Pharmacodynamics of DNL310 in Pediatric Participants With Hunter Syndrome
• Actual Study Start Date: July 16, 2020
• Estimated Primary Completion Date: July 2027
• Estimated Study Completion Date: July 2027

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort A; Dose escalation followed by a consistent dose level in participants with neuronopathic MPS II	Drug: tividenofusp alfa; Intravenous repeating dose
Experimental: Cohort B; 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; Intravenous repeating dose
Experimental: Cohort C; A consistent dose level in participants with neuronopathic MPS II	Drug: tividenofusp alfa; Intravenous repeating dose
Experimental: Cohort D; A consistent dose level in participants with non-neuronopathic MPS II or neuronopathic MPS II	Drug: tividenofusp alfa; Intravenous repeating dose
Experimental: Cohort E; A consistent dose level in participants with non-neuronopathic MPS II or neuronopathic MPS II	Drug: tividenofusp alfa; Intravenous repeating dose

Outcome Measures

Primary Outcome Measures :

1. Incidence and severity of treatment-emergent adverse events (TEAEs) [ Time Frame: 24 weeks, 104 weeks, and 261 weeks ]
2. Change from baseline in urine total glycosaminoglycan (GAG) concentrations [ Time Frame: 24 weeks, 104 weeks, and 261 weeks ]
3. Incidence and severity of infusion-related reactions (IRRs) [ Time Frame: 24 weeks, 104 weeks, and 261 weeks ]
4. Change from baseline in concomitant medications [ Time Frame: 24 weeks, 104 weeks, and 261 weeks ]

Secondary Outcome Measures :

1. Percentage change from baseline in cerebrospinal fluid (CSF) of heparan sulfate [ Time Frame: 24 weeks ]
2. Participants with improvement in individual disease progression in the Vineland Adaptive Behavior Scale Adaptive Behavior Composite (ABC) score [ Time Frame: 49 weeks ]
3. Participants with improvement in individual disease progression in the Vineland Adaptive Behavior Scale subdomain scores [ Time Frame: 49 weeks ]
4. PK parameter: Maximum observed concentration (Cmax) of DNL310 in serum [ Time Frame: 24 weeks ]
5. PK parameter: Trough concentration (Cmin) of DNL310 in serum [ Time Frame: 24 weeks ]
6. PK parameter: Time to maximum observed concentration (tmax) of DNL310 in serum [ Time Frame: 24 weeks ]
7. 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 ]
8. PK parameter: Area under the concentration-time curve from time zero to infinity (AUC∞) of DNL310 in serum [ Time Frame: 24 weeks ]
9. PK parameter: Area under the concentration-time curve over a dosing interval (AUCτ) of DNL310 in serum [ Time Frame: 24 weeks ]
10. PK parameter: Apparent terminal elimination half-life (t½) of DNL310 in serum [ Time Frame: 24 weeks ]
11. Characterization of immunogenicity of DNL310 in serum, as measured by the incidence of anti-drug antibodies (ADAs) relative to baseline [ Time Frame: 24 weeks ]
12. Percent change from baseline in urine concentration of heparan sulfate (HS) [ Time Frame: 24 weeks ]
13. Participants with liver volume in the normal range [ Time Frame: 24 weeks and 49 weeks ]
14. Percentage change from baseline in liver volume [ Time Frame: 24 weeks and 49 weeks ]

Eligibility Criteria

• Ages Eligible for Study: up to 18 Years (Child, Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Criteria

Key Inclusion Criteria:

• 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.

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
• 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

Contacts and Locations

Locations

United States, California

UCSF Benioff Children's Hospital

Oakland, California, United States, 94609

United States, Illinois

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

Chicago, Illinois, United States, 60611

United States, North Carolina

UNC Children's Research Institute

Chapel Hill, North Carolina, United States, 27514

United States, Pennsylvania

UPMC | Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, United States, 15224

Canada, Quebec

McGill University Health Centre - Royal Victoria Hospital

Montréal, Quebec, Canada, H4A 3J1

Netherlands

Erasmus Medical Center

Rotterdam, South Holland, Netherlands, 3015 GD

United Kingdom

St Mary's Hospital, Manchester Academic Health Science Centre

Manchester, United Kingdom, M13 9WL

Sponsors and Collaborators

Denali Therapeutics Inc.

Investigators

• Study Director: Katia Meirelles, MD; Denali Therapeutics

More Information

• Responsible Party: Denali Therapeutics Inc.
• ClinicalTrials.gov Identifier: NCT04251026
• Other Study ID Numbers: DNLI-E-0002; 2019-004909-27 ( EudraCT Number )
• First Posted: January 31, 2020
• Last Update Posted: April 26, 2024
• Last Verified: April 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Denali Therapeutics Inc.:

MPS II; Hunter Syndrome; nMPS II

Additional relevant MeSH terms:

Mucopolysaccharidosis II; Mucopolysaccharidoses; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Lysosomal Storage Diseases; Mucinoses; Connective Tissue Diseases; Metabolic Diseases; Mental Retardation, X-Linked; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Genetic Diseases, X-Linked; Heredodegenerative Disorders, Nervous System