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

Mucopolysaccharidosis II Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04251026
• Other study ID #: DNLI-E-0002
• Secondary ID: 2019-004909-27
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: July 16, 2020
• Est. completion date: July 2027

Study information

• Verified date: April 2024
• Source: Denali Therapeutics Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 47
• Est. completion date: July 2027
• Est. primary completion date: July 2027
• Accepts healthy volunteers: No
• Gender: Male
• Age group: N/A to 18 Years

Eligibility

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

Related Conditions & MeSH terms

• Mucopolysaccharidoses
• Mucopolysaccharidosis II

Intervention

Drug:
• tividenofusp alfa
Intravenous repeating dose

Locations

Country	Name	City	State
Canada	McGill University Health Centre - Royal Victoria Hospital	Montréal	Quebec
Netherlands	Erasmus Medical Center	Rotterdam	South Holland
United Kingdom	St Mary's Hospital, Manchester Academic Health Science Centre	Manchester
United States	UNC Children's Research Institute	Chapel Hill	North Carolina
United States	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	UCSF Benioff Children's Hospital	Oakland	California
United States	UPMC | Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Denali Therapeutics Inc.

Countries where clinical trial is conducted

United States,  Canada,  Netherlands,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence and severity of treatment-emergent adverse events (TEAEs)		24 weeks, 104 weeks, and 261 weeks
Primary	Change from baseline in urine total glycosaminoglycan (GAG) concentrations		24 weeks, 104 weeks, and 261 weeks
Primary	Incidence and severity of infusion-related reactions (IRRs)		24 weeks, 104 weeks, and 261 weeks
Primary	Change from baseline in concomitant medications		24 weeks, 104 weeks, and 261 weeks
Secondary	Percentage change from baseline in cerebrospinal fluid (CSF) of heparan sulfate		24 weeks
Secondary	Participants with improvement in individual disease progression in the Vineland Adaptive Behavior Scale Adaptive Behavior Composite (ABC) score		49 weeks
Secondary	Participants with improvement in individual disease progression in the Vineland Adaptive Behavior Scale subdomain scores		49 weeks
Secondary	PK parameter: Maximum observed concentration (Cmax) of DNL310 in serum		24 weeks
Secondary	PK parameter: Trough concentration (Cmin) of DNL310 in serum		24 weeks
Secondary	PK parameter: Time to maximum observed concentration (tmax) of DNL310 in serum		24 weeks
Secondary	PK parameter: Area under the concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) of DNL310 in serum		24 weeks
Secondary	PK parameter: Area under the concentration-time curve from time zero to infinity (AUC8) of DNL310 in serum		24 weeks
Secondary	PK parameter: Area under the concentration-time curve over a dosing interval (AUCt) of DNL310 in serum		24 weeks
Secondary	PK parameter: Apparent terminal elimination half-life (t½) of DNL310 in serum		24 weeks
Secondary	Characterization of immunogenicity of DNL310 in serum, as measured by the incidence of anti-drug antibodies (ADAs) relative to baseline		24 weeks
Secondary	Percent change from baseline in urine concentration of heparan sulfate (HS)		24 weeks
Secondary	Participants with liver volume in the normal range		24 weeks and 49 weeks
Secondary	Percentage change from baseline in liver volume		24 weeks and 49 weeks