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.

Tracking Information

• First Submitted Date: January 28, 2020
• First Posted Date: January 31, 2020
• Last Update Posted Date: April 26, 2024
• Actual Study Start Date: July 16, 2020
• Estimated Primary Completion Date: July 2027 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 15, 2023)

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

Original Primary Outcome Measures (submitted: January 29, 2020)

• Incidence and severity of adverse events (AEs) including infusion-related reactions (IRRs) [ Time Frame: 24 weeks ]
• Urine total glycosaminoglycan (GAG) concentrations [ Time Frame: 24 weeks ]

Current Secondary Outcome Measures (submitted: May 15, 2023)

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

Original Secondary Outcome Measures (submitted: January 29, 2020)

• Change from baseline in cerebrospinal fluid (CSF) of heparan sulfate [ Time Frame: 24 weeks ]
• PK parameter: Maximum observed concentration (Cmax) of DNL310 in serum [ Time Frame: 24 weeks ]
• PK parameter: Trough concentration (Cmin) of DNL310 in serum [ Time Frame: 24 weeks ]
• PK parameter: Time to maximum observed concentration (Tmax) of DNL310 in serum [ Time Frame: 24 weeks ]
• PK parameter: Area under the concentration-time curve from time zero to the time of last quantifiable concentration (AUC[0-last]) of DNL310 in serum [ Time Frame: 24 weeks ]
• PK parameter: Area under the concentration-time curve over a dosing interval (AUC[0-τ]) of DNL310 in serum [ Time Frame: 24 weeks ]
• PK parameter: Apparent terminal elimination rate constant (λz) of DNL310 in serum [ Time Frame: 24 weeks ]
• PK parameter: Apparent terminal elimination t½ of DNL310 in serum [ Time Frame: 24 weeks ]
• PK parameter: Accumulation ratio of DNL310 in serum [ Time Frame: 24 weeks ]
• Characterization of immunogenicity of DNL310 in serum, as measured by the incidence of anti-drug antibodies (ADAs) relative to baseline [ Time Frame: 24 weeks ]
• Change from baseline in urine concentration of heparan sulfate (HS) [ Time Frame: 24 weeks ]

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: January 29, 2020)

• Change from baseline in CSF of dermatan sulfate (DS) [ Time Frame: 24 weeks ]
• Change from baseline in urine concentration of DS [ Time Frame: 24 weeks ]
• Change from baseline in serum concentrations of HS and DS [ Time Frame: 24 weeks ]
• Change from baseline in levels of CSF biomarkers of lysosomal function [ Time Frame: 24 weeks ]
• Liver and spleen volumes as assessed by ultrasound [ Time Frame: 24 weeks ]
• Change from baseline in Clinical Global Impression-Severity (CGI-S) score [ Time Frame: 24 weeks ]
• Clinical Global Impression-Improvement (CGI-I) score [ Time Frame: 24 weeks ]
• Change from baseline in Parent/Caregiver Global Impression-Severity (PGI-S) score [ Time Frame: 24 weeks ]
• Parent/Caregiver Global Impression-Improvement (PGI-I) score [ Time Frame: 24 weeks ]
• Change from baseline in Activities of Daily Living for Hunter Syndrome (ADL-HS) score [ Time Frame: 24 weeks ]
• Change from baseline in stool consistency, per the Bristol Stool Scale [ Time Frame: 24 weeks ]
• Change from baseline in Six-Minute Walk Test (6MWT) for subjects ≥6 years old who are able to follow instructions at baseline [ Time Frame: 24 weeks ]
• Change from baseline in the toileting abilities percentage (TAP), as measured by the Toileting Abilities Survey (TAS) [ Time Frame: 24 weeks ]
• Change from baseline in auditory brainstem response (ABR) parameters [ Time Frame: 24 weeks ]
• Change from baseline in the cognitive-domain and the language- and motor-domain score and scores on either the Bayley Scales of Infant and Toddler Development (BSID-III) or the nonverbal index of the Kaufman Assessment Battery for Children (KABC-II) [ Time Frame: 24 weeks ]
• Change from baseline in the composite age-equivalent score and standard scores on the VABS-II [ Time Frame: 24 weeks ]
• Change from baseline in Infant and Toddler Quality of Life Questionnaire (ITQOL) for subjects <5 years of age [ Time Frame: 24 weeks ]
• Change from baseline in Childhood Health Questionnaire Parent Form (CHQ-PF28) for subjects ≥5 years of age [ Time Frame: 24 weeks ]
• Change from baseline in Pediatric Quality of Life Inventory Family Impact Module (PedsQL-FIM) [ Time Frame: 24 weeks ]

Descriptive Information

• Brief Title: A Study of Tividenofusp Alfa (DNL310) in Pediatric Participants With Hunter Syndrome
• 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

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Mucopolysaccharidosis II

Intervention

Drug: tividenofusp alfa

Intravenous repeating dose

Study Arms

• Experimental: Cohort A
  Dose escalation followed by a consistent dose level in participants with neuronopathic MPS II
  Intervention: Drug: tividenofusp alfa
• 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.
  Intervention: Drug: tividenofusp alfa
• Experimental: Cohort C
  A consistent dose level in participants with neuronopathic MPS II
  Intervention: Drug: tividenofusp alfa
• Experimental: Cohort D
  A consistent dose level in participants with non-neuronopathic MPS II or neuronopathic MPS II
  Intervention: Drug: tividenofusp alfa
• Experimental: Cohort E
  A consistent dose level in participants with non-neuronopathic MPS II or neuronopathic MPS II
  Intervention: Drug: tividenofusp alfa

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: April 24, 2024): 47
• Original Estimated Enrollment (submitted: January 29, 2020): 16
• Estimated Study Completion Date: July 2027
• Estimated Primary Completion Date: July 2027 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: up to 18 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, Netherlands, United Kingdom, United States

Administrative Information

• NCT Number: NCT04251026
• Other Study ID Numbers: DNLI-E-0002; 2019-004909-27 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Denali Therapeutics Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Denali Therapeutics Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Katia Meirelles, MD; Denali Therapeutics

• PRS Account: Denali Therapeutics Inc.
• Verification Date: April 2024