Study of DNL126 in Pediatric Participants With Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome Type A)

Phase 1

Recruiting

• Conditions: Mucopolysaccharidosis Type IIIA
• Interventions: Drug: DNL126

• Registration Number: NCT06181136
• Lead Sponsor: Denali Therapeutics Inc.

Brief Summary

This is a multicenter, open-label, Phase 1/2 study to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and exploratory clinical efficacy of DNL126 in participants with Sanfilippo syndrome Type A (MPS IIIA). The core study period is 25 weeks (approximately 6 months) and is followed by a 72-week (approximately 18 month) open-label extension (OLE). Participants with MPS IIIA will be enrolled in two planned cohorts, and additional participants with MPS IIIA may be enrolled in three optional cohorts.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2023-12-04
• Study Start: 2023-12-07
• Study First Submitted QC: 2023-12-22
• Study First Posted: 2023-12-26
• Status Verified: 2024-08
• Last Update Submitted: 2024-08-20
• Last Update Posted: 2024-08-22
• Primary Completion: 2028-08
• Study Completion: 2028-08

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 20

Inclusion Criteria

• Confirmed diagnosis of MPS IIIA

• For Cohort B1: Have a severe phenotype based on having at least one of the following:

  • An older sibling with the same genotype and severe MPS IIIA, in the opinion of the investigator
  • A definitive genotype indicative of severe MPS IIIA, in the opinion of the investigator
  • Clinical symptoms of MPS IIIA prior to 28 months of age that, in the opinion of the investigator, are indicative of severe MPS IIIA

• For Cohort B2: Are an older sibling of a participant in Cohort B1 (who has already been confirmed to be eligible for dosing) with MPS IIIA, the same causative genotype, and who has severe MPS IIIA in the opinion of the investigator

Key

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Exclusion Criteria

• Have 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
• Have lost the ability to walk independently, in the opinion of the investigator
• Are unable to take the majority of nutrition via mouth, in the opinion of the investigator
• For Cohort B only: Are homozygous or compound heterozygous for the N-sulfoglucosamine sulfohydrolase (SGSH) S298P mutation or any other mutation known to be associated with slow-progressing phenotype
• Have used any CNS-targeted MPS IIIA enzyme replacement therapy (ERT) (eg, intrathecal SGSH or TfR-mediated SGSH delivery to CNS) within 3 months before Day 1
• Have a prior history of hematopoietic stem cell transplantation
• Have a prior history of gene therapy
• Have used genistein or anakinra within 7 days of screening or intended use of genistein or anakinra during the study
• Have a documented likely pathogenic mutation sufficient to cause disease (eg, taking into account zygosity) of other genes that are known to be associated with developmental delay, seizures, or other significant CNS disorders
• Have clinically significant thrombocytopenia, other clinically significant coagulation abnormality, significant active bleeding, or require treatment with an anticoagulant or more than two antiplatelet agents
• Contraindication for lumbar punctures
• Contraindication for MRI scan
• Have a clinically significant history of stroke, status epilepticus, head trauma with loss of consciousness, or any clinically significant CNS disease that is not MPS IIIA-related within 3 months of screening
• Have had a ventriculoperitoneal (VP) shunt placed or a clinically significant VP shunt malfunction within 30 days of screening
• Have any clinically significant CNS trauma or disorder, including severe untreated intracranial hypertension or brain surgery, that, in the opinion of the investigator, may interfere with assessment of study endpoints or make participation in the study unsafe

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Cohort A3	DNL126	Participants with MPS IIIA
Cohort B1	DNL126	Participants with MPS IIIA
Cohort A2	DNL126	Participants with MPS IIIA
Cohort A1	DNL126	Participants with MPS IIIA
Cohort B2	DNL126	Participants with MPS IIIA

Primary Outcome Measures

Name	Time	Method
Number of participants with clinically significant treatment emergent laboratory test abnormalities.	Up to 97 weeks
Incidence, severity, and seriousness of treatment-emergent adverse events (TEAEs)	Up to 97 weeks
Number of participants with treatment emergent vital sign abnormalities.	Up to 97 weeks
Number of participants with clinically significant treatment emergent abnormalities in 12-lead ECG results.	Up to 97 weeks
Number of participants with clinically significant treatment emergent abnormalities in physical examination.	Up to 97 weeks
Number of participants with clinically significant treatment emergent abnormalities in neurological examination.	Up to 97 weeks
Incidence and severity of infusion-related reactions (IRRs)	Up to 97 weeks

Secondary Outcome Measures

Name	Time	Method
Percentage change from baseline in cerebrospinal fluid (CSF) concentration of heparan sulfate (HS)	Up to 97 weeks
Percentage change from baseline in urine concentration of HS (normalized to creatinine)	Up to 97 weeks
Change from baseline in liver volume	Up to 97 weeks
Participants with spleen volume within the normal range	Up to 97 weeks
Change from baseline in spleen volume	Up to 97 weeks
Maximum concentration (Cmax)	Up to 97 weeks	DNL126 serum PK parameters
apparent terminal elimination half-life (t½)	Up to 97 weeks	DNL126 serum PK parameters
Incidence of anti-drug antibodies (ADAs) relative to baseline	Up to 97 weeks
Participants with liver volume within the normal range	Up to 97 weeks
area under the concentration-time curve from time zero to infinity (AUC∞; single dose only)	Up to 97 weeks	DNL126 serum PK parameters
DNL126 serum PK parameters	Up to 97 weeks	area under the concentration-time curve over a dosing interval (AUCτ; multiple doses only)
Participants with CSF HS concentration within the normal range	Up to 97 weeks
Participants with urine HS concentration (normalized to creatinine) within the normal range	Up to 97 weeks
area under the concentration-time curve from time zero to the time of last quantifiable concentration (AUClast)	Up to 97 weeks	DNL126 serum PK parameters
time to maximum observed concentration (Tmax)	Up to 97 weeks	DNL126 serum PK parameters

Trial Locations

Locations (4)

University of Iowa Stead Family Children's Hospital; 🇺🇸 Iowa City, Iowa, United States

UCSF Benioff Children's Hospital Oakland; 🇺🇸 Oakland, California, United States

University of North Carolina at Chapel Hill; 🇺🇸 Chapel Hill, North Carolina, United States

Baylor College of Medicine and Texas Children's Hospita; 🇺🇸 Houston, Texas, United States