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

A Phase 1/2, Multicenter, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL126 in Pediatric Participants With Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome Type A)

This is a multicenter, open-label, Phase 1/2 study to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical efficacy of DNL126 in participants with Sanfilippo syndrome Type A (MPS IIIA). The core study period is 25 weeks (approximately 6 months); followed by an open-label extension (OLE), which extends through Week 97 (approximately 18 months); and a long-term extension (LTE), which extends through Week 193 (Year 4). Participants with MPS IIIA will be enrolled in two planned cohorts, and additional participants with MPS IIIA may be enrolled in three optional cohorts.

Study Overview

• Status: Active, not recruiting
• Conditions: Mucopolysaccharidosis Type IIIA
• Intervention / Treatment: Drug: DNL126

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Oakland, California, United States, 94609
      • UCSF Benioff Children's Hospital Oakland
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Stead Family Children's Hospital
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • University of North Carolina at Chapel Hill
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine and Texas Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• Confirmed diagnosis of MPS IIIA
• For Cohort A2: No more than 1 participant may have predictors of a slow-progressing phenotype
• For Cohort A3: Approximately 2 participants will have predictors of the slow-progressing phenotype

• 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 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort A1; Participants with MPS IIIA	Drug: DNL126; intravenous repeating dose
Experimental: Cohort A2; Participants with MPS IIIA	Drug: DNL126; intravenous repeating dose
Experimental: Cohort A3; Participants with MPS IIIA	Drug: DNL126; intravenous repeating dose
Experimental: Cohort B1; Participants with MPS IIIA	Drug: DNL126; intravenous repeating dose
Experimental: Cohort B2; Participants with MPS IIIA	Drug: DNL126; intravenous repeating dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percentage change from baseline in cerebrospinal fluid (CSF) concentration of heparan sulfate (HS)	49 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Percentage change from baseline in urine concentration of HS (normalized to creatinine)	49 weeks
Change from baseline in liver volume	49 weeks
Percentage change from baseline in serum neurofilament light chain (NfL) concentration	73 weeks
Participants with CSF HS concentration within the normal range	49 weeks

Collaborators and Investigators

• Sponsor: Denali Therapeutics Inc.
• Investigators: Study Director: Ana-Claire Meyer, MD, Denali Therapeutics

Study record dates

Study Major Dates

• Study Start (Actual): December 7, 2023
• Primary Completion (Estimated): August 1, 2028
• Study Completion (Estimated): August 1, 2028

Study Registration Dates

• First Submitted: December 4, 2023
• First Submitted That Met QC Criteria: December 22, 2023
• First Posted (Actual): December 26, 2023

Study Record Updates

• Last Update Posted (Actual): December 5, 2025
• Last Update Submitted That Met QC Criteria: December 1, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: MPS IIIA; Sanfilippo Syndrome
• Additional Relevant MeSH Terms: Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Connective Tissue Diseases; Carbohydrate Metabolism, Inborn Errors; Lysosomal Storage Diseases; Mucinoses; Mucopolysaccharidoses; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Skin and Connective Tissue Diseases; Mucopolysaccharidosis III
• Other Study ID Numbers: DNLI-I-0001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No