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

Study Overview
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Brief Summary
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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).

Official Title
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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)

Conditions
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Mucopolysaccharidosis Type IIIA

Intervention / Treatment
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* Drug: DNL126


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Confirmed diagnosis of MPS IIIA Cohort B only: Have a severe phenotype based on an older sibling with the same genotype and severe MPS IIIA based on 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 within 30 days of screening or intended use of genistein during the study Have a documented likely pathogenic mutation 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 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

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A1<br>Participants with MPS IIIA | Drug: DNL126<br>* intravenous repeating dose<br>|
| Experimental: Cohort A2<br>Participants with MPS IIIA | Drug: DNL126<br>* intravenous repeating dose<br>|
| Experimental: Cohort B<br>Participants with MPS IIIA | Drug: DNL126<br>* intravenous repeating dose<br>|
| Experimental: Cohort C (Optional)<br>Participants with MPS IIIA | Drug: DNL126<br>* intravenous repeating dose<br>|
| Experimental: Cohort D (Optional)<br>Participants with MPS IIIA | Drug: DNL126<br>* intravenous repeating dose<br>|
| Experimental: Cohort E (Optional)<br>Participants with MPS IIIA | Drug: DNL126<br>* intravenous repeating dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence, severity, and seriousness of treatment-emergent adverse events (TEAEs) |  | Up to 97 weeks | 
| Number of participants with clinically significant treatment emergent laboratory test abnormalities. |  | 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

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sanfilippo Syndrome, MPS IIIA