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Preliminary results from phase I/II, first-in-human, open-label study of DNL126 in children with mucopolysaccharidosis type IIIA (MPS IIIA)
Abstract   Peer reviewed

Preliminary results from phase I/II, first-in-human, open-label study of DNL126 in children with mucopolysaccharidosis type IIIA (MPS IIIA)

Elizabeth Jalazo, John Bernat, Jimmy Holder, Ana-Claire L. Meyer, Audrey Gill, Nikhil J. Pandya, Jana Matuskova, Carole Ho, Matt D. Troyer, Young S. Oh, …
Molecular genetics and metabolism, Vol.147(2), 109481
02/2026
DOI: 10.1016/j.ymgme.2025.109481

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Abstract

Introduction: MPS IIIA results from deficiency of the lysosomal enzyme sulfamidase (SGSH) and is characterized by severe neurocognitive deterioration during childhood and premature death. No approved disease-modifying therapies for MPS IIIA are available. DNL126 (Enzyme TransportVehicle™:SGSH) is a novel investigational intravenous enzyme replacement therapy designed to cross the blood-brain barrier and deliver sulfamidase to the brain and peripheral tissues. Methods: A multicenter, open-label, first-in-human, Phase 1/2 study (NCT06181136) is assessing the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of intravenous DNL126 in children with MPS IIIA in up to five cohorts, including two dose-finding cohorts (A1, A2). The core study period duration is 25 weeks followed by a 72-week open-label extension. The primary objective is reduction in cerebrospinal fluid (CSF) heparan sulfate (HS) concentration. Results: Eight participants in the two dose-finding cohorts completed ≥49 weeks of treatment with DNL126; median age was 53.6 months (range, 36-78 months), 75 % (6/8) were female, and 25 % (2/8) were heterozygous for the p.S298P attenuated variant. At Week 49, mean reduction in CSF HS was 80 % (95 % confidence interval: 43-93 %), with normalization in three of seven participants with CSF samples. Reductions in CSF HS were observed at the first post-baseline timepoint at Week 13. Adverse events (AE) were primarily mild or moderate in severity; mild or moderate infusion-related reactions (IRRs) were the most common AE. IRRs were manageable with premedications, infusion‑rate adjustments, and/or infusion interruptions. No treatment-related serious AEs were reported. There were no study discontinuations or treatment discontinuations due to IRRs or AEs. Conclusion: Preliminary data demonstrate that the safety profile of DNL126 in children with MPS IIIA was generally consistent with established ERT therapies and resulted in substantial reductions in CSF HS concentration, including normalization. Evaluation of additional cohorts at the recommended clinical dose is ongoing.

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