Chemically modified recombinant human sulfamidase (SOBI003) in mucopolysaccharidosis IIIA patients: Results from an open, non-controlled, multicenter study

Mol Genet Metab. 2022 Aug;136(4):249-259. doi: 10.1016/j.ymgme.2022.06.008. Epub 2022 Jun 28.


Purpose: Mucopolysaccharidosis IIIA (MPS IIIA) is an inherited lysosomal storage disorder caused by mutations in the N-sulfoglucosamine sulfohydrolase gene that result in deficient enzymatic degradation of heparan sulfate (HS), resulting in progressive neurodegeneration in early childhood and premature death. A chemically modified variant of recombinant human sulfamidase, SOBI003, has shown to cross the blood-brain barrier (BBB) in mice and achieve pharmacologically relevant levels in cerebrospinal fluid (CSF). We report on a phase 1/2, open-label, first-in-human (FIH) study (NCT03423186) and its extension study (NCT03811028) to evaluate the long-term safety, tolerability, pharmacokinetics/pharmacodynamics (PK/PD) and clinical efficacy of SOBI003 in patients with MPS IIIA for up to 104 weeks.

Methods: Six patients aged 1-6 years with confirmed MPS IIIA with developmental age ≥ 12 months received weekly intravenous injections of SOBI003 at 3 mg/kg (Cohort 1, n = 3) or 10 mg/kg (Cohort 2, n = 3). During the extension study, the individual dose of SOBI003 could be adjusted up to 20 mg/kg at the discretion of the investigator.

Results: SOBI003 was generally well tolerated. Serum concentrations of SOBI003 increased in proportion to dose, and presence in CSF confirmed that SOBI003 crosses the BBB. Anti-drug antibodies (ADA) were detected in serum and CSF in all patients, with subsequent reductions in serum SOBI003 exposure at high ADA titers. SOBI003 exerted a clear PD effect: a mean reduction in HS levels in CSF of 79% was recorded at the last assessment, together with reductions in HS levels in serum and urine. Neurocognitive development age-equivalent scores showed a stabilization of cognition for all patients, whereas no clear overall clinical effect was observed on adaptive behavior, sleep pattern or quality of life.

Conclusion: SOBI003 was well tolerated when administered as weekly intravenous infusions at doses of up to 20 mg/kg for up to 104 weeks. ADA development was common and likely affected both PK and PD parameters. SOBI003 crossed the BBB and showed pharmacological activity on HS in CSF.

Keywords: Anti-drug antibodies; Blood–brain barrier; Chemically modified recombinant human sulfamidase; Heparan sulfate; Mucopolysaccharidosis IIIA; Plasma exposure.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies
  • Brain / metabolism
  • Child
  • Child, Preschool
  • Heparitin Sulfate / metabolism
  • Humans
  • Hydrolases
  • Infant
  • Mucopolysaccharidosis III* / drug therapy
  • Mucopolysaccharidosis III* / genetics
  • Quality of Life


  • Antibodies
  • Heparitin Sulfate
  • Hydrolases
  • N-sulfoglucosamine sulfohydrolase

Associated data