First results of a 6 month, open label, phase I/II clinical trial of intrathecal (IT) enzyme replacement therapy (ERT) and its extension in mucopolysaccharidosis IIIA (MPSIIIA, Sanfilippo syndrome) patients. C. Breen1, P. Haslett2, F. A. Wijburg3, J. de Ruijter3, J. P. Marchal3, F. Heap4, S. Rust4, K. Baez2, N. Nair2, S. A. Jones1 1) Manchester Centre for Genomic Medicine, University of Manchester and Central Manchester University Hospitals, Manchester, United Kingdom; 2) Shire, Lexington, MA, USA; 3) Academic Medical Center, Amsterdam, The Netherlands; 4) Royal Manchester Children's Hospital, Manchester, United Kingdom.

   Introduction: MPSIIIA is a lysosomal storage disease caused by a deficiency of heparan N-sulfatase, which results in accumulation of heparan sulfate (HS) leading to progressive neurodegeneration. HGT-1410 is an investigational recombinant heparan N-sulfatase that is under study as ERT for the treatment of MPSIIIA. We report results from the first-in-human trial (NCT01155778) of HGT-1410 and preliminary data from its extension (NCT01299727). Methods: HGT-1410 (10 mg, 45 mg, 90 mg) was administered via IT drug delivery device (IDDD) every 4 weeks in patients aged 3 years (developmental age 1 year). Primary objective: assessment of safety and tolerability of IT-administered HGT-1410. Secondary objectives included: effect of therapy on HS levels in CSF, cognitive status (developmental quotient; DQ) and cortical gray matter volume (MRI) assessed every 6 months. Results: Twelve patients were enrolled, 6 in the Netherlands and 6 in the UK. Median age was 5.7 years (range 3.1 to 23.6) and 11 continue in the ongoing extension study. The patients were heterogeneous with respect to age, disease stage and phenotype. In the initial trial, there were 10 serious adverse events (SAEs) among 7 patients; 9 of them related to the IDDD. No SAEs were considered related to HGT-1410. No patients discontinued from the study. Among the study patients, CSF levels of HS were increased at baseline relative to age-matched non-MPS controls. CSF levels of HS exhibited marked and persistent declines following the first dose of IT HGT-1410. Response profiles among the 45-mg and 90-mg treatment groups appeared superior to the 10-mg group. HGT-1410 had no discernible effect on decline in DQ or on cortical grey matter volume, observed over 6 to 24 months, when compared to the data of an ongoing natural history study in MPSIIIA patients (NCT01047306). Conclusions: This initial, relatively short-term observation suggests that HGT-1410 was biologically active and generally well tolerated after IT delivery to children with MPSIIIA. Mechanical failures of the IDDD present challenges that may be particular to this patient population. These preliminary data do not demonstrate an effect of IT-administered HGT-1410 on cognitive decline or loss of cortical gray-matter volume in children with the severe form of MPSIIIA. However, this phase I/II trial was not designed to test the efficacy of the therapy. Further clinical studies of this new therapeutic approach for MPSIIIA are warranted.