Long-term safety and clinical outcomes of intrathecal heparan-N-sulfatase in patients with Sanfilippo syndrome type A.

INTRODUCTION: Currently, there is no effective therapy for mucopolysaccharidosis IIIA (MPS IIIA). Intravenously-administered enzyme replacement therapies, while effective in other forms of MPS without neurological involvement, have not been successful in patients with MPS IIIA, as they are unable to cross the blood-brain barrier to improve neurological symptoms. We evaluated the long-term safety, tolerability, and clinical outcomes of recombinant human heparan-N-sulfatase (rhHNS) administered intrathecally (IT) in children with MPS IIIA in a phase 1/2 extension study. METHODS: Patients aged ≥3 years with MPS IIIA who had previously completed a phase 1/2 study and received ≥5 of the 6 planned rhHNS infusions via IT administration, were eligible for inclusion. Patients who received 10 mg in the phase 1/2 study had their dose increased to 45 mg. Patients who were treated with 45 mg or 90 mg rhHNS IT in the phase 1/2 study remained on this monthly dose in the extension study. rhHNS was administered via an intrathecal drug delivery device (IDDD). Primary endpoints included the type and severity of adverse events, presence of anti-rhHNS antibodies in the CSF and serum, and changes in laboratory values. Secondary endpoints included standardized neurocognitive assessments and brain magnetic resonance imaging. RESULTS: In the extension study, 12 patients with a mean (SD) age of 9.6 (7.3) years continued treatment with rhHNS IT for a median of 264.4 weeks. Ten of 12 patients completed the extension study. rhHNS IT was generally well-tolerated. All patients experienced at least one treatment-emergent adverse event (TEAE), most being mild or moderate in severity. No serious adverse events (SAEs) were considered related to the study drug, and no deaths occurred. Most SAEs were related to malfunctions of the IDDD. Declines from baseline in Bayley Scales of Infant Development, Third Edition or Kaufman Assessment Battery for Children, Second Edition, Nonverbal Index developmental quotient scores were evident at all rhHNS dosing groups: -17.97%, -18.99%, and -12.12% in the 10/45, 45, and 90 mg groups, respectively, at Month 54. CONCLUSIONS: Overall, rhHNS IT was well tolerated in the extension study. However, rhHNS IT was unable to slow the neurocognitive decline of patients with MPS IIIA. This study was subsequently terminated early because pre-specified efficacy criteria were not met, and the study did not yield clinical proof of concept. (Clinicaltrials.gov Identifier NCT01299727).

A phase 1/2 study of intrathecal heparan-N-sulfatase in patients with mucopolysaccharidosis IIIA.

OBJECTIVE: This was an open-label, phase 1/2 dose-escalation, safety trial of intrathecal recombinant human heparan-N-sulfatase (rhHNS) administered via intrathecal drug delivery device (IDDD) for treating mucopolysaccharidosis IIIA (NCT01155778). STUDY DESIGN: Twelve patients received 10, 45, or 90mg of rhHNS via IDDD once monthly for a total of 6 doses. Primary endpoints included adverse events (AEs) and anti-rhHNS antibodies. Secondary endpoints included standardized neurocognitive assessments, cortical gray matter volume, and pharmacokinetic/pharmacodynamic analyses. RESULTS: All patients experienced treatment-emergent AEs; most of mild-to-moderate severity. Seven patients reported a total of 10 serious AEs (SAEs), all but one due to hospitalization to revise a nonfunctioning IDDD. No SAEs were considered related to rhHNS. Anti-rhHNS antibodies were detected in the serum of 6 patients and in the cerebrospinal fluid (CSF) of 2 of these. CSF heparan sulfate levels were elevated at baseline and there were sustained declines in all tested patients following the first rhHNS dose. No impact of anti-rhHNS antibodies on any pharmacodynamic or safety parameters was evident. 4 of 12 patients showed a decline in developmental quotient, 6 were stable, and 2 patients had only a single data point. No dose group showed a clearly different response pattern. CONCLUSIONS: rhHNS administration via IDDD appeared generally safe and well tolerated. Treatment resulted in consistent declines in CSF heparan sulfate, suggesting in vivo activity in the relevant anatomical compartment. Results of this small study should be interpreted with caution. Future studies are required to assess the potential clinical benefits of rhHNS and to test improved IDDD models.