A multicenter open-label extension study of intrathecal heparan-N-sulfatase in patients with Sanfilippo syndrome type A.

Sanfilippo syndrome type A (mucopolysaccharidosis type IIIA) is a rare autosomal recessive lysosomal disorder characterized by deficient heparan-N-sulfatase (HNS) activity, and subsequent accumulation of heparan sulfate, especially in the central nervous system. The disease is associated with progressive neurodegeneration in early childhood. For this open-label extension study of a phase 2b clinical trial, we report on safety and cognitive decline in patients receiving intrathecal (IT) administration of recombinant human HNS (rhHNS). Of 21 patients who completed the phase 2b study, 17 continued in the open-label extension. Patients receiving rhHNS IT 45 mg continued to receive the same treatment regimen (i.e., every 2 weeks or every 4 weeks) throughout the extension. Patients receiving no treatment in the phase 2b study were re-randomized to the treatment groups. Neurocognition was assessed using the Bayley Scales of Infant and Toddler Development®, Third Edition (BSID-III). Adverse events were recorded over the duration of the treatment period. Cognitive decline was observed in most patients in both treatment groups; however, improvements in BSID-III development quotient score were observed for two patients, in receptive and expressive communication scores for three patients each, in fine motor skills for one patient, and in gross motor skills for six patients. Treatment-emergent adverse events that occurred with rhHNS IT were mostly mild, none led to study discontinuation, and there were no deaths. The extension study was terminated early as the primary endpoints of the phase 2b study were not met, and no statistical analyses were carried out. Although cognitive decline was apparent in most patients, improvements were observed in a small group of patients. Greater declines were observed in patients at the higher end of the age range, suggesting earlier intervention may increase the possibility of a response to treatment. rhHNS IT treatment remained generally well tolerated up to 96 weeks.