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

https://doi.org/10.1016/j.ymgme.2016.05.006Get rights and content
Under a Creative Commons license
open access

Highlights

  • Phase 1/2 trial of intrathecal recombinant human heparan-N-sulfatase for MPS IIIA

  • Intrathecal rhHNS administration appeared generally safe and well tolerated

  • Treatment resulted in consistent declines in CSF heparan sulfate.

  • No impact of anti-rhHNS antibodies on any pharmacodynamic/safety parameters

  • Developmental quotient: decreased in 4/12 pts.; was stable in 6; 2 had single point

Abstract

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 90 mg 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.

Abbreviations

AE
adverse event
BSID-III
Bayley Scales of Infant and Toddler Development, Third Edition
CSF
cerebrospinal fluid
CNS
central nervous system
DQ
developmental quotient
EC
Enzyme Commission
ELISA
enzyme-linked immunosorbent assay
GAG
glycosaminoglycan
IDDD
intrathecal drug delivery device
IT
intrathecal
KABC-II
Kaufman Assessment Battery for Children, Second Edition
LC-MS/MS
liquid chromatography-tandem mass spectrometry
MPS IIIA
mucopolysaccharidosis IIIA/Sanfilippo syndrome type A
MRI
magnetic resonance imaging
rhHNS
recombinant human heparan-N-sulfatase (EC 3.10.1.1)
SAE
serious adverse event
TEAE
treatment-emergent adverse event
Tmax
time to maximum serum concentration
uGAG
urinary glycosaminoglycan
VABS-II
Vineland Adaptive Behavior Scales, Second Edition

Keywords

Enzyme replacement therapy
Heparan sulfate
Intrathecal drug delivery device
Lysosomal storage disease
Mucopolysaccharidosis IIIA (MPS IIIA)
Sanfilippo syndrome A

Cited by (0)

1

Current address: Vertex Pharmaceuticals, Inc., 50 Northern Ave, Boston, MA 02210.

2

Current address: Alnylam Pharmaceuticals, Inc., 300 Third Street, Cambridge, MA 02142.

3

Current address: Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139.