Simon A Jones1, Catherine Breen1, Fiona Heap1, Stewart Rust2, Jessica de Ruijter3, Evelien Tump3, Jan Pieter Marchal3, Luying Pan4, Yongchang Qiu4, Jou-Ku Chung4, Nitin Nair4, Patrick A J Haslett4, Ann J Barbier4, Frits A Wijburg5. 1. Willink Unit, Manchester Centre for Genomic Medicine, St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust (CMFT), University of Manchester, United Kingdom. 2. Paediatric Psychosocial Department, Royal Manchester Children's Hospital, Manchester, United Kingdom. 3. Department of Paediatrics, Academic Medical Center, Amsterdam, The Netherlands. 4. Shire, Lexington, MA, USA. 5. Department of Paediatrics, Academic Medical Center, Amsterdam, The Netherlands. Electronic address: f.a.wijburg@amc.uva.nl.
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 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.
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.
Authors: Barbara King; Neil R Marshall; Sofia Hassiotis; Paul J Trim; Justin Tucker; Kathryn Hattersley; Marten F Snel; Robert D Jolly; John J Hopwood; Kim M Hemsley Journal: J Inherit Metab Dis Date: 2016-11-10 Impact factor: 4.982
Authors: Fan Yi; Xinying Hong; Arun Babu Kumar; Chengli Zong; Geert-Jan Boons; C Ronald Scott; Frantisek Turecek; Bruce H Robinson; Michael H Gelb Journal: Mol Genet Metab Date: 2018-05-23 Impact factor: 4.797