PMID- 25902842
OWN - NLM
STAT- MEDLINE
DCOM- 20160121
LR  - 20181113
IS  - 1750-1172 (Electronic)
IS  - 1750-1172 (Linking)
VI  - 10
DP  - 2015 Apr 24
TI  - Immunogenicity of idursulfase and clinical outcomes in very young patients (16 
      months to 7.5 years) with mucopolysaccharidosis II (Hunter syndrome).
PG  - 50
LID - 10.1186/s13023-015-0265-2 [doi]
LID - 50
AB  - BACKGROUND: Twenty-eight treatment-naive mucopolysaccharidosis II patients (16 
      months-7.5 years) received 0.5 mg/kg idursulfase weekly for one year in 
      NCT00607386. Serum anti-idursulfase immunoglobulin G antibodies (Abs) were seen 
      in 68% of patients. METHODS: This post hoc analysis examined the relationship 
      between Ab status, genotype, adverse events (AEs), and efficacy. Event rate 
      analyses, time-varying proportional hazards (Cox) modeling, and landmark analyses 
      were performed to evaluate the relationship between Ab status and safety. We 
      calculated the cumulative probability of AEs by genotype to evaluate the 
      relationship between genotype and safety. Urinary glycosaminoglycan (uGAG) 
      concentration, index of liver size, and spleen volume were compared by Ab status 
      and genotype. SAFETY RESULTS: The overall infusion-related AE (IRAE) rate was 
      higher in Ab+ patients than in Ab- ones. However, the rate was highest before Abs 
      developed, then decreased over time, suggesting that Abs did not confer the risk. 
      A landmark analysis of patients who were IRAE-naive at the landmark point found 
      that Ab+ patients were no more likely to experience post-landmark IRAEs than were 
      Ab- patients. In the genotype analysis, all patients in the complete 
      deletion/large rearrangement (CD/LR) and frame shift/splice site mutation 
      (FS/SSM) groups seroconverted, compared with only one-third of patients in the 
      missense mutation (MS) group (p < 0.001). The cumulative probability of having >/=1 
      IRAE was 87.5% in the CD/LR group and 46.2% in the MS group, with a shorter time 
      to first IRAE in the CD/LR group (p = 0.004). EFFICACY RESULTS: Ab+ patients had 
      a reduced response to idursulfase for liver size and uGAG concentration, but not 
      for spleen size. However, when percent change from baseline in liver size and in 
      uGAG level at Week 53 were adjusted for genotype, the difference was significant 
      only for neutralizing Ab+ groups. In the genotype analysis, the CD/LR and FS/SSM 
      groups had a reduced response in liver size and uGAG concentration compared with 
      the MS group. CONCLUSIONS: Safety outcomes and spleen size response on 
      idursulfase treatment appeared to be associated with genotype, not Ab status. 
      Liver size and uGAG response on idursulfase treatment at Week 53 appeared to be 
      associated with both neutralizing Ab status and genotype.
FAU - Pano, Arian
AU  - Pano A
AD  - Shire, 300 Shire Way, Lexington, MA, 02421, USA. apano@shire.com.
FAU - Barbier, Ann J
AU  - Barbier AJ
AD  - Shire, 300 Shire Way, Lexington, MA, 02421, USA. abarbier@shire.com.
FAU - Bielefeld, Bonnie
AU  - Bielefeld B
AD  - Shire, 300 Shire Way, Lexington, MA, 02421, USA. nefloorcloth@aol.com.
FAU - Whiteman, David A H
AU  - Whiteman DA
AD  - Shire, 300 Shire Way, Lexington, MA, 02421, USA. dwhiteman@shire.com.
FAU - Amato, David A
AU  - Amato DA
AD  - Shire, 300 Shire Way, Lexington, MA, 02421, USA. David_Amato@vrtx.com.
AD  - Current address: Vertex Pharmaceuticals, Cambridge, MA, USA. 
      David_Amato@vrtx.com.
LA  - eng
SI  - ClinicalTrials.gov/NCT00607386
PT  - Clinical Trial
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150424
PL  - England
TA  - Orphanet J Rare Dis
JT  - Orphanet journal of rare diseases
JID - 101266602
RN  - 0 (Immunoglobulin G)
RN  - EC 3.1.6.13 (Iduronate Sulfatase)
RN  - EC 3.1.6.13 (idursulfase)
SB  - IM
MH  - Child
MH  - Child, Preschool
MH  - *Enzyme Replacement Therapy
MH  - Genotype
MH  - Humans
MH  - Iduronate Sulfatase/administration & dosage/*adverse 
      effects/immunology/*therapeutic use
MH  - Immunoglobulin G/blood
MH  - Infant
MH  - Liver/pathology
MH  - Male
MH  - Mucopolysaccharidosis II/blood/*drug therapy
MH  - Organ Size
MH  - Risk Factors
MH  - Spleen/pathology
MH  - Treatment Outcome
PMC - PMC4416269
EDAT- 2015/04/24 06:00
MHDA- 2016/01/23 06:00
PMCR- 2015/04/24
CRDT- 2015/04/24 06:00
PHST- 2015/01/09 00:00 [received]
PHST- 2015/04/09 00:00 [accepted]
PHST- 2015/04/24 06:00 [entrez]
PHST- 2015/04/24 06:00 [pubmed]
PHST- 2016/01/23 06:00 [medline]
PHST- 2015/04/24 00:00 [pmc-release]
AID - 10.1186/s13023-015-0265-2 [pii]
AID - 265 [pii]
AID - 10.1186/s13023-015-0265-2 [doi]
PST - epublish
SO  - Orphanet J Rare Dis. 2015 Apr 24;10:50. doi: 10.1186/s13023-015-0265-2.