title: Immunogenicity of idursulfase and clinical outcomes in very young patients (16 months to 7.5 years) with mucopolysaccharidosis II (Hunter syndrome).
abstract: BACKGROUND
  Twenty-eight treatment-naïve 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.
  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-naïve 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).
  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.
authors.affiliation: Shire, 300 Shire Way, Lexington, MA, 02421, USA. apano@shire.com.
authors.forename: Arian
authors.initials: A
authors.lastname: Pano
authors.affiliation: Shire, 300 Shire Way, Lexington, MA, 02421, USA. abarbier@shire.com.
authors.forename: Ann J
authors.initials: AJ
authors.lastname: Barbier
authors.affiliation: Shire, 300 Shire Way, Lexington, MA, 02421, USA. nefloorcloth@aol.com.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Bielefeld
authors.affiliation: Shire, 300 Shire Way, Lexington, MA, 02421, USA. dwhiteman@shire.com.
authors.forename: David A H
authors.initials: DA
authors.lastname: Whiteman
authors.affiliation: Shire, 300 Shire Way, Lexington, MA, 02421, USA. David_Amato@vrtx.com.|Current address: Vertex Pharmaceuticals, Cambridge, MA, USA. David_Amato@vrtx.com.
authors.forename: David A
authors.initials: DA
authors.lastname: Amato
mesh_terms: D002648:Child; D002675:Child, Preschool; D056947:Enzyme Replacement Therapy; D005838:Genotype; D006801:Humans; D007066:Iduronate Sulfatase / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology / Q000627:therapeutic use*; D007074:Immunoglobulin G / Q000097:blood; D007223:Infant; D008099:Liver / Q000473:pathology; D008297:Male; D016532:Mucopolysaccharidosis II / Q000097:blood / Q000188:drug therapy*; D009929:Organ Size; D012307:Risk Factors; D013154:Spleen / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D007074:Immunoglobulin G; D007066:Iduronate Sulfatase; C517982:idursulfase