Immunogenicity of idursulfase and clinical outcomes in very young patients (16 months to 7.5 years) with mucopolysaccharidosis II (Hunter syndrome)

Arian Pano, Ann J Barbier, Bonnie Bielefeld, David A H Whiteman, David A Amato, Arian Pano, Ann J Barbier, Bonnie Bielefeld, David A H Whiteman, David A Amato

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.

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-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).

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.

Figures

Figure 1
Figure 1
Ab+, PAb+, NAb+, and PNAb+ percentages of total subjects by Study Week visit in the primary analysis population. Percent of total subjects that are Ab+, PAb+, NAb+, and PNAb+ by Study Week visit in the primary analysis population. For the Ab+, and NAb+ patients, the percentage of patients who have Abs or NAbs, respectively, at that particular study visit are given. For PAb+ and PNAb+ patients, the cumulative percentage of patients is shown. A patient was considered to be PAb+ or PNAb+ at a given week if, by this time point, the patient had the first of 3 or more consecutive visits at which there were measurable anti-idursulfase Abs/NAbs. Ab+, antibody positive; NAb+, neutralizing antibody positive; PAb+, persistently antibody positive; PNAb+, persistently neutralizing antibody positive.
Figure 2
Figure 2
Kaplan-Meier plot of time to the first IRAE after the landmark point for patients with no IRAEs prior to the landmark point, by PAb status at the Study Week 9 visit. IRAE, infusion-related adverse event; PAb+, persistently antibody positive; PAb−, persistently antibody negative.
Figure 3
Figure 3
The ILS over time by PAb status and genotype group. A) ILS over time by PAb status at the landmark point. Week 53, PAb+ vs PAb−, p = 0.025. B) ILS over time by genotype group. Week 53, FS/SSM vs MS, p = 0.049. CD/LR, complete deletion/large rearrangement; FS/SSM, frameshift/splice site mutation; ILS, index of liver size; MS, missense mutation; PAb+, persistently antibody positive; PAb−, persistently antibody negative.
Figure 4
Figure 4
Spleen volume over time by PAb status and genotype group. A) Spleen volume over time by PAb status at the landmark point. There are no statistically significant differences at any time point. B) Spleen volume over time by genotype group. Week 0, FS/SSM vs MS, p = 0.007. Week 18, FS/SSM vs MS, p = 0.007. Week 36, FS/SSM vs MS, p = 0.002. Week 53, FS/SSM vs MS, p = 0.002. Week 53, CD/LR vs FS/SSM, p = 0.034. CD/LR, complete deletion/large rearrangement; FS/SSM, frameshift/splice site mutation; MS, missense mutation; PAb+, persistently antibody positive; PAb−, persistently antibody negative.
Figure 5
Figure 5
Urinary GAG levels over time by PAb status and genotype group. A) Urinary GAG levels over time by PAb status at the landmark point. Weeks 18 and 36, PAb+ vs PAb−, p < 0.001. Week 53, PAb+ vs PAb−, p = 0.002. B) Urinary GAG levels over time by genotype group. Week 18, CD/LR vs MS, p = 0.01. Week 36, CD/LR vs MS, p = 0.005. Week 53, CD/LR vs MS, p = 0.015. There were no other significant differences between groups. CD/LR, complete deletion/large rearrangement; FS/SSM, frameshift/splice site mutation; MS, missense mutation; PAb+, persistently antibody positive; PAb−, persistently antibody negative; uGAG, urinary glycosaminoglycan.

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Source: PubMed

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