Correlation between urinary GAG and anti-idursulfase ERT neutralizing antibodies during treatment with NICIT immune tolerance regimen: A case report.

Antibodies to intravenous idursulfase enzyme replacement therapy (ERT) for patients with Hunter syndrome (mucopolysaccharidosis type II, MPS II) can have a harmful clinical impact, including both increasing risk of infusion reactions and inhibiting therapeutic activity. Thus, failure to monitor anti-idursulfase antibodies and neutralizing antibodies, and delays in reporting results, may postpone critical clinical decisions. Urinary glycosaminoglycan (GAG) levels may be used as a biomarker for anti-idursulfase antibodies and neutralizing antibodies to improve timeliness in monitoring and managing ERT. This is a case report describing a patient with MPS II with high levels of neutralizing antibodies and worsened clinical status who was treated for five years with a non-immunosuppressive and non-cytotoxic immune tolerance (NICIT) regimen, consisting of intravenous immune globulin and frequent infusions of idursulfase. Neutralizing antibodies and total anti-idursulfase antibodies were measured by two different methods, the direct 1,9-dimethylmethylene blue (DMB) assay and cetylpyridinium chloride carbazole-borate (CPC) assay. Neutralizing antibodies, measured as percent inhibition of enzyme activity and also by total neutralizing antibody titer, were correlated with quantitative urinary GAG measured by DMB assay (p=0.026, p=0.0067), and quantitative urinary GAG by CPC assay with percent inhibition of enzyme activity by neutralizing antibodies (p=0.0475). The NICIT regimen showed a sustained immune tolerance after five years and was well-tolerated. Urinary GAG, measured by DMB assay, may be a biomarker for anti-idursulfase neutralizing antibodies and is useful for managing immune tolerance regimens for patients with MPS II who have high levels of anti-idursulfase neutralizing antibodies. This study highlights the importance of regular and frequent monitoring of urinary GAG in patients with MPS II who are receiving ERT. The NICIT regimen, with less drug toxicities, may be preferred in patients with MPS who have a high risk of infections and whose disease progresses less rapidly than some other lysosomal storage diseases, such as infantile Pompe disease.

Kim S ，Whitley CB ，Jarnes Utz JR 《-》

The relationship between anti-idursulfase antibody status and safety and efficacy outcomes in attenuated mucopolysaccharidosis II patients aged 5 years and older treated with intravenous idursulfase.

In the pivotal phase II/III trial of idursulfase administered intravenously to treat mucopolysaccharidosis II, approximately half of the patients developed antibodies to idursulfase. This post-hoc analysis of data from the phase II/III trial and extension study examined the relationship between antibody status and outcomes. A total of 63 treatment-naïve patients received 0.5 mg/kg of intravenous idursulfase weekly for two years. Thirty-two patients (51%) were positive for anti-idursulfase IgG antibodies, 23 of whom (37%) became persistently positive. All patients who developed an antibody response did so by their scheduled Week 27 study visit. Positive antibody status appeared to have no statistically significant effect upon changes in six-minute walk test distance, percent predicted forced vital capacity, or liver and spleen volume. All patients showed significant decreases in urinary GAG levels, although the antibody positive group maintained somewhat higher urinary GAG levels than their antibody-negative counterparts at the end of study (138.7 vs. 94.7 μg/mg creatinine, p = 0.001). Antibody positivity was not associated with a higher event rate for serious adverse events. Among patients who had no prior infusion-related reactions, antibody positive patients were 2.3 times more likely to have a first infusion-related reaction than those who would remain negative (p = 0.017); the risk increased to 2.5 times more likely for those who were persistently positive (p = 0.009). These differences in risk disappeared among patients with a previous infusion-related reaction, likely because of preventive measures. A genotype analysis for the 36 patients with available data found that patients with nonsense or frameshift mutations may be more likely to develop antibodies, to experience infusion-related reactions, and to have a reduced uGAG response than those with missense mutations, suggesting the possibility that antibodies are not a driver of clinical outcomes but rather a marker for genotype.

Barbier AJ ，Bielefeld B ，Whiteman DA ，Natarajan M ，Pano A ，Amato DA ... -  《-》

Safety and efficacy of enzyme replacement therapy with idursulfase beta in children aged younger than 6 years with Hunter syndrome.

Idursulfase beta (Hunterase®) has been used for enzyme replacement therapy (ERT) of patients with mucopolysaccharidosis II (MPS II, Hunter syndrome) aged 6 years or older since 2012 in Korea. The objective of this study was to evaluate the safety and efficacy of ERT with idursulfase beta in Hunter syndrome children younger than 6 years. This study was a 52-week, single center, single arm, open-label clinical trial (NCT01645189). Idursulfase beta (0.5mg/kg/week) was administered intravenously for 52 weeks. The primary endpoint was safety assessed by adverse events (AEs). Secondary endpoints included vital signs, physical examination, ECG, laboratory tests, anti-idursulfase antibodies, and efficacy represented by changes in urinary glycosaminoglycan (GAG) at week 53 from baseline. In addition, growth indices and developmental milestones (Denver II test) were evaluated as exploratory variables. All six patients experienced at least one AE. A total of 109 AEs were reported. One patient experienced a serious AE (hospitalization due to gastroenteritis) that was considered not to be treatment related. One patient (16.7%) experienced infusion-related adverse drug reactions (ADRs), developing urticaria six times and a cough five times. There were no serious ADRs and no clinically significant changes in vital signs, physical exam, laboratory parameters, or ECG. Of the six patients, four (66.7%) showed anti-idursulfase antibodies and neutralizing antibodies on at least one occasion during the study. At week 53, urinary GAG was significantly reduced by -35.1±30.6mgGAG/g creatine from baseline (P=0.038). This study indicates that the safety and efficacy of idursulfase beta are similar to those reported in Hunter syndrome patients aged 6 years or older.

Sohn YB ，Cho SY ，Lee J ，Kwun Y ，Huh R ，Jin DK ... -  《-》

Immune Modulation for Enzyme Replacement Therapy in A Female Patient With Hunter Syndrome.

A 3.5 year old Hispanic female presented with signs and symptoms concerning for MPS II (Hunter Syndrome). The diagnosis of MPS II was confirmed by enzyme and molecular testing. Genetic evaluation revealed undetectable plasma iduronate-2-sulfatase enzyme activity and an inversion between intron 7 of the IDS gene and a region near exon 3 of IDS-2. This inversion is the molecular cause for ~8% of cases of MPS II and often results in a severe phenotype. X-inactivation studies revealed an inactivation ratio of 100:0. Given the patient's undetectable enzyme level, in combination with a severe IDS gene mutation, classic features at time of presentation, and the significantly skewed X inactivation, there was concern that she was at high risk of developing high and sustained antibody titers to idursulfase which would limit her benefit from enzyme replacement therapy (ERT). Anti-drug neutralizing antibodies to idursulfase have been associated with reduced systemic exposure to idursulfase and poorer clinical outcomes. Therefore, the decision was made to concurrently treat the patient with immune tolerance induction therapy during the first month of treatment with idursulfase in order to decrease the risk of developing high sustained antibody titers. The immune tolerance induction protocol consisted of rituximab weekly for 4 weeks, methotrexate three times a week for 3 weeks and monthly IVIG through B-cell and immunoglobulin recovery. Immune tolerance induction was initiated concurrently with the start of ERT. The patient had no significant adverse effects related to undergoing immune tolerance induction therapy and two and half years later is doing well with significantly reduced urine glycosaminoglycans and very low anti-drug antibody titers. This immune tolerance induction protocol could be considered for other patients with MPS II as well as patients with other lysosomal storage disorders who are starting on enzyme replacement therapy and are at high risk of developing neutralizing anti-drug antibodies.

Julien DC ，Woolgar K ，Pollard L ，Miller H ，Desai A ，Lindstrom K ，Kishnani PS ... -  《-》

Incidence and timing of infusion-related reactions in patients with mucopolysaccharidosis type II (Hunter syndrome) on idursulfase therapy in the real-world setting: a perspective from the Hunter Outcome Survey (HOS).

To evaluate the occurrence of infusion-related reactions (IRRs) in patients with mucopolysaccharidosis type II (MPS II) receiving idursulfase enrolled in the observational database HOS - the Hunter Outcome Survey. Information in HOS regarding the frequency, timing and severity of reported IRRs during the first year of treatment with idursulfase was analyzed, and formation of antibodies to idursulfase was characterized. The analysis was restricted to patients who started treatment with idursulfase at or after enrolment in HOS and for whom at least 1 year of follow-up data was available (n=104; data collected on or before 16 October 2009). A total of 65 IRRs were reported in 33 (31.7%) patients in the first year of enzyme replacement therapy (ERT). Six of these patients experienced more than three events. Nearly all of the initial IRRs occurred during the first 3months of ERT; five patients (4.8% of the total patient population) experienced their first IRR after 3months of treatment. Only two patients (1.9% of the total patient population) experienced their first IRR after more than 6 months of ERT. Most of the IRRs were of mild-to-moderate severity. After initially stopping the infusion, IRRs were generally readily managed by slowing the infusion and/or use of antihistamines or antipyretics. No patient in this analysis discontinued ERT because of an IRR event. IgG antibodies to idursulfase were detected in 32/63 patients (50.8%) for whom samples were taken; no patient developed IgE to idursulfase. Serum antibody levels were measured within 24h of an IRR for 10 IRRs in 7 patients; 7/9 samples contained IgG to idursulfase, 2 of which had neutralizing activity. IRRs in patients receiving idursulfase can typically be readily managed without interruption of treatment. Initial IRRs usually occur in the first 3 months of treatment, but in rare instances may occur after more than 6 months of therapy. Physicians using ERT to treat patients with MPS II, either in the clinic or at home, should therefore be familiar with the timing, nature and recommended management of IRRs.

Burton BK ，Whiteman DA ，HOS Investigators 《-》