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Abstract Background Mucopolysaccharidosis II (MPS II) is a rare lysosomal storage disease characterized by iduronate-2-sulfatase gene (IDS) deficiency and downstream glycosaminoglycan accumulation. Two-thirds of patients present with neuronopathic disease and evaluating cognitive function in these patients is challenging owing to limitations of currently available tests. During the clinical development of intrathecal idursulfase (idursulfase-IT), regulatory authorities requested qualitative data to further understand the neurocognitive changes observed by the investigators through the clinical trials. Results This qualitative study consisted of semi-structured interviews with all nine of the principal investigators who participated in the idursulfase-IT phase 2/3 (NCT02055118) and extension (NCT02412787) trials. These investigators enrolled the 56 patients with neuronopathic MPS II who qualified for the extension phase of the trial. The investigators were asked to rate the disease status of their patients. Of the 56 patients, 49 (88%) were rated as having disease that was improved/improving, stabilized or slowing progression compared with the expected outcomes with no treatment. Three patients were rated as worsening, while the remaining four patients were considered to have slowing progression or worsening disease. Similar results were demonstrated for patients aged from 3 to under 6 years at baseline, with 33 of 39 patients (85%) rated as having disease that was improved/improving, stabilized or slowing progression. Of the seven patients rated with slowing progression/worsening or worsening disease, five of them had an IDS variant other than missense, while two had a missense class variant. All the assigned improved/improving ratings were in patients receiving idursulfase-IT from the start of the phase 2/3 trial. Moreover, patients under 3 years of age at baseline were all rated as either improved/improving or stabilized disease. In a blinded review of patient profiles, investigators were requested to assign a disease status rating to 18 patients with large IDS deletions; 67% of these patients were rated as improved/improving or stabilized disease. Conclusions This qualitative analysis provides a snapshot of clinicians’ considerations when evaluating treatment in patients with neuronopathic MPS II, compared with the expected decline in cognitive function in the absence of treatment. The results highlight the importance of robust assessment tools in treatment evaluation.

Abstract Background Approximately two-thirds of patients with mucopolysaccharidosis II (MPS II) have a severe, neuronopathic phenotype, characterized by somatic, cognitive, and behavioral issues. Current standard of care for the treatment of MPS II is enzyme replacement therapy with intravenous recombinant human iduronate-2-sulfatase (idursulfase). To target cognitive manifestations of MPS II, idursulfase has been formulated for intrathecal administration into the cerebrospinal fluid (idursulfase-IT). In accordance with recommendations for patient-focused drug development, semi-structured interviews were conducted to assess caregiver experiences and observations in a 52-week phase 2/3 trial of idursulfase-IT, in addition to intravenous idursulfase in pediatric patients with neuronopathic MPS II, or a substudy which enrolled patients younger than 3 years old, all of whom received idursulfase-IT. Results Overall, 46 caregivers providing care for 50 children (mean [range] age 7.9 [3–17] years at interview) took part in a single 60-min exit interview; six of these children had participated in the substudy. Qualitative and quantitative data were obtained demonstrating the burden of MPS II experienced by caregivers and their families. Following participation in the trials, 39 (78%) of the children were reported by their caregivers to have experienced improvements in the symptoms and impact of disease. Of those with improvements, 37 (95%) experienced cognitive improvements and 26 (67%) experienced emotional/behavioral improvements. Overall, 43 children (86%) were rated by caregivers as having moderate or severe symptoms before the trials; after the trials, 28 children (56%) were considered to have mild or no symptoms. For the six children who participated in the substudy, these proportions were 83% and 100%, respectively. Caregivers’ qualitative descriptions of trial experiences suggested improvements in children’s verbal and non-verbal functioning and spatial and motor skills, as well as a positive impact on family life. Conclusions This study revealed caregiver-reported improvements in children’s MPS II symptoms and the impact of the disease on patients and their families. There was a trend for cognitive improvement and a reduction in severity of MPS II symptoms. After many years of extensive review and regulatory discussions of idursulfase-IT, the clinical trial data were found to be insufficient to meet the evidentiary standard to support regulatory filings.

Abstract Background Mucopolysaccharidosis (MPS) II is a rare, X-linked lysosomal storage disease. Approximately two-thirds of patients have central nervous system involvement with some demonstrating progressive cognitive impairment (neuronopathic disease). The natural history of cognitive and adaptive function in patients with MPS II is not well-defined. This 2-year, prospective, observational study evaluated the neurodevelopmental trajectories of boys with MPS II aged ≥ 2 years and 70); between-group differences were nonsignificant. No clear subgroups or patterns were identified for individual changes in VABS-II ABC scores. In total, 49 patients (89.1%) reported ≥ 1 adverse event (AE) and nine patients (16.4%) reported serious AEs. Conclusions Some patients with MPS II had rapid declines in cognitive ability, whereas others remained relatively stable after an initial decline. These insights provide a basis for more detailed analyses of different patient subgroups, which may enhance the definition and understanding of factors that influence cognitive and adaptive function in MPS II. Trial registration ClinicalTrials.gov, NCT01822184. Registered retrospectively: April 2, 2013.