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Two-thirds of patients with mucopolysaccharidosis II (MPS II; Hunter syndrome) have cognitive impairment. This phase 2/3, randomized, controlled, open-label, multicenter study (NCT02055118) investigated the effects of intrathecally administered idursulfase-IT on cognitive function in patients with MPS II. Children older than 3 years with MPS II and mild-to-moderate cognitive impairment (assessed by Differential Ability Scales-II [DAS-II], General Conceptual Ability [GCA] score) who had tolerated intravenous idursulfase for at least 4 months were randomly assigned (2:1) to monthly idursulfase-IT 10 mg (n = 34) via an intrathecal drug delivery device (IDDD; or by lumbar puncture) or no idursulfase-IT treatment (n = 15) for 52 weeks. All patients continued to receive weekly intravenous idursulfase 0.5 mg/kg as standard of care. Of 49 randomized patients, 47 completed the study (two patients receiving idursulfase-IT discontinued). The primary endpoint (change from baseline in DAS-II GCA score at week 52 in a linear mixed-effects model for repeated measures analysis) was not met: although there was a smaller decrease in DAS-II GCA scores with idursulfase-IT than with no idursulfase-IT at week 52, this was not significant (least-squares mean treatment difference [95% confidence interval], 3.0 [−7.3, 13.3]; p = 0.5669). Changes from baseline in Vineland Adaptive Behavioral Scales-II Adaptive Behavior Composite scores at week 52 (key secondary endpoint) were similar in the idursulfase-IT (n = 31) and no idursulfase-IT (n = 14) groups. There were trends towards a potential positive effect of idursulfase-IT across DAS-II composite, cluster, and subtest scores, notably in patients younger than 6 years at baseline. In a post hoc analysis, there was a significant (p = 0.0174), clinically meaningful difference in change from baseline in DAS-II GCA scores at week 52 with idursulfase-IT (n = 13) versus no idursulfase-IT (n = 6) among those younger than 6 years with missense iduronate-2-sulfatase gene variants. Overall, idursulfase-IT reduced cerebrospinal glycosaminoglycan levels from baseline by 72.0% at week 52. Idursulfase-IT was generally well tolerated. These data suggest potential benefits of idursulfase-IT in the treatment of cognitive impairment in some patients with neuronopathic MPS II. After many years of extensive review and regulatory discussions, the data were found to be insufficient to meet the evidentiary standard to support regulatory filings. • Trends towards cognitive benefits with intrathecal idursulfase for some patients. • Significant effects in those <6 years with missense iduronate-2-sulfatase variants • After 52 weeks, cerebrospinal glycosaminoglycan levels decreased by 72%. • Most adverse events were mild or moderate; none led to discontinuation. • Overall, the data did not meet evidentiary standards for regulatory filing. [ABSTRACT FROM AUTHOR]

Enzyme replacement therapy with weekly infused intravenous (IV) idursulfase is effective in treating somatic symptoms of mucopolysaccharidosis II (MPS II; Hunter syndrome). A formulation of idursulfase for intrathecal administration (idursulfase-IT) is under investigation for the treatment of neuronopathic MPS II. Here, we report 36-month data from the open-label extension (NCT02412787) of a phase 2/3, randomized, controlled study (HGT-HIT-094; NCT02055118) that assessed the safety and efficacy of monthly idursulfase-IT 10 mg in addition to weekly IV idursulfase on cognitive function in children older than 3 years with MPS II and mild-to-moderate cognitive impairment. Participants were also enrolled in this extension from a linked non-randomized sub-study of children younger than 3 years at the start of idursulfase-IT therapy. The extension safety population comprised 56 patients who received idursulfase-IT 10 mg once a month (or age-adjusted dose for sub-study patients) plus IV idursulfase (0.5 mg/kg) once a week. Idursulfase-IT was generally well tolerated over the cumulative treatment period of up to 36 months. Overall, 25.0% of patients had at least one adverse event (AE) related to idursulfase-IT; most treatment-emergent AEs were mild in severity. Of serious AEs (reported by 76.8% patients), none were considered related to idursulfase-IT treatment. There were no deaths or discontinuations owing to AEs. Secondary efficacy analyses (in patients younger than 6 years at phase 2/3 study baseline; n = 40) indicated a trend for improved Differential Ability Scale-II (DAS-II) General Conceptual Ability (GCA) scores in the early idursulfase-IT versus delayed idursulfase-IT group (treatment difference over 36 months from phase 2/3 study baseline: least-squares mean, 6.8 [90% confidence interval: −2.1, 15.8; p = 0.2064]). Post hoc analyses of DAS-II GCA scores by genotype revealed a clinically meaningful treatment effect in patients younger than 6 years with missense variants of the iduronate-2-sulfatase gene (IDS) (least-squares mean [standard error] treatment difference over 36 months, 12.3 [7.24]). These long-term data further suggest the benefits of idursulfase-IT in the treatment of neurocognitive dysfunction in some patients with MPS II. After many years of extensive review and regulatory discussions, the data were found to be insufficient to meet the evidentiary standard to support regulatory filings. • Intrathecal idursulfase was generally well tolerated over 3 years. • Most adverse effects were mild; none led to death or discontinuation. • Efficacy analyses in young patients suggest benefits of early treatment initiation. • Clinically meaningful benefit in patients under 6 years old with missense variants. • Overall, the data did not meet evidentiary standards for regulatory filing. [ABSTRACT FROM AUTHOR]

Several studies have shown serum fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) levels are elevated in patients with mitochondrial disease (MD) where myopathy is a feature. In this study we investigated the utility of FGF21 and GDF15 as biomarkers for MD in a phenotypically and genotypically diverse pediatric cohort with suspected MD against a panel of healthy controls and non-mitochondrial disease controls with some overlapping clinical features. Serum was collected from 56 children with MD, 104 children with non-mitochondrial disease (27 neuromuscular, 26 cardiac, 21 hepatic, 30 renal) and 30 pediatric controls. Serum FGF21 and GDF15 concentrations were measured using ELISA, and their ability to detect MD was determined. Median FGF21 and GDF15 serum concentrations were elevated 17-fold and 3-fold respectively in pediatric MD patients compared to the healthy control group. Non-mitochondrial disease controls had elevated serum GDF15 concentrations while FGF21 concentrations were in the normal range. Elevation of GDF15 in a range of non-mitochondrial pediatric disorders limits its use as a MD biomarker. FGF21 was elevated in MD patients with a spectrum of clinical phenotypes, including those without myopathy. Serum FGF21 had an area under the receiver operating characteristic curve of 0.87, indicating good ability to discriminate between pediatric MD and healthy and non-mitochondrial disease controls. Triaging of pediatric MD patients by clinical phenotyping and serum FGF21 testing, followed by massively parallel sequencing, may enable more rapid diagnosis of pediatric MD. • Serum FGF21 and GDF15 were elevated in a range of pediatric mitochondrial diseases. • Serum GDF15 was elevated in non-mitochondrial pediatric disease cohorts. • Serum FGF21 was not elevated in non-mitochondrial pediatric disease cohorts. • Serum FGF21 was elevated in both mitochondrial myopathy and neuronal phenotypes. • Serum FGF21 was a good biomarker of pediatric mitochondrial disease. [ABSTRACT FROM AUTHOR]

Late-onset Pompe disease (LOPD) is a rare lysosomal storage disorder characterized by progressive loss of muscle and respiratory function resulting from acid α-glucosidase (GAA) deficiency, for which recombinant human GAA enzyme replacement therapy (rhGAA ERT: alglucosidase alfa) is currently available. Here, we report the 12-month interim results from ATB200-02 (NCT02675465), a first-in-human, open-label, phase 1/2 trial evaluating a next-generation rhGAA/chaperone regimen AT-GAA (ATB200/AT2221) in adults with LOPD. The study enrolled 20 patients in 3 cohorts: ERT-switch ambulatory (n=11), ERT-switch nonambulatory (n=4), and ERT-naive ambulatory (n=5). 6-minute walk test (meters) improved in ambulatory ERT-switch patients (n=10 mean change [SD]: month 6, 23.9 [52.2] month 9, 24.5 [40.8] month 12, 42.2 [46.5]) and ERT-naive patients (n=5 month 6, 41.8 [29.4] month 9, 63.5 [23.1] month 12, 63.1 [29.1]). Other motor function tests were generally consistent with these results. Nonambulatory ERT-switch patients demonstrated increases in upper extremity strength at months 6, 9, and 12 as assessed by quantitative and manual muscle testing. Forced vital capacity (% predicted) increased in ERT-naive patients (n=5, mean change: month 6, 4.2 month 9, 6.2 month 12, 4.4), and was generally stable in ambulatory ERT-switch patients (n=9, month 6, -1.3 month 9, -1.7 month 12, -3.3). AT-GAA (ATB200/AT2221) was associated with reductions in creatine kinase and urine hexose tetrasaccharide. The most common treatment-emergent adverse events were upper and lower abdominal pain, diarrhea, and nasopharyngitis. Three events of infusion-associated reactions (skin discoloration, erythema, pruritus) occurred in ≥550 infusions. Data from this interim analysis show clinical benefits of AT-GAA (ATB200/AT2221) in ERT-naive patients and both ambulatory and nonambulatory ERT-experienced patients, suggesting that ATB200/AT2221 can be an effective and well-tolerated treatment for adults with LOPD. Updated 24-month efficacy/safety data will be included in the presentation. [ABSTRACT FROM AUTHOR]